Stefano LUMINARI - personale UniMoRe

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Stefano LUMINARI

Professore Ordinario
Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche con interesse Trapiantologico, Oncologico e di Medicina Rigenerativa

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Pubblicazioni

2023 - A Fondazione Italiana Linfomi cohort study of R-COMP vs R-CHOP in older patients with diffuse large B-cell lymphoma [Articolo su rivista]
Arcari, Annalisa; Rigacci, Lugi; Tucci, Alessandra; Puccini, Benedetta; Usai, Sara Veronica; Cavallo, Federica; Fabbri, Alberto; Balzarotti, Monica; Pelliccia, Sabrina; Luminari, Stefano; Pennese, Elsa; Zilioli, Vittorio Ruggero; Mahmoud, Abdurraouf Mokhtar; Musuraca, Gerardo; Marino, Dario; Sartori, Roberto; Botto, Barbara; Gini, Guido; Zanni, Manuela; Hohaus, Stefan; Tarantini, Giuseppe; Flenghi, Leonardo; Tani, Monica; Di Rocco, Alice; Merli, Michele; Vallisa, Daniele; Pagani, Chiara; Nassi, Luca; Dessì, Daniela; Ferrero, Simone; Cencini, Emanuele; Bernuzzi, Patrizia; Mammi, Caterina; Marcheselli, Luigi; Tabanelli, Valentina; Spina, Michele; Merli, Francesco
abstract

: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the most commonly used regimen for the upfront treatment of diffuse large B-cell lymphoma (DLBCL). However, it is associated with cardiotoxicity, especially in older patients. Substituting doxorubicin with non-PEGylated liposomal doxorubicin (R-COMP) may reduce the risk of cardiac events, but its efficacy has never been demonstrated in prospective trials. We describe the characteristics and outcome of patients with DLBCL aged ≥65 years prospectively enrolled in the Elderly Project by the Fondazione Italiana Linfomi and treated with full doses of R-CHOP or R-COMP per local practice. Starting from 1163 patients, 383 (55%) were treated with R-CHOP and 308 (45%) with R-COMP. Patients treated with R-COMP were older (median age, 76 vs 71 years), less frequently fit at simplified geriatric assessment (61% vs 88%; P < .001), and had a more frequent baseline cardiac disorders (grade >1, 32% vs 8%; P < .001). Three-year progression-free survival (PFS) was similar between R-CHOP and R-COMP (70% and 64%); 3-year overall survival was 77%, and 71% respectively. R-CHOP was associated with better PFS vs R-COMP only in the Elderly Prognostic Index (EPI) low-risk group. The two groups had similar rates of treatment interruptions due to toxicities or of cardiac events (P = 1.00). We suggest R-COMP is a potentially curative treatment for older patients with intermediate- or high-risk EPI, even in the presence of a baseline cardiopathy. R-CHOP is confirmed as the standard therapy for low risk patients.

2023 - Diffuse large B-cell lymphoma in octogenarians aged 85 and older can benefit from treatment with curative intent: a report on 129 patients prospectively registered in the Elderly Project of the Fondazione Italiana Linfomi (FIL) [Articolo su rivista]
Tucci, A.; Merli, F.; Fabbri, A.; Marcheselli, L.; Pagani, C.; Puccini, B.; Marino, D.; Zanni, M.; Pennese, E.; Flenghi, L.; Arcari, A.; Botto, B.; Celli, M.; Mammi, C.; Re, A.; Campostrini, G.; Tafuri, A.; Zilioli, V. R.; Cencini, E.; Sartori, R.; Bottelli, C.; Merli, M.; Petrucci, L.; Gini, G.; Balzarotti, M.; Cavallo, F.; Musuraca, G.; Luminari, S.; Rossi, G.; Spina, M.
abstract

Octogenarian patients with diffuse large B-cell lymphoma are managed mainly with palliation, but recent improvement in their overall condition makes potentially curative treatment a possibility. Studies have shown that half of selected octogenarians may be cured using reduced-dose anthracycline chemoimmunotherapy. However, patients aged >85 (late octogenarians [LO]) were underrepresented, and selection criteria were poorly defined. We analyzed the clinical characteristics and outcomes of LO enrolled in the FIL Elderly Project in terms of the treatment received (palliative vs. curative) and of their simplified geriatric assessment (sGA), then compared them with early octogenarians (EO) aged 80-84 and with those aged 65-79 classified as UNFIT or FRAIL according to sGA enrolled in the same study. Of the 1,163 patients, 370 were >80 and 129 LO. Clinical characteristics were similar between LO and EO, but LO more frequently received palliation (50% vs. 23%; P=0.001) and had worse 2-year overall survival (OS) (48% vs. 63%; P=0.001) and 2-year progression-free survival (PFS) (43% vs. 56%; P=0.01). Patients receiving anthracycline did better than patients receiving palliation (P<0.001), without any difference between full or reduced doses. Rituximab within palliation improved outcome (2-yr OS with or without rituximab 42% vs. 22%; P=0.008). Elderly Prognostic Index (EPI) performed better than sGA in identifying different risk categories, and high-risk EPI retained an independent unfavorable effect on OS and PFS, together with treatment without anthracycline. In conclusion, late octogenarians can benefit from a curative approach with reduced-dose anthracycline and from rituximab within palliation. EPI may help in patient selection more than sGA can.

2023 - European Association of Nuclear Medicine (EANM) Focus 4 consensus recommendations: molecular imaging and therapy in haematological tumours [Articolo su rivista]
Nanni, Cristina; Kobe, Carsten; Baeßler, Bettina; Baues, Christian; Boellaard, Ronald; Borchmann, Peter; Buck, Andreas; Buvat, Irène; Chapuy, Björn; Cheson, Bruce D; Chrzan, Robert; Cottereau, Ann-Segolene; Dührsen, Ulrich; Eikenes, Live; Hutchings, Martin; Jurczak, Wojciech; Kraeber-Bodéré, Françoise; Lopci, Egesta; Luminari, Stefano; Maclennan, Steven; Mikhaeel, N George; Nijland, Marcel; Rodríguez-Otero, Paula; Treglia, Giorgio; Withofs, Nadia; Zamagni, Elena; Zinzani, Pier Luigi; Zijlstra, Josée M; Herrmann, Ken; Kunikowska, Jolanta
abstract

Given the paucity of high-certainty evidence, and differences in opinion on the use of nuclear medicine for hematological malignancies, we embarked on a consensus process involving key experts in this area. We aimed to assess consensus within a panel of experts on issues related to patient eligibility, imaging techniques, staging and response assessment, follow-up, and treatment decision-making, and to provide interim guidance by our expert consensus. We used a three-stage consensus process. First, we systematically reviewed and appraised the quality of existing evidence. Second, we generated a list of 153 statements based on the literature review to be agreed or disagreed with, with an additional statement added after the first round. Third, the 154 statements were scored by a panel of 26 experts purposively sampled from authors of published research on haematological tumours on a 1 (strongly disagree) to 9 (strongly agree) Likert scale in a two-round electronic Delphi review. The RAND and University of California Los Angeles appropriateness method was used for analysis. Between one and 14 systematic reviews were identified on each topic. All were rated as low to moderate quality. After two rounds of voting, there was consensus on 139 (90%) of 154 of the statements. There was consensus on most statements concerning the use of PET in nonHodgkin and Hodgkin lymphoma. In multiple myeloma, more studies are required to define the optimal sequence for treatment assessment. Furthermore, nuclear medicine physicians and haematologists are awaiting consistent literature to introduce volumetric parameters, artificial intelligence, machine learning, and radiomics into routine practice.

2023 - Immune-related pan-cancer gene expression signatures of patient survival revealed by NanoString-based analyses [Articolo su rivista]
D'Angelo, A.; Kilili, H.; Chapman, R.; Generali, D.; Tinhofer, I.; Luminari, S.; Donati, B.; Ciarrocchi, A.; Giannini, R.; Moretto, R.; Cremolini, C.; Pietrantonio, F.; Sobhani, N.; Bonazza, D.; Prins, R.; Song, S. G.; Jeon, Y. K.; Pisignano, G.; Cinelli, M.; Bagby, S.; Urrutia, A. O.
abstract

The immune system plays a central role in the onset and progression of cancer. A better understanding of transcriptional changes in immune cell-related genes associated with cancer progression, and their significance in disease prognosis, is therefore needed. NanoString-based targeted gene expression profiling has advantages for deployment in a clinical setting over RNA-seq technologies. We analysed NanoString PanCancer Immune Profiling panel gene expression data encompassing 770 genes, and overall survival data, from multiple previous studies covering 10 different cancer types, including solid and blood malignancies, across 515 patients. This analysis revealed an immune gene signature comprising 39 genes that were upregulated in those patients with shorter overall survival; of these 39 genes, three (MAGEC2, SSX1 and ULBP2) were common to both solid and blood malignancies. Most of the genes identified have previously been reported as relevant in one or more cancer types. Using Cibersort, we investigated immune cell levels within individual cancer types and across groups of cancers, as well as in shorter and longer overall survival groups. Patients with shorter survival had a higher proportion of M2 macrophages and γδ T cells. Patients with longer overall survival had a higher proportion of CD8+ T cells, CD4+ T memory cells, NK cells and, unexpectedly, T regulatory cells. Using a transcriptomics platform with certain advantages for deployment in a clinical setting, our multi-cancer meta-analysis of immune gene expression and overall survival data has identified a specific transcriptional profile associated with poor overall survival.

2023 - Impact of immunochemotherapy with R-bendamustine or R-CHOP for treatment naïve advanced-stage follicular lymphoma: A subset analysis of the FOLL12 trial by Fondazione Italiana Linfomi [Articolo su rivista]
Nizzoli, M. E.; Manni, M.; Ghiggi, C.; Pulsoni, A.; Musuraca, G.; Merli, M.; Califano, C.; Bari, A.; Massaia, M.; Conconi, A.; Musto, P.; Mannina, D.; Perrone, T.; Re, F.; Galimberti, S.; Gini, G.; Capponi, M.; Vitolo, U.; Usai, S. V.; Stefani, P. M.; Ballerini, F.; Liberati, A. M.; Pennese, E.; Pastore, D.; Skrypets, T.; Catellani, H.; Marcheselli, L.; Federico, M.; Luminari, S.
abstract

We conducted a post hoc analysis of the FOLL12 trial to determine the impact of different initial immunochemotherapy (ICT) regimens on patient outcomes. Patients were selected from the FOLL12 trial, which included adults with stage II–IV follicular lymphoma (FL) grade 1–3a and high tumor burden. Patients were randomized 1:1 to receive either standard ICT followed by rituximab maintenance (RM) or the same ICT followed by a response-adapted approach. ICT consisted of rituximab-bendamustine (RB) or rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP), per physician's decision. A total of 786 patients were included in this analysis, 341 of whom received RB and 445 R-CHOP. RB was more frequently prescribed to older subjects, females, patients without bulky disease, and those with grade 1–2 FL. After a median of 56 months of follow-up, R-CHOP and RB had similar progression-free survival (PFS) (Hazard Ratio for RB 1.11, 95% CI 0.87–1.42, p = 0.392). Standard RM was associated with improved PFS compared to response-adapted management both after R-CHOP and RB. Grade 3–4 hematologic adverse events were more frequent with R-CHOP during induction treatment and more frequent with RB during RM. Grade 3–4 infections were more frequent with RB. RB was also associated with a higher incidence of transformed FL. R-CHOP and RB showed similar activity and efficacy, but with different safety profiles and long-term events, suggesting that the treating physician should carefully select the most appropriate chemotherapy regimen for each patient based on patient's individual characteristics, choices, and risk profile.

2023 - Incidence, mortality, and survival of hematological malignancies in Northern Italian patients: an update to 2020 [Articolo su rivista]
Mangone, L.; Penna, D.; Marinelli, F.; Roncaglia, F.; Bisceglia, I.; Merli, F.; Ruffini, A.; Gamberi, B.; Tieghi, A.; Valli, R.; Albertazzi, L.; Iori, M.; Giorgi Rossi, P.; Vener, C.; Morabito, F.; Neri, A.; Luminari, S.
abstract

BackgroundHematological malignancies (HMs) represent a heterogeneous group of diseases with diverse etiology, pathogenesis, and prognosis. HMs' accurate registration by Cancer Registries (CRs) is hampered by the progressive de-hospitalization of patients and the transition to molecular rather than microscopic diagnosis. Material and methodsA dedicated software capable of automatically identifying suspected HMs cases by combining several databases was adopted by Reggio Emilia Province CR (RE-CR). Besides pathological reports, hospital discharge archives, and mortality records, RE-CR retrieved information from general and biomolecular laboratories. Incidence, mortality, and 5-year relative survival (RS) reported according to age, sex, and 4 HMs' main categories, were noted. ResultsOverall, 7,578 HM cases were diagnosed from 1996 to 2020 by RE-CR. HMs were more common in males and older patients, except for Hodgkin Lymphoma and Follicular Lymphoma (FL). Incidence showed a significant increase for FL (annual percent change (APC)=3.0), Myeloproliferative Neoplasms (MPN) in the first period (APC=6.0) followed by a significant decrease (APC=-7.4), and Myelodysplastic Syndromes (APC=16.4) only in the first period. Over the years, a significant increase was observed in 5-year RS for Hodgkin -, Marginal Zone -, Follicular - and Diffuse Large B-cell-Lymphomas, MPN, and Acute Myeloid Leukemia. The availability of dedicated software made it possible to recover 80% of cases automatically: the remaining 20% required direct consultation of medical records. ConclusionsThe study emphasizes that HM registration needs to collect information from multiple sources. The digitalization of CRs is necessary to increase their efficiency.

2023 - Lenalidomide plus rituximab for the initial treatment of frail older patients with DLBCL: the FIL_ReRi phase 2 study [Articolo su rivista]
Gini, Guido; Tani, Monica; Tucci, Alessandra; Marcheselli, Luigi; Cesaretti, Marina; Bellei, Monica; Pascarella, Anna; Ballerini, Filippo; Petrini, Mauro; Merli, Francesco; Olivieri, Attilio; Lanza, Francesco; Annibali, Ombretta; Zilioli, Vittorio Ruggero; Liberati, Anna Marina; Tisi, Maria Chiara; Arcari, Annalisa; Marino, Dario; Musuraca, Gerardo; Pavone, Vincenzo; Fabbri, Alberto; Pozzi, Samantha; Mannina, Donato; Plenteda, Caterina; Celli, Melania; Luminari, Stefano
abstract

: Treatment of diffuse large B-cell lymphoma (DLBCL) in elderly patients is challenging, especially for those who are not eligible for anthracycline-containing regimens. The Fondazione Italiana Linfomi (FIL) started the FIL_ReRi study, a two-stage single arm trial to investigate the activity and safety of the chemo-free combination of rituximab and lenalidomide (R2)in ≥ 70-year-old untreated frail DLBCL patients. Frailty was prospectively defined according to a simplified geriatric assessment tool. Patients were given a maximum of 6 28-day cycles of 20 mg oral lenalidomide on days 2-22 and intravenous rituximab 375 mg/m2 on day 1, with response assessment after cycles 4 and 6. Patients in partial (PR) or complete response (CR) at cycle 6 were given lenalidomide 10 mg/d on days 1-21 in q28 cycles for a total of 12 cycles or until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) after cycle 6; the co-primary endpoint was the rate of grade 3-4 extra-hematological toxicity. The ORR was 50.8%, with 27.7% of CR. After a median follow-up of 24 months, median progression-free survival (PFS) was 14 months, and two-year duration of response was 64%. Thirty-four patients experienced extra-hematological toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3. Activity of R2 combination was observed in a significant proportion of subjects, warranting further exploration of a chemo-free approach of elderly frail patients with DLBCL. The trial was registered at ClinicalTrials.gov as NCT01805557.

2023 - Long non-coding RNA mitophagy and ALK-negative anaplastic lymphoma-associated transcript: a novel regulator of mitophagy in T-cell lymphoma [Articolo su rivista]
Mularoni, Valentina; Donati, Benedetta; Tameni, Annalisa; Manicardi, Veronica; Reggiani, Francesca; Sauta, Elisabetta; Zanelli, Magda; Tigano, Marco; Vitale, Emanuele; Torricelli, Federica; Ascani, Stefano; Martino, Giovanni; Inghirami, Giorgio; Sanguedolce, Francesca; Ruffini, Alessia; Bavieri, Alberto; Luminari, Stefano; Pizzi, Marco; Dei Tos, Angelo Paolo; Fesce, Cinzia; Neri, Antonino; Ciarrocchi, Alessia; Fragliasso, Valentina
abstract

: Long noncoding RNAs (lncRNAs) are emerging as powerful and versatile regulators of transcriptional programs and distinctive biomarkers of T-cell Lymphoma progression disease. Their role in the aggressive ALK- Anaplastic Large Cell Lymphoma (ALCL) subtype has been only in part elucidated. Starting from our previously identified ALCL-associated lncRNA signature and performing digital gene expression profiling of a retrospective cohort of ALCLs, we defined an 11 lncRNA signature able to discriminate among ALCL subtypes. We selected a not previously characterized lncRNA, MTAAT, with an ALK- ALCL preferential expression, for molecular and functional studies. We demonstrated that lncRNA MTAAT contributes to an aberrant mitochondrial turnover restraining mitophagy and promoting cellular proliferation. Functionally, lncRNA MTAAT acts as a repressor of a set of genes related to mitochondria quality control via chromatin reorganization. Collectively, our work demonstrates the transcriptional role of lncRNA MTAAT in orchestrating a complex transcriptional program sustaining ALK- ALCL progression.

2023 - Management of patients with lymphoma and COVID-19: Narrative review and evidence-based practical recommendations [Articolo su rivista]
Passamonti, F.; Nicastri, E.; Di Rocco, A.; Guarini, A.; Ibatici, A.; Luminari, S.; Mikulska, M.; Visco, C.
abstract

Patients with hematologic malignancies can be immunocompromized because of their disease, anti-cancer therapy, and concomitant immunosuppressive treatment. Furthermore, these patients are usually older than 60 years and have comorbidities. For all these reasons they are highly vulnerable to infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and have an increased risk of developing severe/critical Coronavirus disease 2019 (COVID-19) compared to the general population. Although COVID-19 vaccination has proven effective in reducing the incidence of severe/critical disease, vaccinated patients with lymphoma may not be protected as they often fail to develop a sufficient antiviral immune response. There is therefore an urgent need to address the management of patients with lymphoma and COVID-19 in the setting of the ongoing pandemic. Passive immunization with monoclonal antibodies against SARS-CoV-2 is a currently available complementary drug strategy to active vaccination for lymphoma patients, while monoclonal antibodies and antiviral drugs (remdesivir, ritonavir-boosted nirmatrelvir, and molnupiravir) have proven effective in preventing the progression to severe/critical COVID-19. In this narrative review we present the most recent data documenting the characteristics and outcomes of patients with concomitant lymphoma and COVID-19. Our ultimate goal is to provide practice-oriented guidance in the management of these vulnerable patients from diagnosis to treatment and follow-up of lymphoma. To this purpose, we will first provide an overview of the main data concerning prognostic factors and fatality rate of lymphoma patients who develop COVID-19; the outcomes of COVID-19 vaccination will also be addressed. We will then discuss current COVID-19 prophylaxis and treatment options for lymphoma patients. Finally, based on the literature and our multidisciplinary experience, we will summarize a set of indications on how to manage patients with lymphoma according to COVID-19 exposure, level of disease severity and former history of infection, as typically encountered in clinical practice.

2023 - Prevalence and distribution of vascular calcifications at CT scan in patients with and without large vessel vasculitis: A matched cross-sectional study [Articolo su rivista]
Besutti, G.; Marvisi, C.; Mancuso, P.; Fari, R.; Monelli, F.; Revelli, M.; Durmo, R.; Galli, E.; Muratore, F.; Spaggiari, L.; Ottone, M.; Luminari, S.; Pattacini, P.; Giorgi Rossi, P.; Salvarani, C.
abstract

Objectives The aim of this study was to compare the prevalence, entity and local distribution of arterial wall calcifications evaluated on CT scans in patients with large vessel vasculitis (LVV) and patients with lymphoma as reference for the population without LVV. Methods All consecutive patients diagnosed with LVVs with available baseline positron emission tomography-CT (PET-CT) scan performed between 2007 and 2019 were included; non-LVV patients were lymphoma patients matched by age (±5 years), sex and year of baseline PET-CT (≤2013; >2013). CT images derived from baseline PET-CT scans of both patient groups were retrospectively reviewed by a single radiologist who, after setting a threshold of minimum 130 Hounsfield units, semiautomatically computed vascular calcifications in three separate locations (coronaries, thoracic and abdominal arteries), quantified as Agatston and volume scores. Results A total of 266 patients were included. Abdominal artery calcifications were equally distributed (mean volume 3220 in LVVs and 2712 in lymphomas). Being in the LVVs group was associated with the presence of thoracic calcifications after adjusting by age and year of diagnosis (OR 4.13, 95% CI 1.35 to 12.66; p=0.013). Similarly, LVVs group was significantly associated with the volume score in the thoracic arteries (p=0.048). In patients >50 years old, calcifications in the coronaries were more extended in non-LVV patients (p=0.027 for volume). Conclusion When compared with patients without LVVs, LVVs patients have higher calcifications in the thoracic arteries, but not in coronary and abdominal arteries.

2023 - Prognostic tools for older patients with DLBCL: complex patients require complex solutions and a personal touch [Articolo su rivista]
Luminari, Stefano
abstract

2023 - Role of Rituximab Addition to First-line Chemotherapy Regimens in Nodular Lymphocyte-predominant Hodgkin Lymphoma: A Study by Fondazione Italiana Linfomi [Articolo su rivista]
Gotti, M.; Sciarra, R.; Pulsoni, A.; Merli, F.; Luminari, S.; Zerbi, C.; Trentin, L.; Re, A.; Rusconi, C.; Viviani, S.; Rossi, A.; Cocito, F.; Botto, B.; Meli, E.; Pinto, A.; Dogliotti, I.; Gini, G.; Puccini, B.; Ricci, F.; Nassi, L.; Fabbri, A.; Liberati, A. M.; Merli, M.; Filippi, A. R.; Bonfichi, M.; Zoboli, V.; Tartaglia, G.; Annechini, G.; D'Elia, G. M.; Del Giudice, I.; Alvarez, I.; Visentin, A.; Pravato, S.; Dalceggio, D.; Pagani, C.; Ferrari, S.; Cristinelli, C.; Lazic, T.; Ferretti, V. V.; Ricardi, U.; Arcaini, L.
abstract

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare entity whose neoplastic cells retain a B-cell phenotype with expression of CD20. Radiotherapy is recommended for favorable stage IA disease while for other stages guidelines suggest therapeutic strategies similar to those used for classic HL. The role of rituximab, although quite widespread, is not completely elucidated. We retrospectively analyzed baseline characteristics of 308 consecutive patients with NLPHL diagnosed in 19 Italian centers from 2000 to 2018. With a median follow-up of 8.4 years (interquartile range: 4.5-12.4) for treated patients, median overall survival (OS) was not reached and estimated 5-year OS was 97.8% and 5-year progression-free survival (PFS) was 84.5%. Five-year cumulative incidence of histological transformation was 1.4%, 95% confidence interval (CI), 0.5%-3.8%. After adjusting for lymphocyte count, splenic involvement, bulky disease and B symptoms (fever, drenching night sweats, unintentional loss >10% of body weight within the preceding 6 months), patients with stage II or more showed superior PFS with immunochemotherapy in comparison to chemotherapy alone (hazard ratio = 0.4, 95% CI, 0.2-0.8; P = 0.015). Our data suggest an advantage of the use of rituximab combined with chemotherapy ± radiotherapy in the treatment of stage II-III-IV NLPHL.

2023 - The SALENTO prognostic model for limited-stage peripheral T-cell lymphoma from the International T-Cell Project Network [Articolo su rivista]
Hapgood, Greg; Civallero, Monica; Stepanishyna, Yana; Vose, Julie M; Cabrera, Maria Elena; Advani, Ranjana H; Pileri, Stefano A; Manni, Martina; Horwitz, Steven M; Foss, Francine M; Hitz, Felicitas; Radford, John; Dlouhy, Ivan; Chiattone, Carlos Sérgio; Kim, Won-Seog; Skrypets, Tetiana; Nagler, Arnon; Trotman, Judith; Luminari, Stefano; Federico, Massimo
abstract

: The natural history of limited-stage peripheral T-cell lymphomas (PTCLs) remains poorly defined. We investigated outcomes and prognostic variables in patients registered in the T-Cell Project (TCP)(NCT01142674) to develop a model to predict overall survival (OS) for the common nodal PTCL subtypes (PTCL-NOS, AITL, ALCL). The model was validated in an independent data set from Australian and Brazilian registries. 211 patients registered in the TCP between 2006-2018 were studied. The median age was 59 years (range 18-88) and median follow-up was 49 months. 127 patients (78%) received anthracycline-based regimens, 5 patients (3%) radiotherapy alone (RT), 24 patients (15%) chemotherapy+RT. 5-year OS and PFS were 47% and 37%, respectively. Age >60y, elevated LDH and low serum albumin were independent prognostic factors. The model identified three groups with low- (26%, score 0), intermediate- (41%, score 1), and high-risk (33%, score 2-3) with 5-yr OS of 78% [95% CI 29-127], 46% [95% CI 24-68], and 25% [95% CI 20-30], respectively (P<0·001) and 5-yr PFS of 66% [95% CI 33-99], 37% [95% CI 9-65], and 17% [95% CI 9-25], respectively (P<0·001). The model demonstrated greater discriminatory power than established prognostic indices and an analogous distribution and outcomes in the three groups in the validation cohort of 103 patients. The SALENTO Model (Limited Stage Peripheral T Cell Lymphoma Prognostic Model) is an objective, simple and robust prognostic tool. The high-risk group has poor outcomes, comparable to advanced stage disease, and should be considered for innovative first-line approaches.

2022 - An international analysis evaluating frontline bendamustine with rituximab in extranodal marginal zone lymphoma [Articolo su rivista]
Alderuccio, J. P.; Arcaini, L.; Watkins, M. P.; Beaven, A. W.; Shouse, G.; Epperla, N.; Spina, M.; Stefanovic, A.; Sandoval-Sus, J.; Torka, P.; Alpert, A. B.; Olszewski, A. J.; Kim, S. -H.; Hess, B.; Gaballa, S.; Ayyappan, S.; Castillo, J. J.; Argnani, L.; Voorhees, T. J.; Saba, R.; Chowdhury, S. M.; Vargas, F.; Reis, I. M.; Kwon, D.; Alexander, J. S.; Zhao, W.; Edwards, D.; Martin, P.; Cencini, E.; Kamdar, M.; Link, B. K.; Logothetis, C. N.; Herrera, A. F.; Friedberg, J. W.; Kahl, B. S.; Luminari, S.; Zinzani, P. L.; Lossos, I. S.
abstract

Extranodal marginal zone lymphoma (EMZL) is a heterogeneous non-Hodgkin lymphoma. No consensus exists regarding the standard-of-care in patients with advanced-stage disease. Current recommendations are largely adapted from follicular lymphoma, for which bendamustine with rituximab (BR) is an established approach. We analyzed the safety and efficacy of frontline BR in EMZL using a large international consortium. We included 237 patients with a median age of 63 years (range, 21-85). Most patients presented with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (n 5 228; 96.2%), stage III/IV (n 5 179; 75.5%), and intermediate (49.8%) or high (33.3%) Mucosa Associated Lymphoid Tissue International Prognosis Index (MALT-IPI). Patients received a median of 6 (range, 1-8) cycles of BR, and 20.3% (n 5 48) received rituximab maintenance. Thirteen percent experienced infectious complications during BR therapy; herpes zoster (4%) was the most common. Overall response rate was 93.2% with 81% complete responses. Estimated 5-year progression-free survival (PFS) and overall survival (OS) were 80.5% (95% CI, 73.1% to 86%) and 89.6% (95% CI, 83.1% to 93.6%), respectively. MALT-IPI failed to predict outcomes. In the multivariable model, the presence of B symptoms was associated with shorter PFS. Rituximab maintenance was associated with longer PFS (hazard ratio 5 0.16; 95% CI, 0.04-0.71; P 5 .016) but did not impact OS. BR is a highly effective upfront regimen in EMZL, providing durable remissions and overcoming known adverse prognosis factors. This regimen is associated with occurrence of herpes zoster; thus, prophylactic treatment may be considered.

2022 - Brentuximab vedotin consolidation after autologous stem cell transplantation for Hodgkin lymphoma: A Fondazione Italiana Linfomi real-life experience [Articolo su rivista]
Massaro, F.; Pavone, V.; Stefani, P. M.; Botto, B.; Pulsoni, A.; Patti, C.; Cantonetti, M.; Visentin, A.; Scalzulli, P. R.; Rossi, A.; Galimberti, S.; Cimminiello, M.; Gini, G.; Musso, M.; Sorio, M.; Arcari, A.; Zilioli, V. R.; Luppi, M.; Mannina, D.; Fabbri, A.; Pietrantuono, G.; Annibali, O.; Tafuri, A.; Prete, E.; Mule, A.; Barbolini, E.; Marcheselli, L.; Luminari, S.; Merli, F.
abstract

The standard management for relapsed or refractory classical Hodgkin lymphoma (cHL) is salvage therapy followed by autologous stem cell transplantation (ASCT). This strategy allows almost 50% of patients to be cured. Post-ASCT maintenance treatment with brentuximab vedotin (BV) confers improved progression-free survival (PFS) to cHL patients at high risk of relapse. We investigated the outcome of 105 cHL patients receiving post-ASCT BV maintenance in the real-life setting of 23 Italian hematology centers. This population included naïve patients and those previously exposed to BV. Median follow-up was 20 months. Patients presented a median of two lines of treatment pre-ASCT, with 51% receiving BV. Twenty-nine percent of patients had at least two high-risk factors (refractory disease, complete response [CR] less than 12 months, extranodal disease at relapse), while 16% presented none. At PET-CT, a Deauville score (DS) of 1–3 was reported in 75% and 78% of pre- and post-ASCT evaluations, respectively. Grade 3–4 adverse events (AEs), mainly peripheral neuropathy, were observed in 16% of patients. Three-year PFS and overall survival (OS) were 62% and 86%, respectively. According to BV exposure, 3-year PFS and OS were 54% and 71%, respectively, for naïve and 77% and 96%, respectively, for previously exposed patients. Refractory disease (hazard ratio [HR] 4.46; p = 0.003) and post-ASCT DS 4–5 (HR 3.14; p = 0.005) were the only two factors significantly associated with PFS reduction in multivariable analysis. Post-ASCT BV maintenance is an effective, safe treatment option for cHL naïve patients and those previously exposed to BV.

2022 - Characteristics and clinical outcomes of patients with ALK-positive anaplastic large cell lymphoma: Report from the prospective international T-cell lymphoma project [Articolo su rivista]
Chiattone, C.; Civallero, M.; Fischer, T.; Miranda, E.; Manni, M.; Zing, N. P. C.; Pileri, S. A.; Montoto, S.; Horwitz, S. M.; Cabrera, M. E.; De Souza, C. A.; Nagler, A.; Luminari, S.; Ferreri, A. J. M.; Carson, K. R.; Re, A.; Rigacci, L.; Nassi, L.; Stepanishyna, Y.; Federico, M.; Inghirami, G.
abstract

The T-cell Lymphoma Project is an international registry prospective study that enrolled patients with newly diagnosed peripheral T-cell and NK-cell lymphomas (PTCL). The main objective was to define the clinical features and outcomes, establishing a robust benchmark for future clinical trials. Seventy-four institutions from 14 countries in North America, South America, Europe, and Asia collected data on patients diagnosed and treated at their respective centers between September 2006 and February 2018. Among 1553 PTCL patients, 131 (8.4% of the total cohort) were confirmed to have anaplastic large cell lymphoma - kinase positive (ALCL, ALK+). The median age of the patients was 39 years (18–84). Sixty-five patients (66%) had advanced-stage disease, although majority (45 patients, 54%) had a low-risk International Prognostic Index (IPI) score (0–1). Of 97 patients treated with chemotherapy, 97% received anthracycline-containing regimens. The overall response rate was 81%, with 69 patients (70%) achieving complete remission. Estimated OS and PFS at 3 years were 77% (95% CI: 54%–99%) and 68% (95% CI: 46%–90%), respectively, and at 5 years were very similar, 77% of OS (95% CI: 62%–92%) and 64% of PFS (95% CI: 34%–94%). Multivariate analysis for PFS showed advanced stage (hazard ratios [HR]: 4.72, 95% CI: 1.43–23.9, p = 0.015), elevated lactate dehidrogenade (LDH) (HR 4.85; 95% CI: 1.73–13.60, p = 0.001), and Eastern Cooperative Oncology Group Performance Status scale (ECOG-PS) ≥2 (HR: 5.25; 95% CI: 1.68–16.4, p = 0.024). For OS, elevated LDH (HR: 3.77; 95% CI: 1.98–14.17, p = 0.014) and ECOG-PS ≥2 (HR: 4.59; 95% CI: 1.46–14.39, p = 0.004) were identified. In summary, although the outcome of ALK+ ALCL is superior to that of other PTCLs, it remains sufficiently favorable, given the young median age of the patients. Our results confirm the usefulness of both IPI and Prognostic Index for T-cell Lymphoma (PIT) in identifying groups of patients with different outcomes. Clinical Trials ID: NCT01142674.

2022 - Direct-Acting Antivirals as Primary Treatment for Hepatitis C Virus-Associated Indolent Non-Hodgkin Lymphomas: The BArT Study of the Fondazione Italiana Linfomi [Articolo su rivista]
Merli, M.; Rattotti, S.; Spina, M.; Re, F.; Motta, M.; Piazza, F.; Orsucci, L.; Ferreri, A. J. M.; Perbellini, O.; Dodero, A.; Vallisa, D.; Pulsoni, A.; Santoro, A.; Sacchi, P.; Zuccaro, V.; Chimienti, E.; Russo, F.; Visco, C.; Zignego, A. L.; Marcheselli, L.; Passamonti, F.; Luminari, S.; Paulli, M.; Bruno, R.; Arcaini, L.
abstract

PURPOSEWe prospectively treated patients with hepatitis C virus (HCV)-associated indolent lymphomas with genotype-appropriate direct-acting antivirals (DAAs) with the aim to evaluate virologic and hematologic outcomes. No prospective studies in this setting have been published so far.METHODSFIL-BArT is a prospective, multicenter, phase II trial that evaluated genotype-appropriate DAAs in untreated HCV-positive patients with indolent lymphomas without criteria for immediate conventional antilymphoma treatment. The primary objective was sustained virologic response, whereas the main secondary objectives were overall response rate of lymphoma and progression-free survival.RESULTSForty patients were enrolled, including 27 with marginal zone lymphoma. Median age was 68 years. Extranodal sites were involved in 14 cases (35%). Main genotypes were 1 in 16 patients and 2 in 21 patients. All patients received genotype-guided DAAs: 17 ledipasvir/sofosbuvir, eight sofosbuvir plus ribavirin, and 15 sofosbuvir/velpatasvir. All patients achieved sustained virologic response (100%). DAAs were well tolerated, with only two grade 3-4 adverse events. Overall response rate of lymphoma was 45%, including eight patients (20%) achieving complete response and 10 (25%) partial response, whereas 16 exhibited stable disease and six progressed. With a median follow-up of 37 months, two patients died (3-year overall survival 93%; 95% CI, 74 to 98) and three additional patients progressed, with a 3-year progression-free survival of 76% (95% CI, 57 to 87).CONCLUSIONHCV eradication by DAAs was achieved in 100% of HCV-positive patients with indolent lymphomas not requiring immediate conventional treatment and resulted in non-negligible rate of lymphoma responses. Treatment with DAAs should be considered as the first-line therapy in this setting.

2022 - IgM-secreting diffuse large B-cell lymphoma: results of a multicentre clinicopathological and molecular study [Articolo su rivista]
Cox, M. C.; Marcheselli, L.; Scafetta, G.; Visco, C.; Hohaus, S.; Annibali, O.; Musuraca, G.; Fabbri, A.; Cantonetti, M.; Pelliccia, S.; Papotti, R.; Petrucci, L.; Tani, M.; Battistini, R.; Arcari, A.; Luminari, S.; Lopez, G.; Alma, E.; Pupo, L.; Carli, G.; Marchesi, F.; Re, F.; Scarpino, S.; D'Amore, E. S. G.; Larocca, L. M.; Bianchi, A.; Pepe, G.; Natalino, F.; Anticoli-Borza, P.; Cenfra, N.; Andriani, A.; Abruzzese, E.; Tesei, C.; Leoncini, L.; Asioli, S.; Ruco, L.; Di Napoli, A.
abstract

2022 - Prognostic value of lesion dissemination in doxorubicin, bleomycin, vinblastine, and dacarbazine-treated, interimPET-negative classical Hodgkin Lymphoma patients: A radio-genomic study [Articolo su rivista]
Durmo, R.; Donati, B.; Rebaud, L.; Cottereau, A. S.; Ruffini, A.; Nizzoli, M. E.; Ciavarella, S.; Vegliante, M. C.; Nioche, C.; Meignan, M.; Merli, F.; Versari, A.; Ciarrocchi, A.; Buvat, I.; Luminari, S.
abstract

We evaluated the prognostic role of the largest distance between two lesions (Dmax), defined by positron emission tomography (PET) in a retrospective cohort of newly diagnosed classical Hodgkin Lymphoma (cHL) patients. We also explored the molecular bases underlying Dmax through a gene expression analysis of diagnostic biopsies. We included patients diagnosed with cHL from 2007 to 2020, initially treated with ABVD, with available baseline PET for review, and with at least two FDG avid lesions. Patients with available RNA from diagnostic biopsy were eligible for gene expression analysis. Dmax was deduced from the three-dimensional coordinates of the baseline metabolic tumor volume (MTV) and its effect on progression free survival (PFS) was evaluated. Gene expression profiles were correlated with Dmax and analyzed using CIBERSORTx algorithm to perform deconvolution. The study was conducted on 155 eligible cHL patients. Using its median value of 20 cm, Dmax was the only variable independently associated with PFS (HR = 2.70, 95% CI 1.1–6.63, pValue = 0.03) in multivariate analysis of PFS for all patients and for those with early complete metabolic response (iPET-). Among patients with iPET-low Dmax was associated with a 4-year PFS of 90% (95% CI 82.0–98.9) significantly better compared to high Dmax (4-year PFS 72.4%, 95% CI 61.9–84.6). From the analysis of gene expression profiles differences in Dmax were mostly associated with variations in the expression of microenvironmental components. In conclusion our results support tumor dissemination measured through Dmax as novel prognostic factor for cHL patients treated with ABVD.

2022 - Reply to M. Shibusawa et al [Articolo su rivista]
Luminari, S.; Arcaini, L.; Federico, M.
abstract

2022 - Survival and Recurrence in Vitreoretinal Lymphoma Simulating Uveitis at Presentation: The Possible Role of Combined Chemotherapy [Articolo su rivista]
Gozzi, F.; Aldigeri, R.; Mastrofilippo, V.; De Simone, L.; Bolletta, E.; Marzano, J.; Iannetta, D.; Coassin, M.; Ilariucci, F.; Ferrari, A.; Luminari, S.; Merli, F.; Croci, S.; Zerbini, A.; Farnetti, E.; Nicoli, D.; Valli, R.; Tamagnini, I.; Cavazza, A.; Salvarani, C.; Fontana, L.; Cimino, L.
abstract

Purpose: To investigate the role of combined systemic and local chemotherapy in improving the survival of patients with vitreoretinal lymphoma (VRL). Methods: Patients with VRL consecutively seen from 2006 to 2020 were retrospectively reviewed; data on the presence and time of central nervous system (CNS) involvement and treatment regimen (systemic, local or combined chemotherapy) were collected. Overall survival (OS) and progression-free survival (PFS) were calculated for each group. Results: Forty-three eyes of 22 subjects with histology-proven VRL were included. Mean time of survival was 64.8 months (SE±10.8). Twelve patients (57%) presented CNS involvement, which was significantly associated with progression (r = 0.48, P =.03) and death (r = 0.56, P =.009). The isolated primary VRL group had a 5-year OS of 80%. Combined systemic and local chemotherapy reduced the risk of death by 82% (hazard ratio 0.18[0.04– 0.85]) in the entire cohort. Conclusion: Combined systemic and local chemotherapy significantly improved OS but not PFS of patients affected by VRL.

2021 - ALK-negative anaplastic large cell lymphoma: Features and outcomes of 235 patients from the International T-Cell Project [Articolo su rivista]
Shustov, A.; Cabrera, M. E.; Civallero, M.; Bellei, M.; Ko, Y. H.; Manni, M.; Skrypets, T.; Horwitz, S. M.; de Souza, C. A.; Radford, J. A.; Bobillo, S.; Prates, M. V.; Ferreri, A. J. M.; Chiattone, C.; Spina, M.; Vose, J. M.; Chiappella, A.; Laszlo, D.; Marino, D.; Stelitano, C.; Federico, M.; Savage, K.; Connors, J.; Gascoyne, R.; Chhanabhai, M.; Wilson, W.; Jaffe, E. S.; Armitage, J. O.; Weisenburger, D. D.; Anderson, J.; Ullrich, F.; Bast, M.; Hochberg, E.; Harris, N.; Smogorzews ka, A.; Levine, A.; Nathwani, B. N.; Miller, T.; Rimsza, L.; Montserrat, E.; Lopez-Guillermo, A.; Campo, E.; Cuadros, M.; Ferreira, J. A.; Delgado, B. M.; Holte, H.; Delabie, J.; Rudiger, T.; Muller-Hermelink, K.; Reimer, P.; Adam, P.; Wilhelm, M.; Schmitz, N.; Nerl, C.; Lister, A.; Norton, A.; Maclennan, K. A.; Zinzani, P. L.; Pileri, S. A.; Bellai, M.; Luminari, S.; Coiffier, B.; Berger, F.; Tanin, I.; Wannakrairot, P.; Au, W. Y.; Liang, R.; Loong, F.; Rajan, S.; Sng, I.; Tobinai, K.; Matsuno, Y.; Morishima, Y.; Nakamura, S.; Seto, M.; Tanimoto, M.; Yoshino, T.; Suzumiya, J.; Ohshima, K.; Kim, W. -S.
abstract

Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK- ALCL) is an aggressive neoplasm of T-cell/null-cell lineage. The T-Cell Project is a global prospective cohort study that consecutively enrolled patients newly diagnosed with peripheral T-cell lymphoma, registered through a centralized computer database between September 2006 and February 2018. Of 1553 validated cases from 74 sites in 13 countries worldwide, 235 were reported as ALK- ALCL. The median age at diagnosis was 54 years (range, 18-89 years), with a male predominance (62%). Stage III to IV disease was identified in 71% of patients, bulky disease and bone marrow involvement were uncommon, and 66% of patients presented with a low (0-1) International Prognostic Index score. Of all treated patients, 85% received multiagent initial chemotherapy, and 8% were consolidated with autologous hematopoietic cell transplantation. The initial overall and complete response rates were 77% and 63%, respectively. After a median follow-up of 52 months (95% confidence interval [CI], 41-63), the median progression-free survival (PFS) and overall survival (OS) were 41 months (95% CI, 17-62) and 55 months (95% CI, 36-75), respectively. The 3- and 5-year PFS rates were 52% and 43%, and the 3- and 5-year OS rates were 60% and 49%. Treatments containing both anthracycline and etoposide were associated with superior OS (P 5.05) but not PFS (P 5.18). In this large prospective cohort study, outcomes comparable to those previously reported in the retrospective International Peripheral T-Cell Lymphoma Project were observed. The study underscores the need for introducing novel platforms for ALK- ALCL and establishes a benchmark for future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT01142674.

2021 - Allogeneic stem cell transplantation in mantle cell lymphoma in the era of new drugs and CAR-T cell therapy [Articolo su rivista]
Marangon, M.; Visco, C.; Barbui, A. M.; Chiappella, A.; Fabbri, A.; Ferrero, S.; Galimberti, S.; Luminari, S.; Musuraca, G.; Re, A.; Zilioli, V. R.; Ladetto, M.
abstract

MCL is an uncommon lymphoproliferative disorder that has been regarded as incurable since its identification as a distinct entity. Allogeneic transplantation for two decades has represented the only option capable of ensuring prolonged remissions and possibly cure. Despite its efficacy, its application has been limited by feasibility limitations and substantial toxicity, particularly in elderly patients. Nevertheless, the experience accumulated over time has been wide though often scattered among retrospective and small prospective studies. In this review, we aimed at critically revise and discuss available evidence on allogeneic transplantation in MCL, trying to put available evidence into the 2020 perspective, characterized by unprecedented development of novel promising therapeutic agents and regimens.

2021 - Gene expression profile unveils diverse biological effect of serum vitamin D in Hodgkin's and diffuse large B-cell lymphoma [Articolo su rivista]
Donati, B.; Ferrari, A.; Ruffini, A.; Manzotti, G.; Fragliasso, V.; Merli, F.; Zanelli, M.; Valli, R.; Luminari, S.; Ciarrocchi, A.
abstract

The primary function of 25(OH)Vitamin D (VitD) is to control calcium; however, recent evidence associated serum VitD deficiency to high aggressiveness and worse outcome in different type of malignancies including lymphomas, and the reasons of such effect are to be defined. In this study, we investigated the association of VitD blood levels with gene expression in a retrospective cohort of 181 lymphomas (104 diffuse large B-cell lymphomas [DLBCLs] and 77 classical Hodgkin's lymphomas [cHLs]) of whom 116 with available gene expression profiles (52 DLBCLs and 64 cHLs, respectively). In DLBCL, VitD deficiency did not cause significant alteration in gene expression suggesting different mechanisms of action including a possible systemic effect or an effect on pharmacokinetics. By contrast, in cHLs, VitD deficiency induced profound changes in the transcriptional program leading to the NF-κB-mediated activation of stress-protective and pro-survival pathways. Coherently, VitD signaling defined by vitamin D Receptor (VDR) expression analysis, resulted highly activated in cHLs but not in DLBCLs. Even if preliminary, these data represent the first evidence of a direct role of VitD in the biology of cHL and suggest a multimodality and disease-specific activity of this vitamin in lymphomas.

2021 - Indolent t-cell lymphoproliferative disorders of the gastrointestinal tract (Itlpd-gi): A review [Articolo su rivista]
Sanguedolce, F.; Zanelli, M.; Zizzo, M.; Luminari, S.; Martino, G.; Soriano, A.; Ricci, L.; Caprera, C.; Ascani, S.
abstract

iTLPD-GI is a low-grade clonal T-cell lymphoproliferative disease arising in GI organs. It is an uncommon disease, and only recently has it been enlisted as a distinct provisional entity in the current WHO Classification. Data from the literature disclose high heterogeneity in terms of pathological and molecular features; on the other hand, establishing an accurate diagnosis of iTLPD-GI is of pivotal importance, since treatment options are different from that of other, more frequent lymphomas that arise in the gastrointestinal tract. In this review, we aimed to better define this novel entity, and to identify useful diagnostic biomarkers; moreover, we provide a biomarker-based approach to the diagnosis and describe the most common issues in differentiating iTLPD-GI from other neoplastic and non-neoplastic disorders.

2021 - Long-term results of the MCL01 phase II trial of rituximab plus HyperCVAD alternating with high-dose cytarabine and methotrexate for the initial treatment of patients with mantle cell lymphoma [Articolo su rivista]
Massaro, F.; Stepanishyna, Y.; Manni, M.; Luminari, S.; Galimberti, S.; Marcheselli, L.; Visco, C.; Tecchio, C.; Stelitano, C.; Angrilli, F.; Petrini, M.; Merli, F.; Federico, M.
abstract

Mantle cell lymphoma is a rare and incurable lymphoproliferative disorder. In the MCL01 trial, patients were treated with the R-HCVAD regimen [rituximab plus HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; R-CVAD) alternating with high-dose methotrexate and cytarabine (AM)] for four cycles followed by autologous stem cell transplantation (ASCT) for those who reached only a partial response. After a median follow-up of 10·5 years, we reported 10-year progression-free and overall survival rates of 35% and 61% respectively, with a 10-years cumulative incidence rate of second malignancies of 10·6%. Mature results of the MCL01 trial confirmed the efficacy of HyperCVAD-AM as a frontline regimen for younger patients (≤65 years).

2021 - Pet imaging [Capitolo/Saggio]
Luminari, S.; Trotman, J.
abstract

FDG-PET has significantly contributed to improve the management of most aggressive and Hodgkin lymphomas. Although more heterogeneous, FDG avidity has been demonstrated also for indolent lymphomas, leading to increased use of functional imaging in this setting. In this chapter we review available data about the contribution of FDG-PET for staging and response assessment and for the identification of histologic transformation of follicular lymphomas and of other low-grade B-cell lymphoma subtypes.

2021 - Prognostic Impact of Muscle Quantity and Quality and Fat Distribution in Diffuse Large B-Cell Lymphoma Patients [Articolo su rivista]
Besutti, G.; Massaro, F.; Bonelli, E.; Braglia, L.; Casali, M.; Versari, A.; Ligabue, G.; Pattacini, P.; Cavuto, S.; Merlo, D. F.; Luminari, S.; Merli, F.; Vaccaro, S.; Pellegrini, M.
abstract

Baseline CT scans of 116 patients (48% female, median 64 years) with diffuse large B-cell lymphoma (DLBCL) were retrospectively reviewed to investigate the prognostic role of sarcopenia and fat compartment distributions on overall survival (OS), progression-free survival (PFS), and early therapy termination. Skeletal muscle index (SMI), skeletal muscle density (SMD), and intermuscular adipose tissue (IMAT) were quantified at the level of the third lumbar vertebra (L3) and proximal thigh (PT). Low L3-SMD, but not low L3-SMI, was associated with early therapy termination (p = 0.028), shorter OS (HR = 6.29; 95% CI = 2.17–18.26; p < 0.001), and shorter PFS (HR = 2.42; 95% CI = 1.26–4.65; p = 0.008). After correction for sex, International Prognostic Index (IPI), BMI, and R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), low L3-SMD remained associated with poor OS (HR = 3.54; 95% CI = 1.10–11.40; p = 0.034) but not with PFS. Increased PT-IMAT was prognostic for poor OS and PFS after correction for sex, IPI, BMI, and R-CHOP therapy (HR = 1.35; CI = 1.03–1.7; p = 0.03, and HR = 1.30; CI = 1.04–1.64; p = 0.024, respectively). Reduced muscle quality (SMD) and increased intermuscular fat (IMAT), rather than low muscle quantity (SMI), are associated with poor prognosis in DLBCL, when measured at the L3 level, and particularly at the level of the proximal thigh. The proximal thigh represents a novel radiological landmark to study body composition.

2021 - Response-Adapted Postinduction Strategy in Patients With Advanced-Stage Follicular Lymphoma: The FOLL12 Study [Articolo su rivista]
Luminari, Stefano; Manni, Martina; Galimberti, Sara; Versari, Annibale; Tucci, Alessandra; Boccomini, Carola; Farina, Lucia; Olivieri, Jacopo; Marcheselli, Luigi; Guerra, Luca; Ferrero, Simone; Arcaini, Luca; Cavallo, Federica; Kovalchuk, Sofya; Skrypets, Tetiana; Del Giudice, Ilaria; Chauvie, Stephane; Patti, Caterina; Stelitano, Caterina; Ricci, Francesca; Pinto, Antonello; Margiotta Casaluci, Gloria; Zilioli, Vittorio R; Merli, Anna; Ladetto, Marco; Bolis, Silvia; Pavone, Vincenzo; Chiarenza, Annalisa; Arcari, Annalisa; Anastasia, Antonella; Dondi, Alessandra; Mannina, Donato; Federico, Massimo
abstract

Purpose: We compared 2 years of rituximab maintenance (RM) with a response-adapted postinduction approach in patients with follicular lymphoma who responded to induction immunochemotherapy. Methods: We randomly assigned treatment-naïve, advanced-stage, high-tumor burden follicular lymphoma patients to receive standard RM or a response-adapted postinduction approach on the basis of metabolic response and molecular assessment of minimal residual disease (MRD). The experimental arm used three types of postinduction therapies: for complete metabolic response (CMR) and MRD-negative patients, observation; for CMR and MRD-positive (end of induction or follow-up) patients, four doses of rituximab (one per week, maximum three courses) until MRD-negative; and for non-CMR patients, one dose of ibritumomab tiuxetan followed by standard RM. The study was designed as noninferiority trial with progression-free survival (PFS) as the primary end point. Results: Overall, 807 patients were randomly assigned. After a median follow-up of 53 months (range 1-92 months), patients in the standard arm had a significantly better PFS than those in the experimental arm (3-year PFS 86% v 72%; P < .001). The better PFS of the standard vs experimental arm was confirmed in all the study subgroups except non-CMR patients (n = 65; P = .274). The 3-year overall survival was 98% (95% CI, 96 to 99) and 97% (95% CI, 95 to 99) in the reference and experimental arms, respectively (P = .238). Conclusion: A metabolic and molecular response-adapted therapy as assessed in the FOLL12 study was associated with significantly inferior PFS compared with 2-year RM. The better efficacy of standard RM was confirmed in the subgroup analysis and particularly for patients achieving both CMR and MRD-negative.

2021 - Simplified Geriatric Assessment in Older Patients With Diffuse Large B-Cell Lymphoma: The Prospective Elderly Project of the Fondazione Italiana Linfomi [Articolo su rivista]
Merli, F.; Luminari, S.; Tucci, A.; Arcari, A.; Rigacci, L.; Hawkes, E.; Chiattone, C. S.; Cavallo, F.; Cabras, G.; Alvarez, I.; Fabbri, A.; Re, A.; Puccini, B.; Barraclough, A.; Delamain, M. T.; Ferrero, S.; Usai, S. V.; Ferrari, A.; Cencini, E.; Pennese, E.; Zilioli, V. R.; Marino, D.; Balzarotti, M.; Cox, M. C.; Zanni, M.; Di Rocco, A.; Lleshi, A.; Botto, B.; Hohaus, S.; Merli, M.; Sartori, R.; Gini, G.; Nassi, L.; Musuraca, G.; Tani, M.; Bottelli, C.; Kovalchuk, S.; Re, F.; Flenghi, L.; Molinari, A.; Tarantini, G.; Chimienti, E.; Marcheselli, L.; Mammi, C.; Spina, M.
abstract

PURPOSE: To prospectively validate the use of a simplified geriatric assessment (sGA) at diagnosis and to integrate it into a prognostic score for older patients with diffuse large B-cell lymphoma (DLBCL). METHODS: We conducted the prospective Elderly Project study on patients with DLBCL older than 64 years who underwent our Fondazione Italiana Linfomi original geriatric assessment (oGA) (age, Cumulative Illness Rating Scale for Geriatrics, activities of daily living, and instrumental activities of daily living) before treatment. Treatment choice was left to the physician's discretion. The primary end point was overall survival (OS) (ClinicalTrials.gov identifier: NCT02364050). RESULTS: We analyzed 1,163 patients (median age 76 years), with a 3-year OS of 65% (95% CI, 62 to 68). Because at multivariate analysis on oGA, age > 80 years retained an independent correlation with OS, we also developed a new, simplified version of the GA (sGA) that classifies patients as fit (55%), unfit (28%), and frail (18%) with significantly different 3-year OS of 75%, 58%, and 43%, respectively. The sGA groups, International Prognostic Index, and hemoglobin levels were independent predictors of OS and were used to build the Elderly Prognostic Index (EPI). Three risk groups were identified: low (23%), intermediate (48%), and high (29%), with an estimated 3-year OS of 87% (95% CI, 81 to 91), 69% (95% CI, 63 to 73), and 42% (95% CI, 36 to 49), respectively. The EPI was validated using an independent external series of 328 cases. CONCLUSION: The Elderly Project validates sGA as an objective tool to assess fitness status and defines the new EPI to predict OS of older patients with DLBCL.

2021 - Targeted locus amplification to detect molecular markers in mantle cell and follicular lymphoma [Articolo su rivista]
Genuardi, E.; Klous, P.; Mantoan, B.; Drandi, D.; Ferrante, M.; Cavallo, F.; Alessandria, B.; Dogliotti, I.; Grimaldi, D.; Ragaini, S.; Clerico, M.; Lo Schirico, M.; Saraci, E.; Yilmaz, M.; Zaccaria, G. M.; Cortelazzo, S.; Vitolo, U.; Luminari, S.; Federico, M.; Boccadoro, M.; van Min, M.; Splinter, E.; Ladetto, M.; Ferrero, S.
abstract

Minimal residual disease (MRD) monitoring by PCR methods is a strong and standardized predictor of clinical outcome in mantle cell lymphoma (MCL) and follicular lymphoma (FL). However, about 20% of MCL and 40% of FL patients lack a reliable molecular marker, being thus not eligible for MRD studies. Recently, targeted locus amplification (TLA), a next-generation sequencing (NGS) method based on the physical proximity of DNA sequences for target selection, identified novel gene rearrangements in leukemia. The aim of this study was to test TLA in MCL and FL diagnostic samples lacking a classical, PCR-detectable, t(11; 14) MTC (BCL1/IGH), or t(14; 18) major breakpoint region and minor cluster region (BCL2/IGH) rearrangements. Overall, TLA was performed on 20 MCL bone marrow (BM) or peripheral blood (PB) primary samples and on 20 FL BM, identifying a novel BCL1 or BCL2/IGH breakpoint in 16 MCL and 8 FL patients (80% and 40%, respectively). These new breakpoints (named BCL1-TLA and BCL2-TLA) were validated by ASO primers design and compared as MRD markers to classical IGH rearrangements in eight MCL: overall, MRD results by BCL1-TLA were superimposable (R Pearson = 0.76) to the standardized IGH-based approach. Moreover, MRD by BCL2-TLA reached good sensitivity levels also in FL and was predictive of a primary refractory case. In conclusion, this study offers the proof of principle that TLA is a promising and reliable NGS-based technology for the identification of novel molecular markers, suitable for further MRD analysis in previously not traceable MCL and FL patients.

2021 - The First 2 Years of Biosimilar Epoetin for Cancer and Chemotherapy-Induced Anemia in the U.S.: A Review from the Southern Network on Adverse Reactions [Articolo su rivista]
Bennett, C. L.; Nagai, S.; Bennett, A. C.; Hoque, S.; Nabhan, C.; Schoen, M. W.; Hrushesky, W. J.; Luminari, S.; Ray, P.; Yarnold, P. R.; Witherspoon, B.; Riente, J.; Bobolts, L.; Brusk, J.; Tombleson, R.; Knopf, K.; Fishman, M.; Llm, Y. T. Y.; Carson, K. R.; Djulbegovic, B.; Restaino, J.; Armitage, J. O.; Sartor, O. A.
abstract

Biosimilars are biologic drug products that are highly similar to reference products in analytic features, pharmacokinetics and pharmacodynamics, immunogenicity, safety, and efficacy. Biosimilar epoetin received Food and Drug Administration (FDA) approval in 2018. The manufacturer received an FDA nonapproval letter in 2017, despite receiving a favorable review by FDA's Oncologic Drugs Advisory Committee (ODAC) and an FDA nonapproval letter in 2015 for an earlier formulation. We discuss the 2018 FDA approval, the 2017 FDA ODAC Committee review, and the FDA complete response letters in 2015 and 2017; review concepts of litigation, naming, labeling, substitution, interchangeability, and pharmacovigilance; review European and U.S. oncology experiences with biosimilar epoetin; and review the safety of erythropoiesis-stimulating agents. In 2020, policy statements from AETNA, United Health Care, and Humana indicated that new epoetin oncology starts must be for biosimilar epoetin unless medical need for other epoetins is documented. Empirical studies report that as of 2012, reference epoetin use decreased from 40%–60% of all patients with cancer with chemotherapy-induced anemia to <5% of such patients because of safety concerns. Between 2018 and 2020, biosimilar epoetin use varied, increasing to 81% among one private insurer's patients covered by Medicare whose cancer care is administered with Oncology Analytics and to 41% with the same private insurer's patients with cancer covered by commercial health insurance and administered by the private insurer, to 0% in several Veterans Administration Hospitals, increasing to 100% in one large county hospital in California, and with yet-to-be-reported data from most oncology settings. We conclude that biosimilar epoetin appears to have overcome some barriers since 2015, although current uptake in the U.S. is variable. Pricing and safety considerations for all erythropoiesis-stimulating agents are primary determinants of biosimilar epoetin oncology uptake. Implications for Practice: Few oncologists understand substitution and interchangeability of biosimilars with reference drugs. Epoetin biosimilar is new to the market, and physician and patient understanding is limited. The development of epoetin biosimilar is not familiar to oncologists.

2021 - The use of frailty assessments in treating older adults with aggressive lymphomas [Articolo su rivista]
Cordoba, R.; Luminari, S.; Eyre, T. A.
abstract

Non-Hodgkin lymphomas (NHL) are most commonly diagnosed among people aged 65–74 years, with a median age at diagnosis of 67 years. The percentage of NHL-related deaths is highest among people aged 75–84 years, with a median age at death of 76 years from cases between 2014 and 2018. In light of these recent data, attending physicians of patients with NHL will recognize that the majority of their patients will be of advanced age, with many suffering from a spectrum of frailties. The excess rate of death among older adults with NHL may be related to a range of different factors such as more challenging biologic features, undertreatment received due to a patient’s chronology and treatment-related toxicity. The aim of this review is to provide an updated overview of the knowledge generated over recent years regarding epidemiology, prognosis and treatment options in older adults with lymphoma, focusing on Diffuse Large B-cell Lymphoma (DLBCL) where the most robust evidence base is available.

2021 - Venetoclax Shows Low Therapeutic Activity in BCL2-Positive Relapsed/Refractory Peripheral T-Cell Lymphoma: A Phase 2 Study of the Fondazione Italiana Linfomi [Articolo su rivista]
Ballotta, L.; Zinzani, P. L.; Pileri, S.; Bruna, R.; Tani, M.; Casadei, B.; Tabanelli, V.; Volpetti, S.; Luminari, S.; Corradini, P.; Lucchini, E.; Tisi, M. C.; Merli, M.; Re, A.; Varettoni, M.; Pesce, E. A.; Zaja, F.
abstract

Patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL) have a poor prognosis, with an expected survival of less than 1 year using standard salvage therapies. Recent advances in our understanding of the biology of PTCL have led to identifying B-Cell Lymphoma 2 (BCL2) protein as a potential therapeutic target. BLC2 inhibitor venetoclax was investigated in a prospective phase II trial in patients with BCL2-positive R/R PTCL after at least one previous standard line of treatment (NCT03552692). Venetoclax given alone at a dosage of 800 mg/day resulted in one complete response (CR) and two stable diseases (SDs) among 17 enrolled patients. The majority of patients (88.2%) interrupted the treatment due to disease progression. No relationship with BCL2 expression was documented. At a median follow-up of 8 months, two patients are currently still on treatment (one CR and one SD). No case of tumor lysis syndrome was registered. Therefore, venetoclax monotherapy shows activity in a minority of patients whose biological characteristics have not yet been identified. Clinical Trial Registration: www.clinicaltrials.gov (NCT03552692, EudraCT number 2017-004630-29).

2021 - What's new in peripheral T-cell lymphomas [Articolo su rivista]
Luminari, S.; Skrypets, T.
abstract

Peripheral T-cell lymphomas (PTCLs) are a rare, heterogeneous group of hematological malignancies with extremely poor prognosis for almost all subtypes. The diverse clinicopathological features of PTCLs make accurate diagnosis, prognosis, and choice of optimal treatment strategies difficult. Moreover, the best therapeutic algorithms are still under debate due to the extrapolated approaches developed for B-cell lymphomas and to the absence of few treatment protocol specifically developed for PTCLs. Some advances have been made with CD30 monoclonal antibody, mainly for anaplastic large-cell lymphomas, with improvements in progression-free survival and overall survival. Several new drugs are under evaluation in clinical trials, although not all the results are as encouraging as expected. In this review, we briefly present the most updated information on diagnosis, prognostication, and treatment strategies in PTCLs.

2020 - A Gene Expression–based Model to Predict Metabolic Response after Two Courses of ABVD in Hodgkin Lymphoma Patients [Articolo su rivista]
Luminari, Stefano; Donati, Benedetta; Casali, Massimiliano; Valli, Riccardo; Santi, Raffaella; Puccini, Benedetta; Kovalchuk, Sofya; Ruffini, Alessia; Fama, Angelo; Berti, Valentina; Fragliasso, Valentina; Zanelli, Magda; Vergoni, Federica; Versari, Annibale; Rigacci, Luigi; Merli, Francesco; Ciarrocchi, Alessia
abstract

Purpose: Early response to ABVD, assessed with interim FDG-PET (iPET), is prognostic for classical Hodgkin lymphoma (cHL) and supports the use of response adapted therapy. The aim of this study was to identify a gene-expression profile on diagnostic biopsy to predict iPET positivity (iPET+). Experimental Design: Consecutive untreated patients with stage I-IV cHL who underwent iPET after two cycles of ABVD were identified. Expression of 770 immune-related genes was analyzed by digital expression profiling (NanoString Technology). iPET was centrally reviewed according to the five-point Deauville scale (DS 1-5). An iPET+ predictive model was derived by multivariate regression analysis and assessed in a validation set identified using the same inclusion criteria. Results: A training set of 121 and a validation set of 117 patients were identified, with 23 iPET+ cases in each group. Sixty-three (52.1%), 19 (15.7%), and 39 (32.2%) patients had stage I-II, III, and IV, respectively. Diagnostic biopsy of iPET+ cHLs showed transcriptional profile distinct from iPET-. Thirteen genes were stringently associated with iPET+. This signature comprises two functionally stromal-related nodes. Lymphocytes/monocytes ratio (LMR) was also associated to iPET+. In the training cohort a 5-gene/LMR integrated score predicted iPET+ [AUC, 0.88; 95% confidence interval (CI), 0.80-0.96]. The score achieved a 100% sensitivity to identify DS5 cases. Model performance was confirmed in the validation set (AUC, 0.68; 95% CI, 0.52-0.84). Finally, iPET score was higher in patients with event versus those without. Conclusions: In cHL, iPET is associated with a genetic signature and can be predicted by applying an integrated gene-based model on the diagnostic biopsy.

2020 - Advances in Treatment of Follicular Lymphoma [Articolo su rivista]
Luminari, S.; Trotman, J.; Federico, M.
abstract

Follicular lymphoma (FL) is a heterogeneous disease with varying prognosis owing to differences in clinical, laboratory, and disease parameters. Although generally considered incurable, prognosis for early and advanced stage disease has improved because of therapeutic advances, several of which have resulted from elucidation of the biologic and molecular basis of the disease. The choice of treatment for FL is highly dependent on patient and disease characteristics. Several tools are available for risk stratification, although limitations in their routine clinical use exist. For limited disease, treatment options include radiotherapy, rituximab monotherapy or combination regimens, and surveillance. Treatment of advanced disease is often determined by tumor burden, with surveillance or rituximab considered for low tumor burden and chemoimmunotherapy for high tumor burden disease. Treatment for relapsed or refractory disease is influenced by initial first-line therapy and the duration and quality of the response. At present, there is no consensus for treatment of patients with early or multiply-relapsed disease; however, numerous agents, combination regimens, and transplant options have demonstrated efficacy. While the number of therapies available to treat FL has increased together with an improved understanding of the underlying biologic basis of disease, the best approach to select the most appropriate treatment strategy for an individual patient at a particular time continues to be elucidated. This chapter considers prognostic factors and the evolving treatment landscape of FL, including recent and emerging therapies, as well as remaining unmet needs.

2020 - Droplet digital PCR is a sensitive tool for the detection of TP53 deletions and point mutations in chronic lymphocytic leukaemia [Articolo su rivista]
Frazzi, Raffaele; Bizzarri, Veronica; Albertazzi, Laura; Cusenza Vincenza, Ylenia; Coppolecchia, Lia; Luminari, Stefano; Ilariucci, Fiorella
abstract

2020 - Early palliative care in haematological patients: A systematic literature review [Articolo su rivista]
Tanzi, S.; Venturelli, F.; Luminari, S.; Merlo, F. D.; Braglia, L.; Bassi, C.; Costantini, M.
abstract

Background Early palliative care together with standard haematological care for advanced patients is needed worldwide. Little is known about its effect. The aim of the review is to synthesise the evidence on the impact of early palliative care on haematologic cancer patients' quality of life and resource use. Patients and methods A systematic review was conducted. The search terms were early palliative care or simultaneous or integrated or concurrent care and haematological or oncohaematological patients. The following databases were searched: PubMed, Embase, Cochrane, CINHAL and Scopus. Additional studies were identified through cross-checking the reference articles. Studies were in the English language, with no restriction for years. Two researchers independently reviewed the titles and abstracts, and one author assessed full articles for eligibility. Results A total of 296 studies titles were reviewed. Eight articles were included in the synthesis of the results, two controlled studies provided data on the comparative efficacy of PC interventions, and six one-arm studies were included. Since data pooling and meta-analysis were not possible, only a narrative synthesis of the study results was performed. The quality of the two included comparative studies was low overall. The quality of the six non-comparative studies was high overall, without the possibility of linking the observed results to the implemented interventions. Conclusions Studies on early palliative care and patients with haematological cancer are scarce and have not been prospectively designed. More research on the specific population target, type and timing of palliative care intervention and standardisation of collected outcomes is required. PROSPERO registration number CRD42020141322.

2020 - Early palliative care versus standard care in haematologic cancer patients at their last active treatment: Study protocol of a feasibility trial [Articolo su rivista]
Tanzi, S.; Luminari, S.; Cavuto, S.; Turola, E.; Ghirotto, L.; Costantini, M.
abstract

Background: Patients with advanced haematological malignancies suffer from a very high symptom burden and psychological, spiritual, social and physical symptoms comparable with patients with metastatic non-haematological malignancy. Referral to palliative care services for these patients remains limited or often confined to the last days of life. We developed a palliative care intervention (PCI) integrated with standard haematological care. The aim of the study was focussed on exploring the feasibility of the intervention by patients, professionals and caregivers and on assessing its preliminary efficacy. Methods/design. This is a mixed-methods phase 2 trial. The Specialist Palliative Care Team (SPCT) will follow each patient on a monthly basis in the outpatient clinic or will provide consultations during any hospital admission. SPCT and haematologists will discuss active patient issues to assure a team approach to the patient's care. This quantitative study is a monocentric parallel-group superiority trial with balanced randomisation comparing the experimental PCI plus haematological standard care versus haematological standard care alone. The primary endpoint will calculate on adherence to the planned PCI, measured as the percentage of patients randomised to the experimental arm who attend all the planned palliative care visits in the 24 weeks after randomisation. The qualitative study follows the methodological indications of concurrent nested design and was aimed at exploring the acceptability of the PCI from the point of view of patients, caregivers and physicians. Discussion: In this trial, we will test the feasibility of an integrated palliative care approach starting when the haematologist decides to propose the last active treatment to the patient, according to his/her clinical judgement. We decided to test this criterion because it is able to intercept a wide range of patients'needs. The feasibility of this approach requires that we enrol at least 60 patients and that more than 50% of them be followed by the palliative care team for at least 24 weeks. The trial will include integrated qualitative data analysis; to give essential information on feasibility and acceptability. Trial registration: ClinicalTrials.gov: NCT03743480 (November 16, 2018).

2020 - Five-year results of the BEGEV salvage regimen in relapsed/refractory classical Hodgkin lymphoma [Articolo su rivista]
Santoro, A.; Mazza, R.; Pulsoni, A.; Re, A.; Bonfichi, M.; Zilioli, V. R.; Zanni, M.; Merli, F.; Anastasia, A.; Luminari, S.; Annechini, G.; Gotti, M.; Peli, A.; Liberati, A. M.; Di Renzo, N.; Castagna, L.; Giordano, L.; Ricci, F.; Carlo-Stella, C.
abstract

The complete remission (CR) rate achieved with induction chemotherapy prior to autologous stem cell transplantation (ASCT) represents the strongest prognostic factor in relapsed/ refractory (R/R) classical Hodgkin lymphoma (cHL). By inducing a CR rate of 75%, the bendamustine, gemcitabine, vinorelbine (BEGEV) regimen represents an optimal chemotherapy regimen prior to ASCT. Presented here are the 5-year results of BEGEV followed by ASCT in R/R cHL. With a median follow-up of 5 years, progression-free survival (PFS) and overall survival (OS) for the whole series (n 5 59) were 59% and 78%, respectively. ASCT was performed in 43 of 49 responding patients (73% by intention to treat [ITT]; 88% by response to BEGEV) and resulted in 33 with continuous CR (56% by ITT; 77% of transplanted patients), 7 with disease relapse, and 3 with nonrelapse mortality. For patients who received transplants, the 5-year PFS and OS were 77% and 91%, respectively, with no significant difference between relapsed and refractory patients. No patient experienced secondary leukemia or myelodysplasia. In summary, the long-term efficacy data, the benefits for both relapsed and refractory patients, and the excellent safety profile provide a strong rationale for further development of the BEGEV regimen.

2020 - Germinotropic lymphoproliferative disorder: a systematic review [Articolo su rivista]
Zanelli, M.; Zizzo, M.; Bisagni, A.; Froio, E.; De Marco, L.; Valli, R.; Filosa, A.; Luminari, S.; Martino, G.; Massaro, F.; Fratoni, S.; Ascani, S.
abstract

Germinotropic lymphoproliferative disorder is a rare and rather enigmatic novel entity with distinctive clinicopathological features, one of which is the typical co-infection by Human herpesvirus 8 and Epstein-Barr virus. Human herpesvirus 8 is a lymphotropic virus detected in Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, Human herpesvirus 8-positive diffuse large B cell lymphoma not otherwise specified, and germinotropic lymphoproliferative disorder. Co-infection by Human herpesvirus 8 and Epstein-Barr virus is identified only in two lymphoproliferative diseases: germinotropic lymphoproliferative disorder and primary effusion lymphoma, which are otherwise diseases with totally different clinical presentations and outcomes. Unlike primary effusion lymphoma mostly occurring in immunocompromised individuals and following an aggressive course, germinotropic lymphoproliferative disorder usually presents with single or multiple lymphadenopathy affecting mainly immunocompetent individuals and mostly follows an indolent course. Based on the PRISMA guidelines, we carried out a systematic search on PubMed/MEDLINE, Web of Science, Scopus, EMBASE, and Cochrane Library using the search terms “germinotropic” and “lymphoproliferative disorder.” Current scientific literature reports just 19 cases of germinotropic lymphoproliferative disorder. The purpose of our systematic review is to improve our understanding of the disease, focusing on epidemiology, clinical presentation, pathological features, treatment, and outcome. In addition, we discuss the differential diagnosis with the other Human herpesvirus 8-related lymphoproliferative diseases as currently recognized in the World Health Organization classification, adding a focus on lymphoproliferative disorders showing overlapping features.

2020 - New IMiD on the block [Articolo su rivista]
Luminari, S.
abstract

2020 - New information flows for cancer registries: Testing the use of laboratory data in the province of Reggio Emilia, Italy [Articolo su rivista]
Roncaglia, F.; Mancuso, P.; Vicentini, M.; Vitiello, A.; Vecchia, L.; Luminari, S.; Mangone, L.; Zorzi, M.; Vecchia, C. L.; Rossi, P. G.
abstract

Introduction Haematological malignancies often escape the standard information flows of cancer registries because diagnosis is not always based on bone marrow histology but, rather, on other laboratory tests. Objective To quantify incident haematological malignancies identified exclusively through the laboratory information system and to measure the impact of that source on the sensitivity and accuracy of registering these malignancies. Methods We collected data from the only provincial laboratory of Reggio Emilia on molecular biology, flow cytometry tests and bone marrow smears to detect specific markers of some chronic haematological malignancies. We carried out a record linkage between laboratory reports (period 2013–2017) of patients resident in the province of Reggio Emilia and the Cancer Registry of Reggio Emilia. Results Of the 303 patients who underwent at least one of these tests, 85 were not included in our Cancer Registry. Of these 85 patients, 42 had received a diagnosis of cancer: 34 myeloproliferative neoplasms, 3 chronic myeloid leukaemias, 3 myelodysplastic neoplasms, 1 multiple myeloma and 1 chronic lymphocytic leukaemia. We recovered 4.2% of the total number of chronic haemolymphopoietic cancers registered in the study period, accounting for 15% of myeloproliferative neoplasms. For 30% of prelinkage cases, the specificity of the morphological code improved. Conclusions Although the laboratory information system’s contribution to the completeness of Cancer Registry incident cases was modest, it is useful to add laboratory data to routine cancer registry information flows due to the increasing use of molecular characterisation and to the phenomenon of dehospitalisation.

2020 - Nonpeghylated liposomal doxorubicin combination regimen (R-COMP) for the treatment of lymphoma patients with advanced age or cardiac comorbidity [Articolo su rivista]
Rigacci, L.; Annibali, O.; Kovalchuk, S.; Bonifacio, E.; Pregnolato, F.; Angrilli, F.; Vitolo, U.; Pozzi, S.; Broggi, S.; Luminari, S.; Merli, F.; Spina, M.; Bolis, S.; Margiotta-Casaluci, G.; Scalzulli, R.; Cox, C.; Mamusa, A. M.; Santoro, A.; Zinzani, P. L.; Ferrari, S.; Gini, G.; Vigliotti, M. L.; Mule, A.; Flenghi, L.
abstract

Doxorubicin is the most effective single agent in the treatment of non-Hodgkin's lymphoma (NHL). Its use is limited because of the cardiac toxicity primarily in elderly patients (pts) and in pts with history of cardiac disease. Liposomal doxorubicin has been proven to reduce cardiotoxicity. The aim of this retrospective study was the use of nonpeghylated liposomal doxorubicin (NPLD) in term of efficacy, response rate and incidence of cardiac events. We retrospectively collected the experience of 33 Hematological Italian Centers in using NPLD. Nine hundred and forty-six consecutive pts treated with R-COMP (doxorubicin was substituted with NPLD, Myocet) were collected. Median age was 74 years, the reasons for use of NPLD were: age (466 pts), cardiac disease (298 pts), uncontrolled hypertension (126 pts), other reasons (56 pts). According to clinicians' evaluation, 49.9% of pts would not have used standard doxorubicin for different situations (age, cardiomyopathy, previous use of doxorubicin, and uncontrolled hypertension). Overall 687 pts (72.6%) obtained a complete remission (CR). About 5% (n = 51) of subjects developed major cardiotoxic events including heart failure (N = 31), ischemic heart disease (N = 16), acute heart attack (N = 3), and acute pulmonary oedema (N = 1). After a median follow-up of 32 months, 651 pts were alive and the overall survival (OS) was 72%. After a median observation period of 23 months disease free survival (DFS) was 58%. Either in univariate or in multivariate analysis OS and DFS were not significantly affected by age or cardiac disease. Our findings strongly support that including R-COMP is effective and safe when the population is at high risk of cardiac events and negatively selected. Moreover, the use of this NPLD permitted that about half of our population had the opportunity to receive the best available treatment.

2020 - Nursing role in the assessment and care of hepatic sinusoidal obstruction syndrome patients: a consensus paper by the “Gruppo Italiano Trapianto di Midollo Osseo” [Articolo su rivista]
Botti, Stefano; Agreiter, Iris; Orlando, Laura; Gargiulo, Gianpaolo; Bonifazi, Francesca; Banfi Marina, Marialuisa; Cappucciati, Lorella; Caffarri, Cristiana; De Cecco, Valentina; Deiana Giuseppe, Marco; Gavezzotti, Marta; Magar`o, Antonio; Netti Maria, Giovanna; Pignatelli Adriana, Concetta; Rostagno, Elena; Samarani, Emanuela; Cardoso Janini, Silva; Soave, Sonia; Valente Concetta, Maria; Vedovetto, Alessio; Zecca, Marco; Luminari, Stefano; Merli, Francesco; Guberti, Monica
abstract

Purpose: Sinusoidal obstruction syndrome (SOS) is one of the most serious complications post haematopoietic stem cell transplantation (HSCT). The diagnosis of SOS is clinical, but nurses should be involved in the pre-transplant risk assessment period and play a crucial role in the early detection of signs and symptoms during and after hospitalization. The aim of this work is to achieve a consensus on nurses' behaviour in caring for SOS. Methods: On behalf of the Italian Group for Bone and Marrow Transplantation (GITMO), a promoter committee was established to put in place a consensus conference approach. A multidisciplinary group of GITMO together with four nurses, three haematology physicians and one patient representative acted as jury, who reviewed the reports and wrote recommendations and suggestions. Recommendations gaining 100% of consensus were considered ‘Golden Points of Care'; if a consensus was achieved by ≥ 75% of the jury's members, those recommendations were defined as ‘Good Practices'. Results: Eighteen papers written by nurses as first authors have been identified. Golden Points of Care and Good Practices were worked out for the following topics: nurses' role in general, nurses' role in pre-transplant assessment, pre-transplant risk assessment and risk stratification, baseline monitoring, suspected mild or moderate SOS, suspected severe or very severe SOS and late-onset cases. Conclusion: SOS is relatively rare; therefore, a holistic approach to the patients' needs considering nursing role as essential may result in better care outcomes.

2020 - Obinutuzumab and miniCHOP for unfit patients with diffuse large B-cell lymphoma. A phase II study by Fondazione Italiana Linfomi [Articolo su rivista]
Merli, Francesco; Cavallo, Federica; Salvi, Flavia; Tucci, Alessandra; Musuraca, Gerardo; Nassi, Luca; Merli, Michele; Tani, Monica; Gini, Guido; Ferrari, Angela; Molinari Anna, Lia; Liberati Anna, Marina; Conconi, Annarita; Matteucci, Paola; Bari, Alessia; Scalone, Renato; Ferrero, Simone; Zanni, Manuela; Mammi, Caterina; Luminari, Stefano
abstract

Objective: To evaluate activity and safety of obinutuzumab-miniCHOP (Ga101-miniCHOP) combination in older patients with Diffuse Large B-Cell Lymphoma (DLBCL) unfit to receive full dose immunochemotherapy. Materials and Methods: We conducted a Simon's two-stage phase II multicenter trial to investigate response rate (primary endpoint) and safety of six courses of Ga101-miniCHOP in older patients with DLBCL (≥65 years), prospectively defined as unfit according to a simplified Comprehensive Geriatric Assessment (sCGA). Results: Overall, 34 patients were enrolled (median age 82 years; range 68–89), with 27 out of the 33 eligible patients completing all six planned courses. Complete Remission (CR) rate was reported in fourteen patients (42%). After a median follow-up of sixteen months, the two-year Progression Free and Overall Survival (PFS and OS) were 49% (95% Confidence Interval (CI), 28 to 67) and 68% (95% CI, 49 to 81), respectively. The most frequent grade 3–4 adverse event was neutropenia in thirteen patients (26%). Conclusions: Based on the observed CR rate, study accrual was interrupted due to the very low probability of demonstrating the initial study hypothesis that Ga101-miniCHOP could improve results of historical data obtained with R-miniCHOP in this group of patients. Nonetheless, results achieved with the 33 treated patients confirm activity and good tolerability of the Ga101-miniCHOP regimen for older unfit adult patients with DLBCL.

2020 - Positron-emission tomography–based staging reduces the prognostic impact of early disease progression in patients with follicular lymphoma [Articolo su rivista]
Batlevi Connie, L.; Sha, Fushen; Alperovich, Anna; Ni, Ai; Smith, Katy; Ying, Zhitao; Gerecitano John, F; Hamlin Paul, A; Horwitz, ; Steve, M.; Joffe, Erel; Kumar, Anita; Matasar Matthew, J; Moskowitz Alison, J; Moskowitz Craig, H; Noy, Ariela; Owens, Colette; Palomba, Lia; Straus, David; von Keudell, Gottfried; Zelenetz Andrew, D; Seshan Venkatraman, E; Luminari, Stefano; Marcheselli, Luigi; Federico, Massimo; Younes, Anas
abstract

Background: Previous studies reported that early progression of disease (POD) after initial therapy predicted poor overall survival (OS) in patients with follicular lymphoma (FL). Here, we investigated whether pre-treatment imaging modality had an impact on prognostic significance of POD. Methods: In this retrospective study, we identified 1088 patients with grade I–IIIA FL; of whom, 238 patients with stage II–IV disease were initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), and 346 patients were treated with rituximab-based chemotherapy. Patients (N = 484) from the FOLL05 study served as an independent validation cohort. We risk-stratified patients based on pre-treatment radiographic imaging (positron-emission tomography [PET] versus computed tomography [CT]) and early POD status using event-defining and landmark analyses. A competing risk analysis evaluated the association between early POD and histologic transformation. Results: In the discovery cohort, patients with POD within 24 months (PFS24) of initiating R-CHOP therapy had a 5-year OS of 57.6% for CT-staged patients compared with 70.6% for PET-staged patients. In the validation cohort, the 5-year OS for patients with early POD was 53.9% and 100% in CT- and PET-staged patients, respectively. The risk of histologic transformation in patients whose disease progressed within one year of initiating therapy was higher in CT-staged patients than in PET-staged patients (16.7% versus 6.3%, respectively), which was associated with a 9.7-fold higher risk of death. Conclusion: In FL, pre-treatment PET staging reduced the prognostic impact of early POD compared with CT staging. Patients with early POD and no histologic transformation have an extended OS with standard therapy.

2020 - Stem cell mobilization after bendamustine in indolent lymphomas: a multicenter study on behalf of the Fondazione Italiana Linfomi [Articolo su rivista]
Merli, M.; Luminari, S.; Farina, L.; Cocito, F.; Defrancesco, I.; Gini, G.; Arcari, A.; Scapinello, G.; Gentile, M.; Goldaniga, M.; Loseto, G.; Cencini, E.; Greco, A.; Molinari, A. L.; Ferrario, A.; Bianchi, B.; Mora, B.; Bertu, L.; Saturni, V.; Bergamini, F.; Fabbri, N.; Rossi, F. G.; Bolis, S.; Passamonti, F.; Arcaini, L.
abstract

2020 - Texture analysis and multiple-instance learning for the classification of malignant lymphomas [Articolo su rivista]
Lippi, Marco; Gianotti, Stefania; Fama, Angelo; Casali, Massimiliano; Barbolini, Elisa; Ferrari, Angela; Fioroni, Federica; Iori, Mauro; Luminari, Stefano; Menga, Massimo; Merli, Francesco; Trojani, Valeria; Versari, Annibale; Zanelli, Magda; Bertolini, Marco
abstract

Background and objectives: Malignant lymphomas are cancers of the immune system and are characterized by enlarged lymph nodes that typically spread across many different sites. Many different histological subtypes exist, whose diagnosis is typically based on sampling (biopsy) of a single tumor site, whereas total body examinations with computed tomography and positron emission tomography, though not diagnostic, are able to provide a comprehensive picture of the patient. In this work, we exploit a data-driven approach based on multiple-instance learning algorithms and texture analysis features extracted from positron emission tomography, to predict differential diagnosis of the main malignant lymphomas subtypes. Methods: We exploit a multiple-instance learning setting where support vector machines and random forests are used as classifiers both at the level of single VOIs (instances) and at the level of patients (bags). We present results on two datasets comprising patients that suffer from four different types of malignant lymphomas, namely diffuse large B cell lymphoma, follicular lymphoma, Hodgkin's lymphoma, and mantle cell lymphoma. Results: Despite the complexity of the task, experimental results show that, with sufficient data samples, some cancer subtypes, such as the Hodgkin's lymphoma, can be identified from texture information: in particular, we achieve a 97.0% of sensitivity (recall) and a 94.1% of predictive positive value (precision) on a dataset that consists in 60 patients. Conclusions: The presented study indicates that texture analysis features extracted from positron emission tomography, combined with multiple-instance machine learning algorithms, can be discriminating for different malignant lymphomas subtypes.

2020 - Younger patients with Waldenström Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies [Articolo su rivista]
Varettoni, M.; Ferrari, A.; Frustaci, A. M.; Ferretti, V. V.; Rizzi, R.; Motta, M.; Piazza, F.; Merli, M.; Benevolo, G.; Visco, C.; Laurenti, L.; Ferrero, S.; Gentile, M.; Del Fabro, V.; Abbadessa, A.; Klersy, C.; Musto, P.; Fabbri, N.; Deodato, M.; Dogliotti, I.; Greco, C.; Corbingi, A.; Luminari, S.; Arcaini, L.
abstract

We analyzed 160 young Waldenström Macroglobulinemia (WM) patients with a median age of 49 years (range 23-55 years), diagnosed between January 2000 and January 2019 in 14 Italian centers. At diagnosis, 70% of patients were asymptomatic. With a median follow-up of 5.6 years, 57% have been treated. As initial therapy 79% of patients received chemo-immunotherapy, 13% a chemo-free induction and 8% chemotherapy only. At relapse or progression, 6% underwent an autologous stem cell transplantation. Overall, 19% of patients received ibrutinib during the course of the disease. According to IPSSWM, 63% were classified as low risk, 27% as intermediate risk and 10% as high risk. Five-year OS was shorter in high-risk as compared with low or intermediate risk patients (92.9% vs 100% P =.002). According to revised IPSSWM, 92% were classified as very low or low risk and 8% as intermediate risk, with a shorter 5-year OS in the latter group (87.5% vs 100%, P =.028). The OS of young WM patients was not significantly reduced as compared with age-matched, sex-matched and calendar year-matched general population. Early diagnosis, absence of high-risk features in symptomatic patients and high efficacy of modern treatments are the main determinants of the excellent outcome of young WM patients.

2019 - Bleomycin, vinblastine and dacarbazine combined with nonpegylated liposomal doxorubicin (MBVD) in elderly (≥70 years) or cardiopathic patients with Hodgkin lymphoma: a phase-II study from Fondazione Italiana Linfomi (FIL) [Articolo su rivista]
Salvi, Flavia; Luminari, Stefano; Tucci, Alessandra; Massidda, Stefania; Liberati Anna, Marina; Stelitano, Caterina; Zanni, Manuela; Re, Alessandro; Centurioni, Riccardo; Freilone, Roberto; Musuraca, Gerardo; Nassi, Luca; Patti, Caterina; Arcari, Annalisa; Tani, Monica; Pulsoni, Alessandro; Pavone, Vincenzo; Volpetti, Stefano; Peli, Annalisa; Evangelista, Andrea; Spina, Michele; Ladetto, Marco; Merli, Francesco
abstract

This phase-II study assessed activity and toxicity of substituting conventional doxorubicin with nonpegylated liposomal doxorubicin in the conventional ABVD regimen for the treatment of elderly or cardiopathic patients with HL. Stage I–IIA and IIB–IV patients were treated with three courses of MBVD plus radiotherapy, or six courses of MBVD, respectively, plus radiotherapy limited to bulky or residual disease areas. The primary endpoints were CR rate and the rate of cardiac events. Forty-seven patients were enrolled. Median age was 75 years, 13 had stage I–II disease. Overall, CR was achieved by 36 patients (77%, 95% CI: 62–88), 100% and 68% in stage I–II and III–IV, respectively. With a median follow-up of 40 months (IQR: 36–45). Three-year overall survival (OS) and progression-free survival (PFS) were 70% and 43%, respectively. Cardiac events grades 3–5 were reported in two patients. In conclusion, MBVD's activity and safety profile was comparable to historical ABVD data.

2019 - Early progression as a predictor of survival in marginal zone lymphomas: An analysis from the FIL-NF10 study [Articolo su rivista]
Luminari, Stefano; Merli, Michele; Rattotti, Sara; Tarantino, Vittoria; Marcheselli, Luigi; Cavallo, Federica; Varettoni, Marzia; Bianchi, Benedetta; Merli, Francesco; Tedeschi, Alessandra; Cabras, Giuseppina; Re, Francesca; Visco, Carlo; Delamain Marcia, Torresan; Cencini, Emanuele; Spina, Michele; Ferrero, Simone; Ferrari, Angela; Deodato, Marina; Mannina, Donato; Annibali, Ombretta; Rago, Angela; Orsucci, Lorella; Defrancesco, Irene; Frigeni, Marco; Cesaretti, Marina; Arcaini, Luca
abstract

Marginal zone lymphomas (MZLs) are indolent nonfollicular B-cell lymphomas (INFLs) and have heterogeneous clinical behavior. Recently, time to progression of disease at 24 months (POD24) was identified to stratify overall survival (OS) in follicular non-Hodgkin lymphoma and in INFL. Here, we examined the ability of POD24 to predict subsequent OS in a large, international cohort of MZL as part of the NF10 prospective international registry headed by Fondazione Italiana Linfomi (FIL). POD24 was only calculated for MZL patients requiring immediate therapy and was defined as experiencing lymphoma progression within 24 months from diagnosis. Among the 1325 patients enrolled in the NF10 study, we identified 321 patients with MZL for whom immediate therapy was planned right after lymphoma diagnosis. Overall, POD24 was confirmed in 59 patients (18%). Three-year OS for patients with POD24 was 53% with a hazard ratio of 19.5 (95% confidence interval, 8.4-45) compared with patients without POD24 (3-year OS, 95%). Association of POD24 with OS was confirmed for the subgroup of splenic and extranodal MZLs. Assessment of POD24 stratifies subsequent outcome inMZL and identifies a high-risk population.

2019 - Follicular Lymphoma: Recent and Emerging Therapies, Treatment Strategies, and Remaining Unmet Needs [Articolo su rivista]
Matasar Matthew, J.; Luminari, Stefano; Barr Paul, M.; Barta Stefan, K.; Danilov Alexey, V.; Hill Brian, T.; Phillips Tycel, J.; Jerkeman, Mats; Magagnoli, Massimo; Nastoupil Loretta, J.; Persky Daniel, O.; Okosun, Jessica
abstract

Follicular lymphoma (FL) is a heterogeneous disease with varying prognosis owing to differences in clinical, laboratory, and disease parameters. Although generally considered incurable, prognosis for early- and advanced-stage disease has improved because of therapeutic advances, several of which have resulted from elucidation of the biologic and molecular basis of the disease. The choice of treatment for FL is highly dependent on patient and disease characteristics. Several tools are available for risk stratification, although limitations in their routine clinical use exist. For limited disease, treatment options include radiotherapy, rituximab monotherapy or combination regimens, and surveillance. Treatment of advanced disease is often determined by tumor burden, with surveillance or rituximab considered for low tumor burden and chemoimmunotherapy for high tumor burden disease. Treatment for relapsed or refractory disease is influenced by initial first-line therapy and the duration and quality of the response. Presently, there is no consensus for treatment of patients with early or multiply relapsed disease; however, numerous agents, combination regimens, and transplant options have demonstrated efficacy. Although the number of therapies available to treat FL has increased together with an improved understanding of the underlying biologic basis of disease, the best approach to select the most appropriate treatment strategy for an individual patient at a particular time continues to be elucidated. This review considers prognostication and the evolving treatment landscape of FL, including recent and emergent therapies as well as remaining unmet needs. IMPLICATIONS FOR PRACTICE: In follicular lymphoma, a personalized approach to management based on disease biology, patient characteristics, and other factors continues to emerge. However, application of current management requires an understanding of the available therapeutic options for first-line treatment and knowledge of current development in therapies for previously untreated and for relapsed or refractory disease. Thus, this work reviews for clinicians the contemporary data in follicular lymphoma, from advances in characterizing disease biology to current treatments and emerging novel therapies.

2019 - Home care of acute leukaemia patients: From active therapy to end-of-life and palliative care. The 3-year experience of a single centre [Articolo su rivista]
Capodanno, Isabella; Tamagnini, Enrica; Alfieri, Pierluigi; Codeluppi, Katia; Luminari, Stefano; Merli, Francesco
abstract

Purpose: The aim of the study was to evaluate the feasibility and the potential effects of the Haematological Home Care (HHC) programme for acute leukaemia (AL) patients, either in active chemotherapy or in the terminal phase of disease. Methods: We retrospectively assessed a group of AL patients assisted at home in terms of number of hospitalisations, accesses to emergency department and place of death. We also used historical data to evaluate potential effects of HHC. Results: The study group consisted of 44 patients, 36 of whom (82%) required palliative treatment, and eight (18%) had ongoing active chemotherapy. The mean number of hospitalisations was 0.64 (range 0-7) per patient, and the number of emergency department (ED) visits was 0.82 (range 0-4) per patient. Place of death was at home for 51.4% of patients and in hospital for 40.5%. Considering a historical group of 17 patients assisted at home the rate of hospitalisations and ED visits were 2.53 (range 0-9) and one (range 0-3), respectively. Place of death was home and hospital in 6% and 65%, respectively. Conclusions: Haematological Home Care for AL patients is feasible and has potential positive effects in terms rate of hospitalisations and place of death.

2019 - Novel prognostic tools that identify high-risk follicular lymphoma [Articolo su rivista]
Luminari, Stefano
abstract

2019 - Phase II trial to investigate efficacy and safety of bendamustine, dexamethasone and thalidomide in relapsed or refractory multiple myeloma patients after treatment with lenalidomide and bortezomib [Articolo su rivista]
Mian, Michael; Pescosta, Norbert; Badiali, Stefania; Cappelletto Paola, Cristina; Marcheselli, Luigi; Luminari, Stefano; Patriarca, Francesca; Zambello, Renato; Pascarella, Anna; Tagariello, Giuseppe; Marabese, Alessandra; Mondello, Patrizia; Billio Atto Cortelazzo, Sergio
abstract

2019 - Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada [Articolo su rivista]
Chen, Brian; Naga, Sumimasa; Armitage James, O.; Witherspoon, Bartlett; Nabhan, Chadi; Godwin Ashley, C; Yang, ; Y., Tony; Kommalapati, Anuhya; Tella, ; Sri, Harsha; Deangelis, Carlo; Raisch Dennis, W.; Sartor, Oliver; Hrushesky William, J.; Ray Paul, S.; Yarnold Paul, R.; Love, ; Bryan, L.; Norris LeAnn, B.; Knopf, Kevin; Bobolts, Laura; Riente, Joshua; Luminari, Stefano; Kane Robert, C.; Hoque, Shamia; Bennett Charles, L.
abstract

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%-40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the "rebate trap" with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. IMPLICATIONS FOR PRACTICE: We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing "rebate traps" where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

2019 - Treatment of aggressive non-Hodgkin's lymphoma in frail patients: cardiac comorbidities and advanced age [Articolo su rivista]
Lugtenburg Pieternella, J.; Lyon Alexander, R.; Marks, Reinhard; Luminari, Stefano
abstract

The decisive factor in selecting a treatment regimen for a frail patient with aggressive non-Hodgkin's lymphoma is identifying whether a patient is fit enough to tolerate curative-intent anthracycline-containing regimens or too frail and therefore at risk of being undertreated. As cardiac comorbidities are an important contributor to both the health status and the selection of treatment, cardiovascular profiling and baseline risk stratification prior to treatment should be considered. Comprehensive geriatric assessment is an efficient means of identifying elderly patients with non-Hodgkin's lymphoma who may benefit from a curative treatment approach. If anthracycline-based therapy is not suitable, alternative treatment options are available in frail patients with cardiac comorbidities, but these must be adjusted to the patient's health status to achieve a maximal benefit-risk ratio.

2018 - A B-cell receptor-related gene signature predicts survival in mantle cell lymphoma: Results from the Fondazione Italiana Linfomi MCL-0208 trial [Articolo su rivista]
Bomben, Riccardo; Ferrero, Simone; D'Agaro, Tiziana; Dal Bo, Michele; Re, Alessandro; Evangelista, Andrea; Carella Angelo, Michele; Zamo, Alberto; Vitolo, Umberto; Omede, Paola; Rusconi, Chiara; Arcaini, Luca; Rigacci, Luigi; Luminari, Stefano; Piccin, Andrea; Liu, Delong; Wiestner, Adrian; Gaidano, Gianluca; Cortelazzo, Sergio; Ladetto, Marco; Gattei, Valter
abstract

Mantle cell lymphoma patients have variable clinical courses, ranging from indolent cases that do not require immediate treatment to aggressive, rapidly progressing diseases. Thus, diagnostic tools capable of stratifying patients according to their risk of relapse and death are needed. This study included 83 samples from the Fondazione Italiana Linfomi MCL-0208 clinical trial. Through gene expression profiling and quantitative real-time PCR we analyzed 46 peripheral blood and 43 formalin-fixed paraffin-embedded lymph node samples. A prediction model to classify patients was developed. By analyzing the transcriptome of 27 peripheral blood samples, two subgroups characterized by a differential expression of genes from the B-cell receptor pathway (B-cell receptor low and B-cell receptor high ) were identified. The prediction model based on the quantitative real-time PCR values of six representative genes (AKT3, BCL2, BTK, CD79B, PIK3CD, and SYK), was used to classify the 83 cases (43 B-cell receptor low and 40 B-cell receptor high ). The B-cell receptor high signature associated with shorter progression-free survival (P=0.0074), selected the mantle cell lymphoma subgroup with the shortest progression-free survival and overall survival (P=0.0014 and P=0.029, respectively) in combination with high ( extgreater30%) Ki-67 staining, and was an independent predictor of short progression-free survival along with the Mantle Cell Lymphoma International Prognostic Index-combined score. Moreover, the clinical impact of the 6-gene signature related to the B-cell receptor pathway identified a mantle cell lymphoma subset with shorter progression-free survival intervals also in an external independent mantle cell lymphoma cohort homoge-nously treated with different schedules. In conclusion, this 6-gene signature associates with a poor clinical response in the context of the MCL-0208 clinical trial. (clinicaltrials.gov identifier: 02354313).

2018 - Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma [Articolo su rivista]
Connors, Joseph M; Jurczak, Wojciech; Straus, David J; Ansell, Stephen M; Kim, Won S; Gallamini, Andrea; Younes, Anas; Alekseev, Sergey; Illés, Árpád; Picardi, Marco; Lech-Maranda, Ewa; Oki, Yasuhiro; Feldman, Tatyana; Smolewski, Piotr; Savage, Kerry J; Bartlett, Nancy L; Walewski, Jan; Chen, Robert; Ramchandren, Radhakrishnan; Zinzani, Pier L; Cunningham, David; Rosta, Andras; Josephson, Neil C; Song, Eric; Sachs, Jessica; Liu, Rachael; Jolin, Hina A; Huebner, Dirk; Radford, John; Luminari, Stefano
abstract

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma.

2018 - Corrigendum: ESMO consensus conference on malignant lymphoma: General perspectives and recommendations for prognostic tools in mature B-cell lymphomas and chronic lymphocytic leukaemia. [Ann Oncol 27, (2016) (2149-2160)] DOI: 10.1093/annonc/mdw419 [Articolo su rivista]
Ladetto, M.; Buske, C.; Hutchings, M.; Dreyling, M.; Gaidano, G.; Le Gouill, S.; Luminari, S.; Pott, C.; Zamo, A.; Zucca, E.
abstract

Ann Oncol 2016; 27: 2149-2160 (doi:10.1093/annonc/mdw419) This paper was corrected to update author names in the appendix.

2018 - ESMO Consensus Conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma [Articolo su rivista]
Buske, C; Hutchings, M; Ladetto, M; Goede, V; Mey, U; Soubeyran, P; Spina, MARIA EMANUELA; Stauder, R; Trnený, M; Wedding, U; Fields, P; Luminari, S
abstract

The European Society for Medical Oncology (ESMO) consensus conference on mature B cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use, and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically-relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were presented to the entire panel and a consensus was reached. This consensus, which was further developed in continuous post-meeting discussions, formed the basis of three manuscripts, each covering one of the three key areas identified. This manuscript presents the consensus recommendations regarding the clinical management of elderly patients diagnosed with malignant lymphoma. Four clinically-relevant topics identified by the panel were: 1) how to define patient fitness, 2) assessing quality of life, 3) diagnostic work-up and 4) clinical management of elderly patients with lymphoma. Each of these key topics is addressed in the context of five different lymphoma entities, namely: CLL, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma and diffuse large B-cell lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript.

2018 - High-risk follicular lymphoma patients: Identification and treatment [Articolo su rivista]
Luminari, Stefano; Stefano and, Merli; Francesco,
abstract

Over the last 15 years, the outcome of patients with follicular lymphoma (FL) has dramatically improved mainly as a result of effective therapies and of a better understanding of lymphoma biology. Although progression-free survival is approximately 10 years with standard treatment and overall survival upwards of 20 years, the clinical behavior among individual patients is highly heterogenous, and a significant number of subjects have a higher and earlier risk of dying from FL within a few years from diagnosis. In this article, we provide an overview of available prognostic tools that can be used to identify high-risk patients with FL and describe which therapies are available and can be recommended for this group of hard-to-treat FL patients.

2018 - Long-Term Results of the FOLL05 Trial Comparing R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Symptomatic Follicular Lymphoma [Articolo su rivista]
Luminari, Stefano; Ferrari, Angela; Manni, Martina; Dondi, Alessandra; Chiarenza, Annalisa; Merli, Francesco; Rusconi, Chiara; Tarantino, Vittoria; Tucci, Alessandra; Vitolo, Umberto; Kovalchuk, Sofia; Angelucci, Emanuele; Pulsoni, Alessandro; Arcaini, Luca; Angrilli, Francesco; Gaidano, Gianluca; Stelitano, Caterina; Bertoldero, Giovanni; Cascavilla, Nicola; Salvi, Flavia; Ferreri, Andrés J M; Vallisa, Daniele; Marcheselli, Luigi; Federico, Massimo
abstract

Purpose The FOLL05 trial compared R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-FM (rituximab plus fludarabine and mitoxantrone) regimens without rituximab maintenance as initial therapy for patients with advanced-stage follicular lymphoma (FL). A previous analysis with a median follow-up of 34 months showed a superior 3-year time to treatment failure, the primary study end point, with R-CHOP and R-FM versus R-CVP and showed R-CHOP to have a better risk-benefit ratio in terms of toxicity than R-FM. We report a post hoc analysis of this trial after a median follow-up of 7 years. Patients and Methods Of the 534 enrolled patients, 504 were evaluable. At the time of analysis, the median follow-up was 84 months (range, 1 to 119 months). Results The 8-year time to treatment failure and progression-free survival rates were 44% (95% CI, 39% to 49%) and 48% (95% CI, 43% to 53%), respectively. The hazard ratio for progression-free survival adjusted by FL International Prognostic Index 2 versus R-CVP was 0.73 for R-CHOP (95% CI, 0.54 to 0.98; P = .037) and 0.67 for R-FM (95% CI, 0.50 to 0.91; P = .009). The 8-year overall survival (OS) rate was 83% (95% CI, 79% to 87%), with no significant differences among study arms. Overall, we observed a higher risk of dying as a result of causes unrelated to lymphoma progression with R-FM versus R-CVP. Conclusion With an 83% 8-year OS rate, long-term follow-up of the FOLL05 trial confirms the favorable outcome of patients with advanced-stage FL treated with immunochemotherapy. The three study arms had similar OS but different activity and toxicity profiles. Patients initially treated with R-CVP had a higher risk of lymphoma progression compared with those receiving R-CHOP, as well as a higher risk of requiring additional therapy.

2018 - Nonpegylated liposomal doxorubicin combination regimen in patients with diffuse large B-cell lymphoma and cardiac comorbidity. Results of the HEART01 phase II trial conducted by the Fondazione Italiana Linfomi [Articolo su rivista]
Luminari, Stefano; Viel, Elda; Ferreri, Andrés José Maria; Zaja, Francesco; Chimienti, Emanuela; Musuraca, Gerardo; Tucci, Alessandra; Balzarotti, Monica; Tani, Monica; Salvi, Francesca; Pesce, Emanuela A; Ferrari, Angela; Liberati, Anna M; Spadea, Antonio; Marino, Dario; Bruno-Ventre, Maria; Volpetti, Stefano; Bottelli, Chiara; Ravaioli, Elena; Merli, Francesco; Spina, Michele
abstract

The purpose of this phase 2, multicenter study was to determine the activity and safety of nonpegylated liposomal doxorubicin as part of "R-COMP" combination in patients with diffuse large B-cell lymphoma and coexisting cardiac disorders. The study was conducted using a Bayesian continuing assessment method using complete remission rate and rate of cardiac events as study endpoints. Between November 2009 and October 2011, 50 evaluable patients were enrolled (median age, 76 years). Median baseline left ventricular ejection fraction (LVEF) was 60%. Ischemic cardiopathy was the most frequent preexisting cardiac disorder (35%), followed by atrial fibrillation (15%), left ventricular hypertrophy (13%), and baseline LVEF <50% (12%). Based on the intent to treat analysis, overall response rate was 72%, including 28 patients in complete remission (complete remission rate, 56%), and 8 in partial remission (16%). At the end of treatment, grades 3 to 4 cardiac events were observed in 6 patients. No significant modifications from baseline values of LVEF were observed during treatment and follow-up. Nonpegylated liposomal doxorubicin instead of doxorubicin in the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is a feasible option for patients with diffuse large B-cell lymphoma presenting with concomitant cardiac disorders.

2018 - Personalised approach in follicular lymphoma [Articolo su rivista]
Luminari, Stefano
abstract

2018 - Prognostic model for high-tumor-burden follicular lymphoma integrating baseline and end-induction PET: a LYSA/FIL study [Articolo su rivista]
Cottereau, Anne Ségolène; Versari, Annibale; Luminari, Stefano; Dupuis, Jehan; Chartier, Loïc; Casasnovas, René-Olivier; Berriolo-Riedinger, Alina; Menga, Massimo; Haioun, Corinne; Tilly, Hervé; Tarantino, Vittoria; Federico, Massimo; Salles, Gilles; Trotman, Judith; Meignan, Michel
abstract

Both total metabolic tumor volume (TMTV), computed on baseline positron emission tomography (PET), and end of induction (EOI) PET are imaging biomarkers showing promise for early risk stratification in patients with high-tumor-burden follicular lymphoma. A model was built incorporating these 2 factors in 159 patients from three prospective trials: 2 Lymphoma Study Association (LYSA) studies and 1 Fondazione Italiana Linfomi (FIL) trial. Median follow up was 64 months. High TMTV (>510 cm3) and positive EOI PET were independent, significant risk factors for progression. Their combination stratified the population into 3 risk groups: patients with no risk factors (n 5 102; 64%) had a 5-year progression-free survival (PFS) of 67% vs 33% (hazard ratio [HR], 2.9; 95% confidence interval [CI], 1.8-4.9) for patients with 1 risk factor (n 5 44; 27%) and only 23% (HR, 4.6; 95% CI, 2.3-9.2) for patients with both risk factors (n 5 13; 8%). 2-year PFS was respectively 90% vs 61% (HR, 4.8; 95% CI, 2.2-10.4) and 46% (HR, 8.1; 95%CI, 3.1-21.3). This model enhances the prognostic value of PET staging and response assessment, identifying a subset of patients with a very high risk of progression and early treatment failure at 2 years. (Blood. 2018;131(22): 2449-2453)

2018 - Renewed interest for low-dose radiation therapy in follicular lymphomas: From biology to clinical applications [Articolo su rivista]
Ciammella, Patrizia; Luminari, Stefano; Arcaini, Luca; Filippi Andrea, Riccardo
abstract

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoproliferative disorders. Treatment strategies for FL may include several therapeutic choices, ranging from a “watchful waiting” approach to stem cell transplantation, mostly depending on staging, age, risk factors, and disease burden at diagnosis. The high radiosensitivity of FL compared with other solid tumors has been known since the beginning of radiotherapy treatment in lymphoma patients. Doses of 24 to 40 Gy were considered appropriate in first line curative treatment for localized disease (stages I-II), but several publications investigating low-dose radiotherapy (LDRT) of 4Gy (2 × 2Gy) reported an overall response rate surprisingly high. Due to its high local efficacy and negligible toxicity, LDRT might be offered to both early and advanced stage FL patients in combination with new agents, at diagnosis or after several lines of systemic therapy. The aim of this review is to summarize and discuss the current knowledge on LDRT for FL and its potential application in a curative setting in combination with new drugs for both early and advanced disease.

2018 - Rituximab plus bendamustine as front-line treatment in frail elderly ( extgreater70 years) patients with diffuse large b-cell non-hodgkin lymphoma: A phase ii multicenter study of the fondazione italiana linfomi [Articolo su rivista]
Storti, Sergio; Spina, Michele; Pesce, ; Emanuela, Anna; Salvi, Flavia; Merli, Michele; Ruffini, Alessia; Cabras, Giuseppina; Chiappella, Annalisa; Angelucci, Emanuele; Fabbri, Alberto; Liberati Anna, Marina; TaniM, Onica; Musuraca, Gerardo; Molinari, Annalia; Petrilli Maria, Pia; Palladino, Carmela; Ciancia, Rosanna; Ferrario, Andrea; Gasbarrino, Cristiana; Monaco, Federico; Fraticelli, Vincenzo; De Vellis, Annalisa; Merli, Francesco; Luminari, Stefano
abstract

We conducted a phase II study to assess activity and safety profile of bendamustine and rituximab in elderly patients with untreated diffuse large B-cell lymphoma (DLBCL) who were prospectively defined as frail using a simplified version of the Comprehensive Geriatric Assessment (CGA). Patients had to be over 70 years of age, with histologically confirmed DLBCL. Frail patients were those younger than 80 years with a frail profile at CGA or older than 80 years with an unfit profile. Treatment consisted of 4-6 courses of bendamustine [90 mg/m 2 days (d)1-2] and rituximab (375 mg/m 2 d1) administered every 28 days. Other main study end points were complete remission rate and the rate of extra-hematologic adverse events. Forty-nine patients were enrolled of whom 45 were confirmed eligible. Overall, 24 patients achieved a complete remission (53%; 95%CI: 38-68%) and the overall response rate was 62% (95%CI: 47-76%). The most frequent grade 3-4 adverse event was neutropenia (37.8%). Grade 3-4 extra-hematologic adverse events were observed in 7 patients (15.6%; 95%CI: 6.5-29.5%); the most frequent was grade 3 infection in 2 patients. With a median follow up of 33 months (range 1-52), the median progression-free survival was ten months (95%CI: 7-25). The study shows promising activity and manageable toxicity profile of BR combination as first-line therapy for patients with DLBCL who are prospectively defined as frail according to a simplified CGA, as adopted in this trial (clinicaltrials.gov identifier: 01990144).

2018 - The impact of introducing tyrosine kinase inhibitors on chronic myeloid leukemia survival: a population-based study [Articolo su rivista]
Di Felice, Enza; Roncaglia, Francesca; Venturelli, Francesco; Mangone, Lucia; Luminari, Stefano; Cirilli, Claudia; Carrozzi, Giuliano; Giorgi Rossi, Paolo
abstract

Background Chronic myeloid leukemia is associated with a BCR/ABL oncoprotein inhibited by imatinib mesylate, the first tyrosine kinase inhibitor. Although experimental studies have clearly demonstrated the efficacy of imatinib, up-to-date data on its effectiveness at the population level are limited. Our study aims to assess the change in disease-specific survival for chronic myeloid leukemia after introducing tyrosine kinase inhibitors in first-line treatment. Methods This study analyzed data from two population-based cancer registries in Italy. Disease-specific survival for chronic myeloid leukemia cases diagnosed before and after the introduction of tyrosine kinase inhibitors (February 2002) were calculated up to 10 years. Hazard ratios were calculated using Cox regression models adjusted for sex, age at diagnosis and residency. An interrupted time series analysis was also performed. Results Between 1996 and 2012, 357 new cases of chronic myeloid leukemia were diagnosed (standardized incidence rate of 1.2 per 100,000 residents), quite constant throughout the period. The interrupted time series analysis showed a gain of 40.4% in 5 years of disease-specific survival for chronic myeloid leukemia (from 47.3, 95%CI 38.5–55.5% to 80.8%, 95%CI 74.5–85.8%) after the introduction of tyrosine kinase inhibitors. The hazard ratio was 0.36 (95%CI 0.25–0.52) for cases diagnosed after tyrosine kinase inhibitor introduction, with differences per age at diagnosis: <65yo 0.17 (95%CI 0.08–0.39), >74yo 0.41 (95%CI 0.23–0.73). An improvement in survival (hazard ratio 0.66, 95%CI 0.36–1.20) was also observed in cases diagnosed before, and alive at, tyrosine kinase inhibitors introduction. Conclusions Tyrosine kinase inhibitors increased disease-specific survival both for new and prevalent chronic myeloid leukemia cases. The effectiveness was similar to that observed in trials only in patients ages 65 years or younger.

2018 - Transformed follicular lymphoma [Articolo su rivista]
Fischer, Thais; Zing, Natalia Pin Chuen; Chiattone, Carlos Sergio; Federico, Massimo; Luminari, Stefano
abstract

Follicular Lymphoma (FL) is the second most common type of non-Hodgkin lymphoma and is considered to be the prototype of indolent lymphomas. Histologic transformation into an aggressive lymphoma, which is expected to occur at a rate of 2 to 3% each year, is associated with rapid progression, treatment resistance, and poor prognosis. Recent modifications to the physiopathologic mechanism of transformed follicular lymphoma (t-FL) have been proposed, including genetic and epigenetic mechanisms as well as a role for the microenvironment. Although t-FL is considered a devastating complication, as it is associated with treatment-refractory disease and a dismal outcome, recent data in the rituximab era have suggested that not only is the prognosis less severe than reported in the previous literature but the risk of transformation is also lower. Thus, this study aimed to review the most recent research on t-FL in an attempt to better understand the clinical meaning of transformation from FL to diffuse large B cell lymphoma (DLBCL) and the impact of current treatment strategies on the curability of this intriguing subentity of lymphoma.

2017 - Durable remission in a patient with leptomeningeal relapse of a MYC/BCL6-positive double-hit DLBCL treated with lenalidomide monotherapy [Articolo su rivista]
Salati, Massimiliano; Tarantino, Vittoria; Maiorana, Antonino; Bettelli, Stefania Raffaella; Luminari, Stefano
abstract

Secondary central nervous system involvement is an uncommon event that typically occurs early in the natural history of diffuse large B-cell lymphoma and presents as leptomeningeal dissemination in two-thirds of cases. The prognosis of this event is dismal, and treatment options are meagre. Although major validated risk factors for central nervous system dissemination are clinical, concomitant MYC/BCL2 rearrangements as well as MYC/BCL2 protein expression have been recently associated with an increased risk of this complication. Here we present the first case, to our knowledge, of a MYC/BCL6-positive double-hit diffuse large B-cell lymphoma relapsing in the leptomeninges that achieved an outstanding durable remission with single-agent lenalidomide following salvage chemotherapy.

2017 - Khorana score and histotype predicts incidence of early venous thromboembolism in Non-Hodgkin lymphomas: A Pooled-Data analysis of 12 clinical trials of fondazione italiana linfomi (FIL) [Articolo su rivista]
Santi, Roberto Mario; Ceccarelli, Manuela; Bernocco, Elisa; Monagheddu, Chiara; Evangelista, Andrea; Valeri, Federica; Monaco, Federico; Vitolo, Umberto; Cortelazzo, Sergio; Cabras, Maria Giuseppina; Spina, Michele; Baldini, Luca; Boccomini, Carola; Chiappella, Annalisa; Bari, Alessia; Luminari, Stefano; Visco, Carlo; Calabrese, Marco; Limberti, Giulia; Levis, Alessandro; Contino, Laura; Ciccone, Giovannino; Ladetto, Marco
abstract

Current data suggests that the risk of venous thromboembolism (VTE) in patients with non-Hodgkin lymphoma (NHL) is comparable to that observed in patients with solid tumours, although more robust confirmatory analyses are required. With that in mind, we investigated the occurrence of VTE in a pooled analysis of 12 âFondazione Italiana Linfomiâ (FIL) prospective clinical studies. Specifically, we wished to assess the cumulative incidence of VTE in NHL patients, evaluate the predictive value of the Khorana Score (KS), and identify other potential risk factors for VTEs. Data for VTE occurrence were retrieved from study databases and pharmacovigilance reports. Our analysis includes 1717 patients from 12 prospective phase II and III trials, including newly diagnosed NHL. We observed 53 VTEs (any grade) in 46 patients, with 20 severe VTEs in 17 patients. The cumulative incidences for âall-gradeâ or grade â¥3 VTEs were 2.9 % (95 % CI: 2.1-3.8) and 1.1 % (95 % CI: 0.6-1.6), respectively. KS categories were positively associated with the risk of VTE of any grade, and with severe events (i. e. grade â¥3; Grayâs test p-values = 0.048 and 0.012, respectively). Among NHL patients, those with diffuse large B-cell lymphoma (DLBCL) showed a greater risk of (any grade) VTE (HR: 3.42, 95 % CI: 1.32-8.84, p-value = 0.011). Our study indicates that 1) VTE is a relevant complication for NHL patients, 2) KS is predictive of VTE events and 3) DLBCL histotype is an independent risk factor for VTE incidence, for which preventative interventions could be considered.

2017 - Prognostic value of bone marrow tracer uptake pattern in baseline PET scans in hodgkin lymphoma: Results from an international collaborative study [Articolo su rivista]
Zwarthoed, Colette; El-Galaly, Tarec Cristoffer; Canepari, Maria; Ouvrier, Matthieu John; Viotti, Julien; Ettaiche, Marc; Viviani, Simonetta; Rigacci, Luigi; Trentin, Livio; Rusconi, Chiara; Luminari, Stefano; Cantonetti, Maria; Bolis, Silvia; Borra, Anna; Darcourt, Jacques; Salvi, Flavia; Subocz, Edyta; Tajer, Joanna; Kulikowski, Waldemar; Malkowski, Bogdan; Zaucha, Jan Maciej; Gallamini, Andrea
abstract

PET/CT-ascertained bone marrow involvement (BMI) constitutes the single most important reason for upstaging by PET/CT in Hodgkin lymphoma (HL). However, BMI assessment in PET/CT can be challenging. This study analyzed the clinicopathologic correlations and prognostic meaning of Different patterns of bone marrow (BM)18F-FDG uptake in HL. Methods: One hundred eighty newly Diagnosed early unfavorable and advanced-stage HL patients, all scanned at baseline and after 2 adriamycin-bleomycinvinblastine-dacarbazine (ABVD) courses with18F-FDG PET, enrolled in 2 international stuDies aimed at assessing the role of interim PET scanning in HL, were retrospectively included. Patients were treated with ABVD 4-6 cycles and involved-field raDiation when needed, and no treatment adaptation on interim PET scanning was allowed. Two masked reviewers independently reported the scans. Results: Thirty-eight patients (21.1%) had focal lesions (fPET1), 10 of them with a single (unifocal) and 28 with multiple (multifocal) BM lesions. Fifty-three patients (29.4%) had pure strong (.liver) Diffuse uptake (dPET1) and 89 (48.4%) showed no or faint (#liver) BM uptake (nPET1). BM biopsy was positive in 6 of 38 patients (15.7%) for fPET1, in 1 of 53 (1.9%) for dPET1, and in 5 of 89 (5.6%) for nPET1. dPET1 was correlated with younger age, higher frequency of bulky Disease, lower hemoglobin levels, higher leukocyte counts, and similar Diffuse uptake in the spleen. Patients with pure dPET1 had a 3-y progression-free survival identical to patients without any18F-FDG uptake (82.9% and 82.2%, respectively, P 5 0.918). However, patients with fPET1 (either unifocal or multifocal) had a 3-y progressionfree survival significantly inferior to patients with dPET1 and nPET1 (66.7% and 82.5%, respectively, P 5 0.03). The k values for interobserver agreement were 0.84 for focal uptake and 0.78 for Diffuse uptake. Conclusion: We confirmed that18F-FDG PET scanning is a reliable tool for BMI assessment in HL, and BM biopsy is no longer needed for routine staging. Moreover, the interobserver agreement for BMI in this study proved excellent and only focal18F-FDG BM uptake should be considered as a harbinger of HL.

2017 - Reply to H.J.A. Adams et al and E. Laffon et al [Articolo su rivista]
Meignan, Michel; Cottereau, Anne Ségolène; Versari, Annibale; Chartier, Loïc; Dupuis, Jehan; Boussetta, Sami; Grassi, Ilaria; Casasnovas, René Olivier; Haioun, Corinne; Tilly, Hervé; Tarantino, Vittoria; Dubreuil, Julien; Federico, Massimo; Salles, Gilles; Luminari, Stefano; Trotman, Judith
abstract

not available

2017 - Report of the 6th International Workshop on PET in lymphoma [Articolo su rivista]
Nanni, Cristina; Cottereau, Anne Ségolène; Lopci, Egesta; Bodet-Milin, Caroline; Coronado, Monica; Pro, Barbara; Kim, Wong Seog; Trotman, Judith; Barrington, Sally; Duhrsen, Ulrich; Vander Borght, Thierry; Zamagni, Elena; Kraeber-Bodéré, Françoise; Messiou, Christina; Rahmouni, Alain; Buvat, Irène; Andre, Marc; Hertzberg, Mark; Oyen, Wim; Casasnovas, Olivier; Luminari, Stefano; Garderet, Laurent; Montravers, Françoise; Kobe, Carsten; Kluge, Regine; Versari, Annibale; Zucca, Emanuele; Moreau, Philippe; Cheson, Bruce; Haioun, Corinne; Gallamini, Andrea; Meignan, Michel
abstract

Two hundred and ten nuclear medicine physicians, radiologists, and hematologists from 26 countries attended the 6th International Workshop on Positron Emission Tomography (PET) in Lymphoma and Myeloma held in Menton, France, in September 2016. The meeting was under the auspices of the European Lymphoma Institute (ELI), the European Association of Nuclear Medicine (EANM) the Lymphoma Study Association (LYSA), the Italian Foundation on Lymphoma (FIL) and the Carnot Institute for Lymphoma (CALYM). Forty scientific posters were presented. For the first time, specialists in the field of multiple myeloma (MM) were involved in the expert session. The aim was to establish from the experience of Italian and French studies new guidelines of FDG-PET/CT reporting for myeloma staging and restaging. The meeting dedicated an entire session to MM imaging followed by a session on the role of PET in Peripheral T cell Lymphoma. An entire session addressed the issues of Deauville scale particularly for end treatment assessment and the challenging consequences of immunomodulatory treatments on PET reporting. A specific session presented the potential role of baseline metabolic tumor measurement to predict outcome and identify different risk categories and the main results obtained in different lymphoma entities were described. Whether it could replace clinical staging has been extensively discussed. The more recent results obtained in the H10 trial have been presented and compared to the published data in early stage Hodgkin lymphoma. Finally, the ongoing studies using PET for guiding therapeutic strategies have been reported by the various lymphoma cooperative groups that participated to the meeting.

2017 - Salvage chemotherapy and autologous stem cell transplantation for peripheral T-cell lymphoma: a subset analysis of the Canadian Cancer Trials Group LY.12 randomized phase 3 study* [Articolo su rivista]
Skamene, Tanya; Crump, Michael; Savage, Kerry J.; Reiman, Tony; Kuruvilla, John; Good, David; Lebrun, David; Meyer, Ralph M.; Sehn, Laurie H.; Soulières, Denis; Stakiw, Julie; Laferriere, Nicole; Luminari, Stefano; Shepherd, Lois E.; Djurfeldt, Marina; Zhu, Liting; Chen, Bingshu E.; Hay, Annette E.
abstract

Peripheral T-cell lymphoma (PTCL) is a rare, heterogeneous malignancy. Of the 619 patients with relapsed and refractory (R/R) aggressive lymphoma enrolled in the Canadian Cancer Trials Group LY.12 phase 3 trial, 59 (9.5%) had PTCL. Among these, 81% had advanced stage disease, 41% had an International Prognostic Score â¥3, and 41% were refractory to primary therapy. Within the PTCL cohort, the overall response rate after two cycles of salvage chemotherapy was 36%; no difference was observed between dexamethasone, cytarabine, cisplatin (10/30, 33%), and gemcitabine, cisplatin, dexamethasone (11/29, 38%) therapy. At one year, event-free survival (EFS) was 16% and overall survival (OS) was 28%. For PTCL patients, who received autologous stem cell transplant, two-year EFS and OS were 21% and 42%, respectively. Patients with PTCL had inferior OS (HR 0.49, p <.0001) and EFS (HR 0.53, p <.0001) compared to B-cell lymphoma. Outcomes for patients with R/R PTCL are poor with currently available therapies.

2017 - Secondary malignant neoplasms, progression-free survival and overall survival in patients treated for Hodgkin lymphoma: A systematic review and meta-analysis of randomized clinical trials [Articolo su rivista]
Eichenauer, Dennis A.; Becker, Ingrid; Monsef, Ina; Chadwick, Nicholas; De Sanctis, Vitaliana; Federico, Massimo; Fortpied, Catherine; Gianni, Alessandro M.; Henry-Amar, Michel; Hoskin, Peter; Johnson, Peter; Luminari, Stefano; Bellei, Monica; Pulsoni, Alessandro; Sydes, Matthew R.; Valagussa, Pinuccia; Viviani, Simonetta; Engert, Andreas; Franklin, Jeremy
abstract

Treatment intensification to maximize disease control and reduced intensity approaches to minimize the risk of late sequelae have been evaluated in newly diagnosed Hodgkin lymphoma. The influence of these interventions on the risk of secondary malignant neoplasms, progression-free survival and overall survival is reported in the meta-analysis herein, based on individual patient data from 9498 patients treated within 16 randomized controlled trials for newly diagnosed Hodgkin lymphoma between 1984 and 2007. Secondary malignant neoplasms were meta-analyzed using Petoâs method as time-to-event outcomes. For progression-free and overall survival, hazard ratios derived from each trial using Cox regression were combined by inverse-variance weighting. Five study questions (combined-modality treatment vs. chemotherapy alone; more extended vs. involved-field radiotherapy; radiation at higher doses vs. radiation at 20 Gy; more vs. fewer cycles of the same chemotherapy protocol; standard-dose chemotherapy vs. intensified chemotherapy) were investigated. After a median follow-up of 7.4 years, dose-intensified chemotherapy resulted in better progression-free survival rates (P=0.007) as compared with standard-dose chemotherapy, but was associated with an increased risk of therapy-related acute myeloid leukemia/myelodysplastic syndromes (P=0.0028). No progression-free or overall survival differences were observed between combined-modality treatment and chemotherapy alone, but more secondary malignant neoplasms were seen after combined-modality treatment (P=0.010). For the remaining three study questions, outcomes and secondary malignancy rates did not differ significantly between treatment strategies. The results of this meta-analysis help to weigh up efficacy and secondary malignancy risk for the choice of first-line treatment for Hodgkin lymphoma patients. However, final conclusions regarding secondary solid tumors require longer follow-up.

2017 - Survival of cancer patients in Italy [La sopravvivenza dei pazienti oncologici in Italia [La sopravvivenza dei pazienti oncologici in Italia] [Articolo su rivista]
Coviello, V; Buzzoni, C; Fusco, M; Barchielli, A; Cuccaro, F; De Angelis, R; Giacomin, A; Luminari, S; Randi, G; Mangone, L; AIRTUM Working, Group
abstract

Population-based survival statistics are fundamental to assess the efficacy of services offered to improve cancer patients' prognosis. This study aims to update cancer survival estimates for the Italian population, as well as provide new measures, such as the crude probability of death, which takes into account the possibility of dying from causes other than cancer, and the change in life expectancy after a cancer diagnosis, to properly address various questions.

2016 - A Phase II study of Bendamustine in Combination With Rituximab as Initial Treatment for Patients With Indolent non-follicular non-Hodgkin's Lymphoma [Articolo su rivista]
Luminari, Stefano; Goldaniga, Maria; Cesaretti, Marina; Orsucci, Lorella; Tucci, Alessandra; Pulsoni, Alessandro; Salvi, Flavia; Arcaini, Luca; Carella, Angelo Michele; Tedeschi, Alessandra; Pinto, Antonello; Stelitano, Caterina; Baldini, Luca
abstract

The purpose of this phase 2 study was to determine the activity and safety of 6 cycles of bendamustine and 8 rituximab (RB) as first-line treatment of adult patients with advanced stage non-follicular indolent non-Hodgkin lymphomas (INFL). The primary endpoint was the complete response rate (CRR) with expected CRR of 75%. Sixty-nine patients were enrolled; median age was 65 years (45-75), 65% were male, 93% of patients had stage IV disease. Complete and overall response rates were 48% (95% IC 35.6-60.2), and 86% (IC 75.0-92.8). The most common grade 3/4 adverse events were neutropenia (43%), thrombocytopenia (7%), anemia (4%); whereas the rate of febrile neutropenia was very low (3%). At a median follow up of 22 months (1-43 months), 2-year progression free survival was 89% (IC: 79-95), and 2-year overall survival was 96% (IC: 87-99). RB combination is active and well tolerated in patients with advanced stage previously untreated INFL.

2016 - Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma [Articolo su rivista]
Johnson, Peter; Federico, Massimo; Kirkwood, Amy; Fosså, Alexander; Berkahn, Leanne; Carella, Angelo; D'Amore, Francesco; Enblad, Gunilla; Franceschetto, Antonella; Fulham, Michael; Luminari, Stefano; O'Doherty, Michael; Patrick, Pip; Roberts, Thomas; Sidra, Gamal; Stevens, Lindsey; Smith, Paul; Trotman, Judith; Viney, Zaid; Radford, John; Barrington, Sally
abstract

BACKGROUND: We tested interim positron-emission tomography-computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkin's lymphoma. METHODS: Patients with newly diagnosed advanced classic Hodgkin's lymphoma underwent a baseline PETCT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points. RESULTS: A total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, -3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkin's lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%. CONCLUSIONS: Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy.

2016 - Age-adjusted international prognostic index is a predictor of survival in gastric diffuse B-cell non-Hodgkin lymphoma patients [Articolo su rivista]
Delamain, Marcia Torresan; da Silva, Maria Gomes; Miranda, Eliana Cristina Martins; Desterro, Joana; Luminari, Stefano; Fedina, Anna; Merli, Francesco; Chiattone, Carlos Sergio; Pagnano, Katia Borgia Barbosa; Federico, Massimo; de Souza, Carmino Antonio
abstract

Background The clinical course of gastric lymphoma is heterogeneous and clinical symptoms and some factors have been related to prognosis. Objective The present study aims to identify prognostic factors in gastric diffuse B-cell non-Hodgkin lymphoma diagnosed and treated in different countries. Methods A consecutive series of gastric diffuse B-cell non-Hodgkin lymphoma patients diagnosed and treated in Brazil, Portugal and Italy, between February 2008 and December 2014 was evaluated. Results Of 104 patients, 57 were female and the median age was 69 years (range: 28â88). The distribution of the age-adjusted international prognostic index was 12/95 (13%) high risk, 20/95 (21%) high-intermediate risk and 63/95 (66%) low/low-intermediate risk. Symptoms included abdominal pain (63/74), weight loss (57/73), dysphagia (37/72) and nausea/vomiting (37/72). Bulky disease was found in 24% of the cases, anemia in 33 of 76 patients and bleeding in 22 of 72 patients. The median follow-up time was 25 months (range: 1â77 months), with 1- and 5-year survival rates of 79% and 76%, respectively. The multivariate Cox Regression identified the age-adjusted international prognostic index as a predictor of death (hazard risk: 3.62; 95% confidence interval: 2.21â5.93; p-value <0.0001). Conclusions This series identified the age-adjusted international prognostic index as predictive of mortality in patients treated with conventional immunochemotherapy.

2016 - Baseline Metabolic Tumor Volume Predicts Outcome in High-Tumor-Burden Follicular Lymphoma: A Pooled Analysis of Three Multicenter Studies [Articolo su rivista]
Meignan, Michel; Cottereau, Anne Ségolène; Versari, Annibale; Chartier, Loïc; Dupuis, Jehan; Boussetta, Sami; Grassi, Ilaria; Casasnovas, René Olivier; Haioun, Corinne; Tilly, Hervé; Tarantino, Vittoria; Dubreuil, Julien; Federico, Massimo; Salles, Gilles; Luminari, Stefano; Trotman, Judith
abstract

Identifying patients at high risk of progression and early death among those with high-tumor-burden follicular lymphoma (FL) is unsatisfactory with current prognostic models. This study aimed to determine the prognostic impact of the total metabolic tumor volume (TMTV) measured at baseline with [(18)F]fluorodeoxyglucose/positron emission tomography-computed tomography ([(18)F]FDG/PET-CT) scans and its added value to these models.

2016 - Bendamustine in combination with gemcitabine and vinorelbine is an effective regimen as induction chemotherapy before autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma: Final results of a multicenter phase II study [Articolo su rivista]
Santoro, Armando; Mazza, Rita; Pulsoni, Alessandro; Re, Alessandro; Bonfichi, Maurizio; Zilioli, Vittorio Ruggero; Salvi, Flavia; Merli, Francesco; Anastasia, Antonella; Luminari, Stefano; Annechini, Giorgia; Gotti, Manuel; Peli, Annalisa; Liberati, Anna Marina; Di Renzo, Nicola; Castagna, Luca; Giordano, Laura; Carlo Stella, Carmelo
abstract

Purpose: This multicenter, open-label, phase II study evaluated the combination of bendamustine, gemcitabine, and vinorelbine (BeGEV) as induction therapy before autologous stem-cell transplantation (ASCT) in patients with relapsed or refractory Hodgkin lymphoma (HL). Patients and Methods: Patients with HL who were refractory to or had relapsed after one previous chemotherapy line were eligible. The primary end point was complete response (CR) rate after four cycles of therapy. Secondary end points were: overall response rate, stem-cell mobilization activity, and toxicity. Progression-free and overall survival were also evaluated. Results: In total, 59 patients were enrolled. After four cycles of therapy, 43 patients (73%) achieved CR, and six (10%) achieved partial response, for an overall response rate of 83%. The most common grade 3 to 4 nonhematologic toxicities included febrile neutropenia (n = 7) and infection (n = 4). Regarding hematologic toxicities, grade 3 to 4 thrombocytopenia and neutropenia were each experienced by eight patients (13.5%). CD34+ cells were successfully harvested in 55 of 57 evaluable patients, and 43 of 49 responding patients underwent ASCT. With a median follow-up of 29 months, the 2-year progression-free and overall survival rates for the total population were 62.2% and 77.6%, respectively. The same figures for patients undergoing autograft were 80.8% and 89.3%, respectively. Conclusion: This phase II study demonstrates that BeGEV is an effective salvage regimen able to induce CR in a high proportion of patients with relapsed or refractory HL before ASCT. These data provide a strong rationale for further development of the BeGEV regimen.

2016 - Brentuximab vedotin followed by ABVD +/- radiotherapy in patients with previously untreated Hodgkin lymphoma: final results of a pilot phase II study [Articolo su rivista]
Federico, Massimo; Luminari, Stefano; Pellegrini, Cinzia; Merli, Francesco; Pesce, Emanuela Anna; Chauvie, Stephane; Gandolfi, Letizia; Capodanno, Isabella; Salati, Massimiliano; Argnani, Lisa; Zinzani, Pier Luigi
abstract

N/A

2016 - ESMO consensus conference on malignant lymphoma: general perspectives and recommendations for prognostic tools in mature B-cell lymphomas and chronic lymphocytic leukaemia [Articolo su rivista]
Ladetto, M; Buske, C; Hutchings, M; Dreyling, M; Gaidano, G; Le Gouill, S; Luminari, Stefano; Pott, C; Zamò, A; Zucca, E.
abstract

The European Society for Medical Oncology (ESMO) consensus conference on mature B-cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (i) the elderly patient, (ii) prognostic factors suitable for clinical use and (iii) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address four clinically relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were then presented to the entire panel and a consensus was reached. This manuscript presents recommendations dedicated to the second area of interest, i.e. prognostic factors suitable for clinical use. The four topics [i.e. interim positron emission tomography (PET), TP53 mutations, cell of origin (COO) and minimal residual disease (MRD)] were primarily chosen because of the bulk of available data together with the lack of clear guidance regarding their use in clinical practice and within clinical trials. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript. The panel acknowledged that detection of TP53 inactivation by deletion or mutation in CLL should be implemented in clinical practice (level of evidence I, strength of recommendation A). Due to their potentially high prognostic value, at least in some lymphoma entities, implementation of interim PET, COO and MRD was highly recommended in the context of clinical trials. All expert panel members approved this final article.

2016 - Khorana score and histotype predict the incidence of early venous thromboembolism (VTE) in Non Hodgkin Lymphoma (NHL). A pooled data analysis of twelve clinical trials of Fondazione Italiana Linfomi (FIL) [Abstract in Rivista]
Santi, R. M; Ceccarelli, M; Catania, G; Monagheddu, C; Evangelista, A; Bernocco, E; Monaco, F; Federico, Massimo; Vitolo, U; Cortelazzo, S; Cabras, M. G; Spina, M; Baldini, L; Boccomini, C; Chiappella, A; Bari, Alessia; Luminari, Stefano; Calabrese, M; Levis, A; Visco, C; Contino, L; Ciccone, G; Ladetto, M.
abstract

Recent studies show that the risk of VTE in NHL pts is similar to that observed in high risk solid tumors (i.e. pancreatic, ovarian cancer). VTE in NHL occurs in most cases within three months from diagnosis and can have substantial impact on treatment delivery and outcome as well as on quality of life. However few data are available on potential predictors.

2016 - Long-term results of the HD2000 trial comparing ABVD versus BEACOPP versus COPP-EBV-CAD in untreated patients with advanced hodgkin lymphoma: A study by fondazione Italiana Linfomi [Articolo su rivista]
Merli, Francesco; Luminari, Stefano; Gobbi, Paolo G.; Cascavilla, Nicola; Mammi, Caterina; Ilariucci, Fiorella; Stelitano, Caterina; Musso, Maurizio; Baldini, Luca; Galimberti, Sara; Angrilli, Francesco; Polimeno, Giuseppe; Scalzulli, Potito Rosario; Ferrari, Angela; Marcheselli, Luigi; Federico, Massimo
abstract

Purpose The randomized HD2000 trial compared six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), four escalated plus two standard cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), and six cycles of COPPEBV- CAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin; CEC) in patients with advanced-stage Hodgkin lymphoma. After a median follow-up of 42 months, patients who received BEACOPP were reported to have experienced better progression-free survival (PFS) but not better overall survival (OS) results than those receiving ABVD. Wehere report a post hoc analysis of this trial after a median follow-up of 10 years. Patients and Methods Three hundred seven patients were enrolled, 295 of whom were evaluable. At the time of our analysis, the median follow-up for the entire group was 120 months (range, 4 to 169 months). Results The 10-year PFS results for the ABVD, BEACOPP, and CEC arms were 69%, 75%, and 76%, respectively; corresponding OS results were 85%, 84%, and 86%. Overall, 13 second malignancies were reported: one in the ABVD arm and six each in the BEACOPP and CEC arms. The cumulative risk of developing secondmalignancies at 10 years was 0.9%, 6.6%, and 6% with ABVD, BEACOPP, and CEC, respectively; the risk with either BEACOPP or CEC was significantly higher than that reported with ABVD (P = .027 and .02, respectively). Conclusion With these mature results, we confirm that patients with advanced Hodgkin lymphoma have similar OS results when treated with ABVD, BEACOPP, or CEC. However, with longer follow-up, we were not able to confirm the superiority of BEACOPP over ABVD in terms of PFS, mainly because of higher mortality rates resulting from second malignancies observed after treatment with BEACOPP and CEC.

2016 - PET-CT for staging and early response: Results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study [Articolo su rivista]
Barrington, Sally F; Kirkwood, Amy A.; Franceschetto, Antonella; Fulham, Michael J.; Roberts, Thomas H.; Almquist, Helén; Brun, Eva; Hjorthaug, Karin; Viney, Zaid N.; Pike, Lucy C.; Federico, Massimo; Luminari, Stefano; Radford, John; Trotman, Judith; Fosså, Alexander; Berkahn, Leanne; Molin, Daniel; D'Amore, Francesco; Sinclair, Donald A.; Smith, Paul; O'Doherty, Michael J.; Stevens, Lindsey; Johnson, Peter W.
abstract

International guidelines recommend that positron emission tomography-computed tomography (PET-CT) should replace CT in Hodgkin lymphoma (HL). The aims of this study were to compare PET-CT with CT for staging and measure agreement between expert and local readers, using a 5-point scale (Deauville criteria), to adapt treatment in a clinical trial: Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL). Patients were staged using clinical assessment, CT, and bone marrow biopsy (RATHL stage). PET-CT was performed at baseline (PET0) and after 2 chemotherapy cycles (PET2) in a response-adapted design.PET-CTwasreported centrally by experts at 5 national core laboratories. Local readers optionally scored PET2scans. TheRATHLand PET-CT stages were compared. Agreement among experts and between expert and local readers was measured. RATHL and PET0 stage were concordant in 938 (80%) patients. PET-CT upstaged 159 (14%) and downstaged 74 (6%) patients. Upstaging by extranodal disease in bone marrow (92), lung (11), or multiple sites (12) on PET-CT accounted for most discrepancies. Follow-up of discrepant findings confirmed the PET characterization of lesions in the vast majority. Five patients were upstaged by marrow biopsy and 7 by contrast-enhanced CT in the bowel and/or liver or spleen. PET2 agreement among experts (140 scans) with a k (95% confidence interval) of 0.84 (0.76-0.91) was very good and between experts and local readers (300 scans) at 0.77 (0.68-0.86) was good. These results confirm PET-CT as the modern standard for staging HL and that response assessment using Deauville criteria is robust, enabling translation of RATHL results into clinical practice.

2016 - Positron emission tomography response and minimal residual disease impact on progression-free survival in patients with follicular lymphoma. A subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi [Articolo su rivista]
Luminari, Stefano; Galimberti, Sara; Versari, Annibale; Biasoli, Irene; Anastasia, Antonella; Rusconi, Chiara; Ferrari, Angela; Petrini, Mario; Manni, Martina; Federico, Massimo
abstract

The aim of the present study was to analyze the prognostic role of combined PET and BCL2/IGH analysis, performed at the EOT, in a subset study of the phase III trial FOLL05 (NCT00774826), in which patients with FL were randomized to R-CVP (rituximab plus cyclophosphamide, vincristine and prednisone), R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) or R-FM (rituximab plus fludarabine and mitoxantrone).6 This study was conducted in compliance with the Declaration of Helsinki, was approved by the appropriate research ethics committee, and required each patient to provide written informed consent.

2016 - Reply to T.P. Vassilakopoulos et al [Articolo su rivista]
Merli, Francesco; Federico, Massimo; Luminari, Stefano
abstract

Lettera di risposta all'articolo "Long-term results of the HD2000 trial comparing ABVD versus BEACOPP versus COPP-EBV-CAD in untreated patients with advanced hodgkin lymphoma: A study by fondazione Italiana Linfomi" pubblicato sulla medesima rivista

2016 - The 68Ge phantom-based FDG-PET site qualification program for clinical trials adopted by FIL (Italian Foundation on Lymphoma) [Articolo su rivista]
Chauvie, Stephane; Bergesio, Fabrizio; Fioroni, Federica; Brambilla, Marco; Biggi, Alberto; Versari, Annibale; Guerra, Luca; Storto, Giovanni; Musto, Pellegrino; Luminari, Stefano; Cabras, Maria G.; Balzarotti, Monica; Rigacci, Luigi; Martelli, Maurizio; Vitolo, Umberto; Federico, Massimo; Gallamini, Andrea
abstract

Purpose: The quantitative assessment of Positron Emission Tomography (PET) scans using standardized uptake value and derived parameters proved to be superior to traditional qualitative assessment in several retrospective or mono-centric prospective reports. Since different scanners give different quantitative readings, a program for clinical trial qualification (CTQ) is mandatory to guarantee a reliable and reproducible use of quantitative PET in prospective multi-centre clinical trials and in every-day clinical life. Methods: We set up, under the auspices of Italian Foundation on Lymphoma (FIL), a CTQ program consisting of the PET/CT scan acquisition and analysis of 18F and 68Ge NEMA/IEC image quality phantoms for the reduction of inter-scanner variability. Variability was estimated on background activity concentration (BAC) and sphere to background ratio (SBR). Results: The use of a 68Ge phantom allowed reducing the inter-scanner variability among different scanners from 74.0% to 20.5% in BAC and from 63.3% to 17.4% in SBR compared to using the 18F phantom. The CTQ criteria were fulfilled at first round in 100% and 28% of PET scanners with 68Ge and 18F respectively. Conclusions: The 68Ge phantom proved a reliable tool for PET scanner qualification, able to significantly reduce the potential sources of error while increasing the reproducibility of PET derived quantitative parameter measurement.

2016 - Veno-occlusive disease nurse management: Development of a dynamic monitoring tool by the GITMO nursing group [Articolo su rivista]
Botti, Stefano; Orlando, Laura; Gargiulo, Gianpaolo; De Cecco, Valentina; Banfi, Marina; Duranti, Lorenzo; Samarani, Emanuela; Netti, Maria Giovanna; Deiana, Marco; Galuppini, Vera; Pignatelli, Adriana Concetta; Ceresoli, Rosanna; Vedovetto, Alessio; Rostagno, Elena; Bambaci, Marilena; Dellaversana, Cristina; Luminari, Stefano; Bonifazi, Francesca
abstract

Veno-occlusive disease (VOD) is a complication arising from the toxicity of conditioning regimens that have a significant impact on the survival of patients who undergo stem cell transplantation. There are several known risk factors for developing VOD and their assessment before the start of conditioning regimens could improve the quality of care. Equally important are early identification of signs and symptoms ascribable to VOD, rapid diagnosis, and timely adjustment of support therapy and treatment. Nurses have a fundamental role at the stages of assessment and monitoring for signs and symptoms; therefore, they should have documented skills and training. The literature defines nurses' areas of competence in managing VOD, but in the actual clinical practice, this is not so clear. Moreover, there is an intrinsic difficulty in managing VOD due to its rapid and often dramatic evolution, together with a lack of care tools to guide nurses. Through a complex evidence-based process, the Gruppo Italiano per il Trapianto di Midollo Osseo (GITMO), cellule staminali emopoietiche e terapia cellulare nursing board has developed an operational flowchart and a dynamic monitoring tool applicable to haematopoietic stem cell transplantation patients, whether they develop this complication or not.

2015 - AIRTUM e SIE insieme per una definizione condivisa dei tumori emolinfopoietici [AIRTUM and SIE for a shared definition of haemolymphopoietic cancers] [Articolo su rivista]
Torrisi, Antonina; Castaing, Marine; Giacomin, Adriano; Luminari, Stefano; Mangone, Lucia
abstract

N/A

2015 - Dismal outcome of t-cell lymphoma patients failing first-line treatment: results of a population-based study from the Modena Cancer Registry [Articolo su rivista]
Biasoli, Irene; Cesaretti, Marina; Bellei, Monica; Maiorana, Antonino; Bonacorsi, Goretta; Quaresima, Micol; Salati, Massimiliano; Federico, Massimo; Luminari, Stefano
abstract

We conducted a population-based study to establish the outcome of T-cell lymphoma (TCL) patients failing systemic first-line therapy. All TCL patients failing first-line systemic therapy in the province of Modena were identified from Modena Cancer Registry between 1997 and 2010. A total of 53 patients were analysed. Regarding the type of failure, 18 patients relapsed, and 35 progressed during first treatment. Among relapsed patients, the median time from date of response to relapse after first treatment was 6.2 months (range 1.87-102). A total of 18 patients (34%) died before receiving salvage treatment, 21 received platinum or gemcitabine-containing regimens (7 addressed to autologous stem cell transplant (ASCT)), 12 other CT regimens; 2 received radiotherapy (RT). The median survival after relapse (SAR) was 2.5 months. After a median follow-up for living patients after failure of 35 months (range 8-111 months), 44 patients died, and the cause of death was found to be lymphoma progression in all (98%) but one of them. The median SAR was 2.5 months. The 3-year SAR was 19%. Univariate and multivariate Cox regression analyses for SAR were performed. In multivariate analysis, performance status and type of failure were associated with a higher risk of death after relapse. The outcome of TCL patients failing first-line therapy is poor. Only a few cases that could receive ASCT had promising chances of long remission. There is urgent need for novel agents for patients requiring second-line treatment. Copyright © 2014 John Wiley & Sons, Ltd.

2015 - FDG-PET(CT)-adapted trials in non-Hodgkin lymphoma [Articolo su rivista]
Luminari, Stefano; Ceriani, Luca; Dührsen, Ulrich
abstract

18-F-fluorodeoxyglucose (FDG)-positron emission tomography (PET), is identified as a strong diagnostic and prognostic tool in patients with diffuse large B cell lymphomas (DLBCL), primary mediastinal B cell lymphomas and follicular lymphomas (FL), and its routine use has been recommended in the recently updated criteria for staging and response assessment in lymphomas. Evidences on the role of FDG-PET in foreseeing the outcome of patients with aggressive, and lately FL, have paved the way for several prospective trials that are underway to evaluate either escalation or de-escalation approaches based on the results of both interim and end-of-treatment FDG-PET. These trials are trying to answer important questions that represent real challenges for the management of patients with non-Hodgkin lymphomas. These range from the utility of radiotherapy after induction immunochemotherapy (ICT) in patients with residual masses, to the need and modality for treatment intensification in high-risk patients with DLBCL, to the real need of maintenance therapy in patients with FL responding to initial ICT.

2015 - Positron emission tomography-computed tomography in follicular lymphoma: "One fit for all"? [Articolo su rivista]
Luminari, Stefano; Trotman, Judith
abstract

Editorial article on the role of FDG PET in patients with Follicular Lymphoma

2015 - Report on the 5th International Workshop on Positron Emission Tomography in Lymphoma held in Menton, France, 19-20 September 2014 [Articolo su rivista]
Meignan, Michel; Gallamini, Andrea; Haioun, Corinne; Barrington, Sally; Itti, Emmanuel; Luminari, Stefano; Polliack, Aaron
abstract

Two hundred and thirty-six nuclear medicine physicians, radiologists and hematologists from 28 countries attended the 5th International Workshop on Postron Emission Tomography (PET) in Lymphoma held in Menton, France in September 2014. Forty-five scientific posters were presented. Following Lugano recommendations, the aim of the 5th workshop was to implement PET/computed tomography (CT) interpretation in a quantitative way (Q-PET) and how to use the new proposed metrics such as metabolic tumor volume (MTV). These parameters, in turn, could be combined with clinical, biological and molecular markers to build new indices for better patient risk stratification and to guide personalized therapy. New imaging techniques such as PET/magnetic resonance imaging (MRI) and genomics related to tumor morphological and structural characteristics and PET for assessment of response to new drugs and targeted therapies was also addressed. Finally, a section dedicated to imaging of pediatric lymphoma was also introduced.

2015 - Rituximab with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin and prednisone as first-line treatment for splenic marginal zone lymphoma: a Fondazione Italiana Linfomi phase II study [Articolo su rivista]
Iannitto, Emilio; Luminari, Stefano; Tripodo, Claudio; Mancuso, Salvatrice; Cesaretti, Marina; Marcheselli, Luigi; Merli, Francesco; Stelitano, Caterina; Carella, Angelo Michele; Fragasso, Alberto; Montechiarello, Elisa; Ricciuti, Giuseppina; Pulsoni, Alessandro; Paulli, Marco; Franco, Vito; Federico, Massimo
abstract

Rituximab provides high response rates and effective disease palliation in patients with splenic marginal zone lymphoma (SMZL). We conducted a phase II trial in SMZL patients that were either untreated or were splenectomised, but had shown disease progression within 1 year after splenectomy. Treatment consisted of 6 courses of rituximab with cyclophosphamide, vincristine, non-pegilated liposomal doxorubicin and prednisone (R-COMP). Fifty-one patients were eligible for the analysis. The overall response rate was 84%. The 6-years progression free survival and overall survival was 54% and 72%, respectively. Toxicity was substantial (grade ≥3 neutropenia: 26%; grade ≥3 infections: 8%). Of the 15 deaths, 2 occurred on treatment (one sepsis and one pneumonia). Six deaths were due to lymphoma progression, 4 to secondary neoplasia, 1 to sepsis, 1 to pneumonia and one to splenectomy complications. R-COMP should be restricted to patients with bulky disease associated with symptoms or to patients with possible histological transformation.

2015 - Salvage chemotherapy and autologous stem cell transplantation for transformed indolent lymphoma: A subset analysis of NCIC CTG LY12 [Articolo su rivista]
Kuruvilla, John; Macdonald, David A.; Kouroukis, C. Tom; Cheung, Matthew; Olney, Harold J.; Turner, A. Robert; Anglin, Peter; Seftel, Matthew; Ismail, Walid Sabry; Luminari, Stefano; Couban, Stephen; Baetz, Tara; Meyer, Ralph M.; Hay, Annette E.; Shepherd, Lois; Djurfeldt, Marina S.; Alamoudi, Sameer; Chen, Bingshu E.; Crump, Michael
abstract

The treatment of transformed indolent lymphoma (TRIL) often includes salvage chemotherapy (SC) and autologous stem cell transplant (ASCT). NCIC CTG LY12 is a randomized phase 3 trial comparing gemcitabine, dexamethasone, and cisplatin (GDP) with dexamethasone, cytarabine, and cisplatin (DHAP) before ASCT. This analysis compares the results of SC and ASCT for TRIL with de novo diffuse large B-cell lymphoma (DLBCL). Six-hundred nineteen patients with relapsed/refractory aggressive non-Hodgkin lymphoma were randomized to GDP or DHAP; 87 patients (14%) had TRIL and 429 (69%) had DLBCL. The response rate to SC was 47% in TRIL and 45% in DL (P = .81). Transplantation rates were similar: TRIL 53% and DL 52% (P = 1.0). With a median follow-up of 53 months, 4 year overall survival was 39% for TRIL and 41% for DL (P = .78); 4 year event-free survival (EFS) was 27% for TRIL and 27% for DL (P = .83). Post-ASCT, 4-year EFS was 45% for TRIL and 46% for DL. Histology (TRIL or DL) was not a predictor of any outcome in multivariate models. Patients with relapsed or refractory TRIL and DLBCL have similar outcomes with SC and ASCT; this therapy should be considered the standard of care for patients with TRIL who have received prior systemic chemotherapy. NCIC CTG LY12 is registered at ClinicalTrials.gov as #NCT00078949. ©

2015 - The genotype of MLH1 identifies a subgroup of follicular lymphoma patients who do not benefit from doxorubicin: FIL-FOLL study [Articolo su rivista]
Rossi, Davide; Bruscaggin, Alessio; La Cava, Piera; Galimberti, Sara; Ciabatti, Elena; Luminari, Stefano; Rigacci, Luigi; Tucci, Alessandra; Pulsoni, Alessandro; Bertoldero, Giovanni; Vallisa, Daniele; Rusconi, Chiara; Spina, Michele; Arcaini, Luca; Angrilli, Francesco; Stelitano, Caterina; Merli, Francesco; Gaidano, Gianluca; Federico, Massimo; Palumbo, Giuseppe A.
abstract

Though most follicular lymphoma biomarkers rely on tumor features, the host genetic background may also be relevant for outcome. Here we aimed at verifying the contribution of candidate polymorphisms of FCγ receptor, DNA repair and detoxification genes to prognostic stratification of follicular lymphoma treated with immunochemotherapy. The study was based on 428 patients enrolled in the FOLL05 prospective trial that compared three standard-of-care regimens (rituximab-cyclophosphamide-vincristine-prednisone versus rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone versus rituximab-fludarabine-mitoxantrone) for the first line therapy of advanced follicular lymphoma. Polymorphisms were genotyped on peripheral blood DNA samples. The primary endpoint was time to treatment failure. Polymorphisms of FCGR2A and FCGR3A, which have been suggested to influence the activity of rituximab as a single agent, did not affect time to treatment failure in the pooled analysis of the three FOLL05 treatment arms that combined rituximab with chemotherapy (P=0.742, P=0.252, respectively). These results were consistent even when the analysis was conducted by intention to treat, indicating that different chemotherapy regimens and loads did not interact differentially with the FCGR2A and FCGR3A genotypes. The genotype of MLH1, which regulates the genotoxic effect of doxorubicin, significantly affected time to treatment failure in patients in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone arm (P=0.001; q<0.1), but not in arms in which patients did not receive doxorubicin (i.e., the rituximab-cyclophosphamide-vincristine-prednisone and rituximab-fludarabine-mitoxantrone arms). The impact of MLH1 on time to treatment failure was independent after adjusting for the Follicular Lymphoma International Prognostic Index and other potential confounding variables by multivariate analysis. These data indicate that MLH1 genotype is a predictor of failure to benefit from rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone treatment in advanced follicular lymphoma and confirm that FCGR2A and FCGR3A polymorphisms have no impact when follicular lymphoma is treated with rituximab plus chemotherapy (clinicaltrials.gov identifier: NCT00774826).

2015 - The use of anthracycline at first-line compared to alkylating agents or nucleoside analogs improves the outcome of salvage treatments after relapse in follicular lymphoma The REFOLL study by the Fondazione Italiana Linfomi [Articolo su rivista]
Rossi, Giuseppe; Marcheselli, Luigi; Dondi, Alessandra; Bottelli, Chiara; Tucci, Alessandra; Luminari, Stefano; Arcaini, Luca; Merli, Michele; Pulsoni, Alessandro; Boccomini, Carola; Puccini, Benedetta; Micheletti, Moira; Martinelli, Giovanni; Rossi, Andrea; Zilioli, Vittorio Ruggero; Bozzoli, Valentina; Balzarotti, Monica; Bolis, Silvia; Cabras, Maria Giuseppina; Federico, Massimo
abstract

Follicular lymphoma (FL) patients experience multiple remissions and relapses and commonly receive multiple treatment lines. A crucial question is whether anthracyclines should be used at first-line or whether they would be better "reserved" for relapse and whether FL outcome can be optimized by definite sequences of treatments. Randomized trials can be hardly designed to address this question. In this retrospective multi-institutional study, time-to-next-treatment after first relapse was analyzed in 510 patients who had received either alkylating agents- or anthracycline- or nucleoside analogs-based chemotherapy with/without rituximab at first-line and different second-line therapies. After a median of 42 months, median time-to-next-treatment after relapse was 41 months (CI95%:34-47 months). After adjustment for covariates, first-line anthracycline-based chemotherapy with/without rituximab was associated with better time-to-next-treatment after any salvage than alkylating agents-based chemotherapy with/without rituximab or nucleoside analogs-based chemotherapy with/without rituximab (HR:0.74, P = 0.027). The addition of rituximab to first-line chemotherapy had no significant impact (HR:1.22, P = 0.140). Autologs stem cell transplantation performed better than any other salvage treatment (HR:0.53, P < 0.001). First-line anthracycline-based chemotherapy significantly improved time-to-next-treatment even in patients receiving salvage autologs stem cell transplantation (P = 0.041). This study supports the concept that in FL previous treatments significantly impact on the outcome of subsequent therapies. The outcome of second-line treatments, either with salvage chemoimmunotherapy or with autologs stem cell transplantation, was better when an anthracycline-containing regimen was used at first-line. Am. J. Hematol. 90:56-61, 2015. © 2014 Wiley Periodicals, Inc.

2015 - Utility of baseline 18FDG-PET/CT functional parameters in defining prognosis of primary mediastinal (thymic) large B-cell lymphoma [Articolo su rivista]
Ceriani, Luca; Martelli, Maurizio; Zinzani, Pier Luigi; Ferreri, Andrés J. M.; Botto, Barbara; Stelitano, Caterina; Gotti, Manuel; Cabras, Maria Giuseppina; Rigacci, Luigi; Gargantini, Livio; Merli, Francesco; Pinotti, Graziella; Mannina, Donato; Luminari, Stefano; Stathis, Anastasios; Russo, Eleonora; Cavalli, Franco; Giovanella, Luca; Johnson, Peter W. M.; Zucca, Emanuele
abstract

The International Extranodal Lymphoma Study Group (IELSG) 26 study was designed to evaluate the role of (18)F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) in the management of primary mediastinal (thymic) large B-cell lymphoma (PMBCL). We examined the prognostic impact of functional PET parameters at diagnosis. Metabolic activity defined by the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) was measured on baseline 18FDG PET/CT following a standard protocol in a prospectively enrolled cohort of 103 PMBCL patients. All received combination chemoimmunotherapy with doxorubicin- and rituximab-based regimens; 93 had consolidation radiotherapy. Cutoff values were determined using the receiver-operating characteristic curve. At a median follow-up of 36 months, progression-free survival (PFS) and overall survival (OS) were 87% and 94%, respectively. In univariate analysis, elevated MTV and TLG were significantly associated with worse PFS and OS. Only TLG retained statistical significance for both OS (P = .001) and PFS (P < .001) in multivariate analysis. At 5 years, OS was 100% for patients with low TLG vs 80% for those with high TLG (P = .0001), whereas PFS was 99% vs 64%, respectively (P < .0001). TLG on baseline PET appeared to be a powerful predictor of PMBCL outcomes and warrants further validation as a biomarker. The IELSG 26 study was registered at www.clinicaltrials.gov as #NCT00944567.

2014 - A diachronic-comparative analysis for the identification of the most powerful prognostic index for localized diffuse large B-cell lymphoma [Articolo su rivista]
Mian, M.; Marcheselli, Luigi; Rossi, A.; Visco, C.; Chiappella, A.; Volpetti, S.; Zaja, F.; Mondello, P.; Fiegl, M.; Billio, A.; Federico, Massimo; Luminari, Stefano; Rambaldi, A.; Cortelazzo, S.
abstract

BACKGROUND: In the rituximab era, the conventional International Prognostic index (IPI) lost at least in part its predictive power, while the National Comprehensive Cancer Network-IPI (NCCN-IPI) seems to be a new and valid prognosticator. However, it has not yet been evaluated in patients with localized disease and it has not been compared with the modified IPI (mIPI) of the pre-rituximab era. In order to evaluate the different prognosticators and to assess the importance of rituximab and radiotherapy (RT), we carried out the so far largest retrospective analysis of patients with localized diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: We retrospectively assessed clinical and therapeutical data of 1405 patients treated in from 1987 to 2012 in 10 cancer centers in Italy and 1 in Austria. RESULTS: All patients underwent an anthracycline containing polychemotherapy and 254 additional rituximab. The median follow-up was 5.7 years (range 0.1-23 years). The 5-year overall survival (OS) was 75%, being significantly superior in those who underwent additional rituximab, while RT consolidation did not improve the outcome of those who received immunochemotherapy. Patients with extranodal disease benefited from the addition of rituximab, while RT did not improve OS of the immunochemotherapy subgroup. In the pre-rituximab era, the mIPI showed a better performance than the others. In rituximab-treated patients, the NCCN-IPI had the highest discriminant value and the 5-years OS varied significantly (P < 0.001) between the three risk groups and was 98% in low-risk patients, 82% in those with a low-intermediate risk and 57% among high-intermediate and high-risk cases. CONCLUSIONS: The NCCN-IPI is so far the best prognosticator for patients with localized DLBCL who underwent R-CHOP(-like). The addition of rituximab is indispensable regardless of the risk category and site of involvement, while the addition of RT should be reserved to those cases who are ineligible to rituximab.

2014 - Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi [Articolo su rivista]
Arcaini, L; Vallisa, D; Rattotti, S; Ferretti, Vv; Ferreri, Aj; Bernuzzi, P; Merli, M; Varettoni, M; Chiappella, A; Ambrosetti, A; Tucci, A; Rusconi, C; Visco, C; Spina, M; Cabras, G; Luminari, Stefano; Tucci, M; Musto, P; Ladetto, M; Merli, F; Stelitano, C; D'Arco, A; Rigacci, L; Levis, A; Rossi, D; Spedini, P; Mancuso, S; Marino, D; Bruno, R; Baldini, L; Pulsoni, A.
abstract

Tumor regression after antiviral therapy (AT) is in favor of an etiological role of hepatitis C virus (HCV) in non-Hodgkin's B-cell lymphomas (NHL).

2014 - Bendamustine for Hodgkin lymphoma patients failing autologous or autologous and allogeneic stem cell transplantation: a retrospective study of the Fondazione Italiana Linfomi [Articolo su rivista]
Anastasia, A; Carlo Stella, C; Corradini, P; Salvi, F; Rusconi, C; Pulsoni, A; Hohaus, S; Pregno, P; Viviani, S; Brusamolino, E; Luminari, Stefano; Giordano, L; Santoro, A.
abstract

No abstract is available for this article.

2014 - Early-stage diffuse large B cell lymphoma of the head and neck: clinico-biological characterization and 18 year follow-up of 488 patients (IELSG 23 study) [Articolo su rivista]
Mian, M.; Capello, D.; Ventre, M. B.; Grazio, D.; Svaldi, M.; Rossi, A.; Tsang, R.; Gospodarowicz, M. K.; Oldani, E.; FEDERICO, Massimo; LUMINARI, Stefano; MARCHESELLI, Luigi; Pogliani, E. M.; Rossigni, F.; Cabrera, M. E.; Martelli, M.; Gutierrez Garcia, G.; Busetto, M.; Visco, C.; Fiegl, M.; Rossi, D.; Gaidano, G.; Cavalli, F.; Zucca, E.; Rambaldi, A.; Cortelazzo, S.
abstract

Abstract It is known that extranodal head and neck diffuse large B cell lymphomas (eHN-DLBCL) can affect various anatomical structures what is not well-known, however, is whether they differ in terms of clinical presentation and outcome. Clinical data of the multi-institutional series, the largest of its kind as yet, has been analysed with the aim of answering these open questions and providing long-term follow-up information. Data from 488 patients affected by stage I/II eHN-DLBCL was collected: 300 of the Waldeyer's Ring (WR), 38 of the parotid and salivary glands (PSG), 48 of the thyroid gland (TG), 53 of the nasal cavity and paranasal sinuses (NPS), 24 of the palate and oral cavity (POC) and 25 with more than one involved site. Different eHN-DLBCL arising have distinct characteristics at presentation. The intermediate high risk-modified IPI was 67 % in TG, 44 % in WR, 38 % in PSG and POC and 20 % in MS. The worst 5-year survival rate had TG-DLBCL (61 %) due to the 61 % of patients with a mIPI >1. The addition of radiotherapy (cRT) to remitters did not translate into a survival advantage (5-year disease-free survival of 67 % in the cRT group vs. 70 % in the other). Three of four central nervous system recurrences occurred in NPS-DLBCL. Survival of HN-DLBCL was inferior to nodal DLBCL. This study showed that eHN-DLBCL remitters have an inferior survival when compared to nodal DLBCL, and that the addition of cRT does not provide a survival advantage. Since the standard of care nowadays is chemo-immunotherapy, survival of these patients might have been improved.

2014 - Italian cancer figures, report 2014: Prevalence and cure of cancer in Italy [Articolo su rivista]
Adamo, Ms; Alessi, D; Aletta, P; Amodio, R; Andreone, S; Angelin, T; Anghinoni, E; Annulli, Ml; Arciprete, C; Artioli, Me; Autelitano, M; Baili, P; Balducci, C; Baracco, M; Baracco, S; Battisti, W; Bella, F; Bellatalla, C; Bellini, A; Belluardo, C; Benatti, P; Benedetto, G; Benfatto, L; Bernazza, E; Bianconi, F; Biavati, P; Bidoli, E; Birri, S; Bizzoco, S; Bonelli, L; Bonini, A; Borciani, E; Bordini, M; Bovo, E; Bozzani, F; Braghiroli, B; Brucculeri, Ma; Brunori, V; Bucalo, G; Bucchi, L; Bugliarello, E; Bulatko, A; Busco, S; Busso, P; Buzzoni, C; Calabrese, A; Calabretta, L; Caldarella, A; Candela, G; Cannone, G; Canu, L; Caparelli, M; Capocaccia, R; Cappelletti, M; Caprara, L; Carboni, D; Carletti, N; Caroli, S; Cascio, Ma; Cascone, G; Casella, C; Castaing, M; Cavalieri d'Oro, L; Cecconami, L; Celesia, Mv; Cena, T; Cercato, Mc; Cesaraccio, R; Chiesa, R; Cirilli, C; Cocchioni, M; Codazzi, T; Cogno, R; Colamartini, A; Colanino Ziino, A; Cometti, I; Contiero, P; Contrino, Ml; Corbinelli, A; Cordaro, C; Corti, M; Costa, A; Costarelli, D; Coviello, V; Crapanzano, G; Cremone, L; Crocetti, E; Cuccaro, F; Curatella, S; Cusimano, R; D'Alò, D; Dal Cappello, T; Dal Cin, A; Dal Maso, L; Davini, C; De Dottori, M; De Angelis, R; De Santis, E; De Valiere, E; Dei Tos, Ap; Demurtas, G; Devigili, E; Di Felice, E; di Grazia, L; Di Gregorio, C; di Norcia, R; Di Prima, A; Dinaro, Y; Distefano, R; Doa, N; Domati, F; Fabiano, S; Facchinelli, G; Falcini, F; Falk, M; Fanetti, Ac; Fattoruso, S; Federico, Massimo; Ferrari, F; Ferrari, L; Ferretti, S; Fidelbo, M; Filipazzi, L; Fiore, Ar; Fiori, G; Foca, F; Forgiarini, O; Foschi, R; Francisci, S; Frasca, G; Frassoldi, E; Fusco, M; Fusco, M; Gada, D; Garrone, E; Gasparotti, C; Gatta, G; Gatti, L; Gaudiano, C; Gennaro, V; Gentilini, Ma; Gerevini, C; Ghilardi, S; Ghisleni, S; Giacomin, A; Giavazzi, L; Gigli, A; Gilardi, F; Giorgetti, S; Giorgi Rossi, P; Giubelli, C; Giuliani, O; Giurdanella, Mc; Gola, G; Goldoni, Ca; Golizia, Mg; Greco, A; Guarda, L; Guttadauro, A; Guzzinati, S; Iachetta, F; Iannelli, A; Ieni, A; Intrieri, T; Kaleci, S; La Rosa, F; Lando, C; Lavecchia, Am; Lazzarato, F; Le Rose, L; Leone, A; Leone, R; Lonati, F; Lucchi, S; Luminari, Stefano; Macci, L; Macerata, V; Madeddu, A; Maffei, S; Maghini, A; Magnani, C; Magnani, G; Magoni, M; Mallone, S; Mameli, G; Mancini, S; Mancuso, P; Mangone, L; Manneschi, G; Mannino, R; Mannino, S; Marani, E; Marchesi, C; Mariani, F; Martorana, C; Marzola, L; Maspero, S; Maule, M; Mazzei, A; Mazzoleni, G; Mazzucco, G; Melcarne, A; Merletti, F; Merlo, E; Michiara, M; Migliari, E; Minerba, S; Minicuzzi, A; Mizzi, M; Monetti, D; Morana, G; Moroni, E; Mosso, Ml; Muni, A; Mura, F; Natali, M; Negrino, L; Nemcova, L; Nicita, C; Ocello, C; Pala, F; Palumbo, M; Panciroli, E; Panico, M; Pannozzo, F; Pascucci, C; Pasolini, A; Pastore, G; Patriarca, S; Pedroni, M; Perrotta, C; Pesce, P; Petrinelli, Am; Petrucci, C; Pezzarossi, A; Pezzuto, L; Piffer, S; Pinon, M; Pinto, A; Pintori, N; Pirani, M; Pirino, D; Pironi, V; Ponz de Leon, M; Prandi, R; Prazzoli, R; Puleio, M; Puppo, A; Quarta, F; Quattrocchi, M; Ramazzotti, V; Rashid, I; Ravaioli, A; Ravazzolo, B; Ravegnani, M; Reggiani Bonetti, L; Ricci, P; Rinaldi, E; Rizzello, R; Rognoni, M; Rollo, Pc; Roncaglia, F; Roncucci, Luca; Rosano, A; Rossi, F; Rossi, G; Rossi, M; Rossi, S; Rossini, S; Rosso, S; Rudisi, G; Ruggeri, Mg; Russo, Ag; Russo, M; Sacchettini, C; Sacchetto, L; Sacco, G; Sacerdote, C; Salvatore, S; Salvi, O; Sampietro, G; Santucci, C; Scheibel, M; Sciacca, S; Sciacchitano, C; Sciacchitano, S; Scuderi, T; Sechi, O; Seghini, P; Senatore, G; Serafini, G; Serraino, D; Sgargi, P; Sini, Gm; Sobrato, I; Soddu, M; Solimene, C; Spano, F; Spata, E; Sperduti, I; Spinosa, S; Staiti, R; Stocco, C; Stracci, F; Sunseri, R; Sutera Sardo, A; Tagliabue, G; Tamburo, L; Tamburrino, S; Taranto, V; Terracini, B; Tisano, F; Tittarelli, A; Tognazzo, S; Torrisi, A; Torrisi, A; Traina, A;
abstract

This Report intends to estimate the total number of people still alive in 2010 after cancer diagnosis in Italy, regardless of the time since diagnosis, and to project these estimates to 2015. This study is also aimed to estimate the number of already cured cancer patients, whose mortality rates have become undistinguishable from that of the general population of the same age and sex.

2014 - Metabolic tumour volumes measured at staging in lymphoma: methodological evaluation on phantom experiments and patients [Articolo su rivista]
Meignan, M; Sasanelli, M; Casasnovas, Ro; Luminari, Stefano; Fioroni, F; Coriani, C; Masset, H; Itti, E; Gobbi, Pg; Merli, F; Versari, A.
abstract

The presence of a bulky tumour at staging on CT is an independent prognostic factor in malignant lymphomas. However, its prognostic value is limited in diffuse disease. Total metabolic tumour volume (TMTV) determined on (18)F-FDG PET/CT could give a better evaluation of the total tumour burden and may help patient stratification. Different methods of TMTV measurement established in phantoms simulating lymphoma tumours were investigated and validated in 40 patients with Hodgkin lymphoma and diffuse large B-cell lymphoma.

2014 - Minimal residual disease after conventional treatment significantly impacts on progression-free survival of patients with follicular lymphoma: The FIL FOLL05 trial [Articolo su rivista]
Galimberti, Sara; Luminari, Stefano; Ciabatti, Elena; Grassi, Susanna; Guerrini, Francesca; Dondi, Alessra; Marcheselli, Luigi; Ladetto, Marco; Piccaluga, Pier Paolo; Gazzola, Anna; Mannu, Claudia; Monitillo, Luigia; Mantoan, Barbara; Giudice, Ilaria Del; Starza, Irene Della; Cavalli, Marzia; Arcaini, Luca; Tucci, Alessra; Palumbo, Giuseppe Alberto; Rigacci, Luigi; Pulsoni, Alessro; Vitolo, Umberto; Boccomini, Carola; Vallisa, Daniele; Bertoldero, Giovanni; Gaidano, Gianluca; Musto, Pellegrino; Petrini, Mario; Federico, Massimo
abstract

PURPOSE: The role of the minimal residual disease (MRD) in follicular lymphoma is still debated. In this study, we assessed whether the BCL2/IGH rearrangement could have a prognostic role in patients receiving R-CHOP, R-FM, or R-CVP. EXPERIMENTAL DESIGN: DNAs from 415 patients among the 504 cases enrolled in the FOLL05 trial (NCT00774826) were centralized and assessed for the BCL2/IGH at diagnosis, at the end of treatment, and after 12 and 24 months. RESULTS: At diagnosis, the molecular marker was detected in 53% of cases. Patients without molecular marker or with a low molecular tumor burden (<1 × 10(-4) copies) showed higher complete remission (CR) rate and longer progression-free survival (PFS; 3-year PFS 80% vs. 59%; P = 0.015). PFS was significantly conditioned by the PCR status at 12 and 24 months, with 3-year PFS of 66% for MRD(-) cases versus 41% for those MRD(+) at 12 months (P = 0.015), and 84% versus 50% at 24 months (P = 0.014). The MRD negativity at 12 and 24 months resulted in an improved PFS both in CR and in partial remission (PR) patients (3-year PFS = 72% for cases CR/PCR(-) vs. 32% for those CR/PCR(+) vs. 62% for those PR/PCR(-) and 25% for patients in PR/PCR(+); P = 0.001). The prognostic value of MRD at 12 and 24 months of follow-up was confirmed also in multivariate analysis. CONCLUSIONS: In this study, standardized molecular techniques have been adopted and applied on bone marrow samples from a large cohort. Data reported show that the MRD detection is a powerful independent predictor of PFS in patients with follicular lymphoma receiving conventional chemoimmunotherapy.

2014 - Outcome of frail elderly patients with diffuse large B-cell lymphoma prospectively identified by Comprehensive Geriatric Assessment: Results from a study of the Fondazione Italiana Linfomi [Articolo su rivista]
Merli, F.; Luminari, Stefano; Rossi, G.; Mammi, Caterina; Marcheselli, Luigi; Ferrari, A.; Spina, M.; Tucci, A.; Stelitano, C.; Capodanno, I.; Fragasso, A.; Baldini, L.; Bottelli, C.; Montechiarello, E.; Fogazzi, S.; Lamorgese, C.; Cavalli, L.; Federico, Massimo
abstract

In 2003 the Fondazione Italiana Linfomi (FIL) started a clinical research program for investigating initial treatment of frail elderly patients with diffuse large B-cell lymphoma (DLBCL) identified by Comprehensive Geriatric Assessment (CGA). From 2003 to 2006, 334 elderly patients underwent CGA assessment, and 99 patients were classified as frail. Frail patients had a median age of 78 years, stage III-IV disease in 62% and age-adjusted International Prognostic Index (aaIPI) of 2-3 in 53%. Treatment consisted of several different regimens according to physician discretion. After a median follow-up of 36 months, 5-year overall survival (OS) was 28%. In multivariate analysis, aaIPI 2-3 (p = 0.005) and the presence of respiratory comorbidity (p = 0.044) were the only factors that showed independent correlation with OS. Frail patients had a poorer outcome compared with fit patients also if they were treated with rituximab-containing combination chemotherapy (hazard ratio 2.37, 95% confidence interval 1.48-3.78; p < 0.001). CGA is a valid tool to prospectively identify frail subjects among elderly patients with DLBCL.

2014 - Outcome prediction of diffuse large B-cell lymphomas associated with hepatitis C virus infection: A study on behalf of the Fondazione Italiana Linfomi [Articolo su rivista]
Merli, M.; Visco, C.; Spina, M.; Luminari, S.; Ferretti, V. V.; Gotti, M.; Rattotti, S.; Fiaccadori, V.; Rusconi, C.; Targhetta, C.; Stelitano, C.; Levis, A.; Ambrosetti, A.; Rossi, D.; Rigacci, L.; D'Arco, A. M.; Musto, P.; Chiappella, A.; Baldini, L.; Bonfichi, M.; Arcaini, L.
abstract

A specific prognostication score for hepatitis C virus-positive diffuse large B-cell lymphomas is not available. For this purpose, the Fondazione Italiana Linfomi (FIL, Italian Lymphoma Foundation) carried out a multicenter retrospective study on a large consecutive series of patients with hepatitis C virus-associated diffuse large B-cell lymphoma to evaluate the prognostic impact of clinical and virological features and to develop a specific prognostic score for this subset of patients. All prognostic evaluations were performed on 535 patients treated with an anthracycline- based induction regimen (with rituximab in 255 cases). Severe hepatotoxicity was observed in 14% of patients. The use of rituximab was not associated with increased rate of severe hepatotoxicity. Three-year overall survival and progression-free survival were 71% and 55%, respectively. At multivariate analysis, ECOG performance status of 2 or over, serum albumin below 3.5 g/dL and HCV-RNA viral load over 1000 KIU/mL retained prognostic significance. We combined these 3 factors in a new "HCV Prognostic Score" able to discriminate 3 risk categories with different overall and progression-free survival (low=0; intermediate=1; high-risk ≥2 factors; P<0.001). This score retained prognostic value in the subgroups of patients treated with and without rituximab (P<0.001). The new score performed better than the International Prognostic Index at multivariate analysis and Harrel C-statistic. With the use of three readily available factors (performance status, albumin level and HCV-RNA viral load), the new "HCV Prognostic Score" is able to identify 3 risk categories with different survival, and may be a useful tool to predict the outcome of hepatitis C virus-associated diffuse large B-cell lymphomas. © 2014 Ferrata Storti Foundation.

2014 - Perception of hepatitis B virus infection reactivation-related issues among specialists managing hematologic malignancies: result of an Italian survey [Articolo su rivista]
Marignani, M; Marzano, A; Begini, P; Vitolo, U; Luminari, Stefano; Levis, A; Deli, I; Gigante, E; De Santis, E; delle Fave, G; Monarca, B; Cox, Mc
abstract

Hepatitis B virus (HBV) reactivation strongly affects the practice of physicians dealing with hematological malignancies. In this respect, in collaboration with the Italian Lymphoma Foundation we developed a descriptive study of the real-life approach of physicians caring for patients with these diseases. A questionnaire was designed to explore the perception of HBV reactivation-related issues. Fifty-nine Italian Lymphoma Foundation-affiliated institutions participated, and 504 questionnaires were sent out. Forty institutions (67.8%) returned 154 (30.5%) completed questionnaires. The largest majority (91.5%, 141/154) were aware of possible HBV reactivation as a consequence of immunosuppression. Most of the participants providing an answer (93.3%; 126/135) performed universal screening, and were aware of strategies for managing reactivation (96.4%, 132/137). Specialists treating lymphoma show a high level of awareness concerning the management of HBV reactivation under immunosuppression. However, uncertainties regarding the issue of HBV reactivation still emerge in this setting, and thus continuing collaborative effort between hepatologists and hematologists is necessary.

2014 - Prognostic value of PET-CT after first-line therapy in patients with follicular lymphoma: a pooled analysis of central scan review in three multicentre studies [Articolo su rivista]
Trotman, J.; Luminari, Stefano; Boussetta, S.; Versari, A.; Dupuis, J.; Tychyl, C.; Marcheselli, Luigi; Berriolo Riedinger, A.; Franceschetto, Antonella; Julian, A.; Ricard, F.; Guerra, L.; Haioun, C.; Biasoli, I.; Tilly, H.; Federico, Massimo; Salles, G.; Meignan, M.
abstract

Background The value of 18F-fluorodeoxyglucose (FDG) PET-CT (PET) imaging in response assessment after first-line rituximab chemotherapy for follicular lymphoma has been documented. We analysed the application of the five-point Deauville scale (5PS; used to score FDG uptake on PET images) in a large cohort derived from three studies, to assess the correlation between post-induction PET status and survival in patients with follicular lymphoma. Methods In this pooled analysis, we used data from three multicentre prospective studies of first-line rituximab chemotherapy for patients with high-tumour-burden follicular lymphoma (the PRIMA study, the PET-Folliculaire study, and the Fondazione Italiana Linfomi FOLL05 study). Patients included in this analysis received at least six cycles of rituximab and chemotherapy before response assessment with conventional contrast-enhanced CT and PET low-dose CT (PET). We included only patients who had a PET scan within 3 months of the last dose of induction rituximab. Patient data, including conventional CT-based response assessment, were recorded for all patients undergoing PET review. Scans undergoing central PET review were scored independently by three reviewers according to the 5PS. The primary endpoints were progression-free survival and overall survival according to the 5PS score of post-induction PET scan (ie, positive [≥4 points] or negative [<4 points]), analysed in the central review population. Findings Between Dec 24, 2004, and Sept 22, 2010, 439 of the patients enrolled in the three studies underwent local PET assessment, 246 of whom had centrally reviewed post-induction scans. 41 (17%) of 246 patients had a positive post-induction PET scan according to a cutoff of 4 or higher on the 5PS, with substantial reporter concordance. With a median follow-up of 54·8 months (IQR 39·7–68·5; range 7·7–90·1), the hazard ratio (HR) for progression-free survival for patients with a positive PET scan versus those with a negative PET scan was 3·9 (95% CI 2·5–5·9; p<0·0001), and for overall survival was 6·7 (2·4–18·5; p=0·0002). For patients with a positive PET scan, 23·2% (95% CI 11·1–37·9) of patients were progression free at 4 years compared with 63·4% (55·9–70·0) of those who had a negative PET scan (p<0·0001); 4-year overall survival was 87·2% (95% CI 71·9–94·5) versus 97·1% (93·2–98·8), respectively (p<0·0001). Conventional CT-based response (ie, complete response or unconfirmed complete response vs partial response) was weakly predictive of progression-free survival (HR 1·7 [95% CI 1·1–2·5]; p=0·017). Interpretation PET-CT rather than contrast-enhanced CT scanning should be considered as a new standard for response assessment of follicular lymphoma in clinical practice, and could help guide response-adapted therapy. Funding Groupe d'Etude des Lymphomes de l'Adulte (Paris, France), now LYSA (Lymphoma Study Association), Direction de la Recherche Clinique de l'Assistance Publique–Hôpitaux de Paris, Fondazione Italiana Linfomi, and the Italian Ministry of Health.

2014 - The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale [Articolo su rivista]
Gallamini, A; Barrington, Sf; Biggi, A; Chauvie, S; Kostakoglu, L; Gregianin, M; Meignan, M; Mikhaeel, Gn; Loft, A; Zaucha, Jm; Seymour, Jf; Hofman, Ms; Rigacci, L; Pulsoni, A; Coleman, M; Dann, Ej; Trentin, L; Casasnovas, O; Rusconi, C; Brice, P; Bolis, S; Viviani, S; Salvi, F; Luminari, Stefano; Hutchings, M.
abstract

A retrospective, international, multicenter study was undertaken to assess: (i) the prognostic role of 'interim' positron emission tomography performed during treatment with doxorubicin, bleomycin, vinblastine and dacarbazine in patients with Hodgkin lymphoma; and (ii) the reproducibility of the Deauville five-point scale for the interpretation of interim positron emission tomography scan. Two hundred and sixty patients with newly diagnosed Hodgkin lymphoma were enrolled. Fifty-three patients with early unfavorable and 207 with advanced-stage disease were treated with doxorubicin, bleomycin, vinblastine and dacarbazine ± involved-field or consolidation radiotherapy. Positron emission tomography scan was performed at baseline and after two cycles of chemotherapy. Treatment was not changed according to the results of the interim scan. An international panel of six expert reviewers independently reported the scans using the Deauville five-point scale, blinded to treatment outcome. Forty-five scans were scored as positive (17.3%) and 215 (82.7%) as negative. After a median follow up of 37.0 (2-110) months, 252 patients are alive and eight have died. The 3-year progression-free survival rate was 83% for the whole study population, 28% for patients with interim positive scans and 95% for patients with interim negative scans (P<0.0001). The sensitivity, specificity, and negative and positive predictive values of interim positron emission tomography scans for predicting treatment outcome were 0.73, 0.94, 0.94 and 0.73, respectively. Binary concordance amongst reviewers was good (Cohen's kappa 0.69-0.84). In conclusion, the prognostic role and validity of the Deauville five-point scale for interpretation of interim positron emission tomography scans have been confirmed by the present study.

2014 - The prognostic role of post-induction FDG-PET in patients with follicular lymphoma: a subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi (FIL) [Articolo su rivista]
Luminari, Stefano; Biasoli, I.; Versari, A.; Rattotti, S.; Battelli, C.; Rusconi, C.; Merli, F.; Spina, M.; Ferreri, A. J.; Zinzani, P. L.; Gallamini, A.; Franceschetto, Antonella; Boccomini, C.; Franceschetti, S.; Salvi, F.; Raimondo, F. D.; Carella, A. M.; Quaresima, Micol; Balzarotti, M.; Musto, P.; Federico, Massimo
abstract

BACKGROUND: [18F]fluorodeoxyglucose-positron emission tomography (PET) is emerging as a strong diagnostic and prognostic tool in follicular lymphoma (FL) patients. PATIENTS AND METHODS: In a subset analysis of the FOLL05 trial (NCT00774826), we investigated the prognostic role of post-induction PET (PI-PET) scan. Patients were eligible to this study if they had a PI-PET scan carried out within 3 months from the end of induction immunochemotherapy. Progression-free survival (PFS) was the primary study end point. RESULTS: A total of 202 patients were eligible and analysed for this study. The median age was 55 years (range 33-75). Overall, PI-PET was defined as positive in 49 (24%) patients. Conventional response assessment with CT scan was substantially modified by PET: 15% (22/145) of patients considered as having a complete response (CR) after CT were considered as having partial response (PR) after PI-PET and 53% (30/57) patients considered as having a PR after CT were considered as a CR after PI-PET. With a median follow-up of 34 months, the 3-year PFS was 66% and 35%, respectively, for patients with negative and positive PI-PET (P<0.001). At multivariate analysis, PI-PET (hazard ratio 2.57, 95% confidence interval 1.52-4.34, P<0.001) was independent of conventional response, FLIPI and treatment arm. Also, the prognostic role of PI-PET was maintained within each FLIPI risk group. CONCLUSIONS: In FL patients, PI-PET substantially modifies response assessment and is strongly predictive for the risk of progression. PET should be considered in further updates of response criteria.

2013 - Bendamustine salvage therapy for T cell neoplasms [Articolo su rivista]
Zaja, Francesco; Baldini, Luca; Ferreri, Andrés J. M; Luminari, Stefano; Grossi, Alberto; Salvi, Flavia; Zambello, Renato; Goldaniga, Maria; Volpetti, Stefano; Fanin, Renato
abstract

Treatment of relapsed/refractory T cell neoplasms represents an unmet medical need. We recorded, retrospectively, data on 20 consecutive adult patients with T cell neoplasms (8 T cell lymphoma not otherwise specified (T-NOS), 4 angioimmunoblastic (AILT), 3 prolymphocytic leukemia (T-PLL), 3 advance-stage mycosis fungoides (MF) or Sézary syndrome (SS), and 2 T cell large granular lymphocytic leukemia (T-LGL)), treated with bendamustine. Partial (PR) and complete response (CR) rates were reached in nine (45 %) and two (10 %) patients, respectively, including three PR in T-NOS, one CR in AILT, three PR in T-PLL, two PR in MF/SS, and one CR and one PR in T-LGL lymphoma. The 6 months estimated progression free and overall survival was 44 and 67 %, respectively. Grade 3-4 neutropenia and thrombocytopenia were registered in 44 and 25 % of cases. Four patients developed major infectious complications. At a median follow-up of 6 months (range 1-18), 13 patients are alive and 7 patients died all because of lymphoma progression. Bendamustine deserves further investigation in patients with T cell neoplasms.

2013 - Brentuximab vedotin in relapsed/refractory Hodgkin's lymphoma: the Italian experience and results of its use in daily clinical practice outside clinical trials [Articolo su rivista]
Zinzani, Pier Luigi; Viviani, Simonetta; Anastasia, Antonella; Vitolo, Umberto; Luminari, Stefano; Zaja, Francesco; Corradini, Paolo; Spina, Michele; Brusamolino, Ercole; Gianni, Alessandro M; Santoro, Armando; Botto, Barbara; Derenzini, Enrico; Pellegrini, Cinzia; Argnani, Lisa
abstract

Clinical trial results indicate that brentuximab vedotin brings considerable promise for the treatment of patients with relapsed or refractory Hodgkin's lymphoma. A retrospective multicenter study was conducted on 65 heavily pretreated patients who underwent therapy through a Named Patient Program in Italy (non trial-setting). The primary study endpoint was the objective response rate; secondary endpoints were safety, overall survival and progression-free survival. The best overall response rate (70.7%), including 21.5% complete responses, was observed at the first restaging after the third cycle of treatment. After a median follow up of 13.2 months, the overall survival rate at 20 months was 73.8% while the progression-free survival rate at 20 months was 24.2%. Globally nine patients are in continuous complete response with a median follow up of 14 months (range, 10-19 months). Four patients proceeded to autotransplantation and nine to allotransplantation. The most frequent extra-hematologic toxicity was peripheral neuropathy, observed in 21.5% of cases (9 patients with grade 1/2 and 5 patients with grade 3/4); neurological toxicity led to discontinuation of treatment in three patients and to dose reduction in four. In general the treatment was well tolerated and toxicities, both hematologic and extra-hematologic, were manageable. This report indicates and confirms that brentuximab vedotin as a single agent is effective and safe also when used in standard, everyday clinical practice outside a clinical trial. Best overall responses were recorded after three or four cycles and showed that brentuximab vedotin provides an effective bridge to further therapeutic interventions.

2013 - Bridging the gap between epidemiology and clinical research in lymphoma [Recensione in Rivista]
Luminari, Stefano
abstract

2013 - Clinicopathologic characteristics of angioimmunoblastics T-cell lymphoma (AITL): analysis of 243 cases from the International Peripheral T-cell Lymphoma Project. [Articolo su rivista]
Federico, Massimo; Rudiger, T.; Bellei, Monica; Nathwani, B. N.; Luminari, Stefano; Coiffier, B.; Harris, N. L.; Jaffe, E.; Pileri, S.; Savane, K. J.; Weisenburger, D. D.; Armitage, J. O.; Mounier, N.; Vose, J. M.
abstract

PURPOSE The International Peripheral T-Cell Lymphoma Project was undertaken to better understand the subtypes of T-cell and natural killer (NK) -cell lymphomas. PATIENTS AND METHODSAngioimmunoblastic T-cell lymphoma (AITL) was diagnosed according to the 2001 WHO criteria by a central review process consisting of panels of expert hematopathologists. Clinical, pathologic, immunophenotyping, treatment, and survival data were correlated. RESULTS: age ≥ 60 years, stages III to IV disease, lactic dehydrogenase (LDH) > normal, extranodal sites (ENSs) > one, and performance status (PS) ≥ 2; the Prognostic Index for Peripheral T-Cell Lymphoma, comprising: age ≥ 60 years, PS ≥ 2, LDH > normal, and bone marrow involvement; and the alternative Prognostic Index for AITL (PIAI), comprising: age > 60 years, PS ≥ 2, ENSs > one, B symptoms, and platelet count < 150 × 10(9)/L. The simplified PIAI had a low-risk group (zero to one factors), with 5-year survival of 44%, and a high-risk group (two to five factors), with 5-year survival of 24% (P = .0065). CONCLUSIONAITL is a rare clinicopathologic entity characterized by an aggressive course and dismal outcome with current therapies.

2013 - Follicular lymphoma [Capitolo/Saggio]
Luminari, S.; Dondi, A.; Biasoli, I. B.; Federico, M.
abstract

2013 - Italian cancer figures, report 2013: Multiple tumours [Articolo su rivista]
Adamo, Ms; Alessi, D; Aletta, P; Amodio, R; Andreone, S; Angelin, T; Anghinoni, E; Annulli, Ml; Antonini, S; Artioli, Me; Autelitano, M; Balducci, C; Balottari, P; Baracco, M; Battisti, W; Bella, F; Bellatalla, C; Belluardo, C; Benatti, Piero; Benedetto, G; Benfatto, L; Bernazza, E; Bianconi, F; Biavati, P; Bidoli, E; Birri, S; Bizzoco, S; Bonelli, L; Bonini, A; Borciani, E; Bovo, E; Bozzani, F; Bozzeda, A; Braghiroli, B; Brucculeri, Ma; Brunori, V; Bucalo, G; Bucchi, L; Bugliarello, E; Bulatko, A; Busco, S; Busso, P; Buzzoni, C; Calabretta, L; Caldarella, A; Candela, G; Canu, L; Cappelletti, M; Caprara, L; Carboni, D; Carletti, N; Caroli, S; Carone, S; Cascio, Ma; Cascone, G; Casella, C; Castaing, M; Cecconami, L; Celesia, Mv; Cena, T; Cercato, Mc; Cesaraccio, R; Chiesa, R; Cirilli, C; Civaschi, A; Cocchioni, M; Codazzi, T; Cogno, R; Colamartini, A; Colanino Ziino, A; Cometti, I; Contiero, P; Contrino, Ml; Corbinelli, A; Cordaro, C; Corti, M; Costa, A; Costarelli, D; Cremone, L; Crocetti, E; Curatella, S; Cusimano, R; D'Alò, D; D'Angelo, S; Dal Cappello, T; Dal Cin, A; Dal Maso, L; Dall'Acqua, M; Dalsasso, F; Davini, C; De Dottori, M; De Maria, V; De Santis, E; De Valiere, E; Dei Tos, Ap; Demurtas, G; Devigli, E; Di Felice, E; di Grazia, L; Di Gregorio, C; Di Prima, A; Distefano, R; Doa, N; Domati, F; Fabiano, S; Facchinelli, G; Falcini, F; Falk, M; Fanetti, Ac; Fattoruso, S; Federico, Massimo; Ferrari, L; Ferretti, S; Fidelbo, M; Filipazzi, L; Fiore, Ar; Fiori, G; Foca, F; Forgiarini, O; Frasca, G; Frassoldi, E; Frizza, J; Fusco, M; Fusco, M; Gada, D; Garrone, E; Gasparotti, C; Gatti, L; Gaudiano, C; Gennaro, V; Gentilini, M; Gerevini, C; Ghilardi, S; Ghisleni, S; Giacomin, A; Giavazzi, L; Gilardi, F; Giorgetti, S; Giubelli, C; Giuliani, O; Giurdanella, Mc; Gola, G; Goldoni, Ca; Golizia, Mg; Grandi, L; Greco, A; Guarda, L; Guttadauro, A; Guzzinati, S; Iachetta, F; Iannelli, A; Ieni, A; Intrieri, T; Kaleci, S; La Rosa, F; Lando, C; Lavecchia, Am; Lazzarato, F; Leone, A; Leone, R; Lonati, F; Lottero, B; Lucchi, S; Luminari, Stefano; Macci, L; Macerata, V; Madeddu, A; Maffei, S; Maghini, A; Magnani, C; Magnani, G; Magoni, M; Mameli, G; Mancini, S; Mancuso, P; Mangone, L; Manneschi, G; Mannino, R; Mannino, S; Marani, E; Mariani, F; Martorana, C; Marzola, L; Maspero, S; Maule, M; Mazzei, A; Mazzoleni, G; Mazzucco, G; Melcarne, A; Merletti, F; Michiara, M; Migliari, E; Minerba, S; Minicuzzi, A; Mizzi, M; Monetti, D; Morana, G; Moroni, E; Mosso, Ml; Muni, A; Mura, F; Natali, M; Nemcova, L; Nicita, C; Ocello, C; Paci, E; Pala, F; Palumbo, M; Panico, M; Pannozzo, F; Pascucci, C; Pastore, G; Patriarca, S; Pedroni, Monica; Pellegri, C; Perrotta, C; Pesce, P; Petrinelli, Am; Petrucci, C; Pezzarossi, A; Piffer, S; Pintori, N; Pirani, M; Pirino, D; Pironi, V; PONZ DE LEON, Maurizio; Prandi, R; Prazzoli, R; Preto, L; Puleio, M; Puppo, A; Quaglia, A; Quarta, F; Quattrocchi, M; Raho, Am; Ramazzotti, V; Rashid, I; Ravaioli, A; Ravazzolo, B; Ravegnani, M; Reggiani Bonetti, L; Ribaudo, M; Rinaldi, E; Ricci, P; Rizzello, R; Rollo, Pc; Roncucci, Luca; Rosano, A; Rossi, F; Rossi, G; Rossi, M; Rossini, S; Rosso, S; Rudisi, G; Ruggeri, Mg; Russo, Ag; Russo, M; Sacchettini, C; Sacco, G; Sacerdote, C; Salvatore, S; Salvi, O; Sampietro, G; Sandrini, M; Santucci, C; Scheibel, M; Schiacchitano, S; Sciacca, S; Sciacchitano, C; Scuderi, T; Sechi, O; Seghini, P; Senatore, G; Serafini, G; Serraino, D; Sgargi, P; Sigona, A; Sini, Gm; Sobrato, I; Soddu, M; Solimene, C; Spano, F; Spata, E; Sperduti, I; Staiti, R; Stocco, C; Stracci, F; Sunseri, R; Sardo, As; Tagliabue, G; Tamburo, L; Tamburrino, S; Tanzarella, M; Terracini, B; Tessandori, R; Tisano, F; Tittarelli, A; Tognazzo, S; Torrisi, A; Torrisi, A; Traina, A; Trapani, C; Tschugguel, B; Tumino, R; Usala, M; Vacirca, S; Valerio, O; Valla, K; Varvarà, M; Vasquez, E; Vassante, B; Vattiato, R; Vercelli, M; Vercellino, Pc; Vicentini, M; Villa, M; Vitale, F; Vital
abstract

OBJECTIVES: This collaborative study, based on data collected by the network of Italian association of cancer registries (AIRTUM), provides updated estimates on the incidence risk of multiple primary cancer (MP). The objective is to highlight and quantify the bidirectional associations between different oncological diseases. The quantification of the excess or decreased risk of further cancers in cancer patients, in comparison with the general population, may contribute to understand the aetiology of cancer and to address clinical follow-up. MATERIAL AND METHODS: Data herein presented were provided by AIRTUM population-based cancer registries, which cover nowadays 48% of the Italian population. This monograph utilizes the AIRTUM database (December 2012), considering all malignant cancer cases diagnosed between 1976 and 2010. All cases are coded according to ICD-O-3. Non-melanoma skin cancer cases, cases based on death certificate only, cases based on autopsy only, and cases with follow-up time equal to zero were excluded. To define multiple primaries, IARC-IACR rules were adopted (http://www.iacr.com.fr/MPrules_july2004.pdf). Data were subjected to standard quality control procedures (described in the AIRTUM data management protocol) and specific quality control checks defined for the present study. A cohort of cancer patients was followed over time from first cancer diagnosis until the date of second cancer diagnosis, death, or the end of follow-up, to evaluate whether the number of observed second cancer cases was greater than expected. Person years at risk (PY) were computed by first cancer site, geographic area (North, Centre, South and Islands), attained age, and attained calendar-year group. All second cancers diagnosed in the cohort's patients were included in the observed numbers of cases. The expected number of cancer cases was computed multiplying the accumulated PY by the expected rates, calculated from the AIRTUM database stratified by cancer site, geographic area, age, and calendar-year group. The Standardized Incidence Ratio (SIR) was calculated as the ratio of observed to expected cancer cases. The Excess Absolute Risk (EAR) beyond the expected amount were calculated subtracting the expected number of subsequent cancers from the observed number of cancer cases; the difference was then divided by the PY and the number of cancer cases in excess (or deficit) was expressed per 1,000 PY. Confidence intervals were stated at 95%. The two months (60 days) after first cancer diagnosis were defined as "synchronicity period", and in the main analysis observed and expected cases during this period were excluded. It was estimated the excess risk in the period after first diagnosis (≥ 0 months), excluding the synchronicity period (≥ 2 months), and during the following periods: 2-11, 12-59, 60-119 and 120 months after diagnosis. First-cancer-site-and-gender-specific sheets are presented, reporting both SIRs and EARs. RESULTS: For 5,979,338 person-years a cohort of 1,635,060 cancer patients (880,361 males and 754,699 females) diagnosed between 1976 and 2010 was followed. The mean follow-up length was 14 years. Overall, 85,399 metachronous (latency ≥2 months) cancers were observed, while 77,813 were expected during the study period: SIR: 1.10 (95%CI 1.09-1.10), EAR: 1.32 x 1,000 person-years (95%CI 1.19 - 1.46). The SIR was 1.08 (95%CI 1.08-1.09) for men (54,518 observed and 50,260 expected) and 1.12 (95%CI 1.11-1.13) for women (30,881/27,553), and the EAR 1.61 (95%CI 1.37-1.84) and 1.08 x 1,000 person-years (95%CI 0.93-1.24), respectively.Moreover, during the first two months after first cancer diagnosis (synchronous period) 14,807 cancers were observed while 3,536 were expected (SIR: 4.16; 95%CI 4.09-4.22); the SIR was 4.08 (95%CI 4.00-4.16) for men and 4.32 (95%CI 4.20-4.45) for women.The mean age of patients at first cancer diagnosis was 67.0 years among males and

2013 - Monocytosis has adverse prognostic significance and impacts survival in patients with T-cell lymphomas [Articolo su rivista]
Bari, Alessia; Tadmor, T.; Sacchi, Stefano; Marcheselli, L.; Liardo, ELIANA VALENTINA; Pozzi, Samantha; Luminari, Stefano; Baldini, L.; Marmiroli, Sandra; Federico, Massimo; Polliack, A.
abstract

In this retrospective study we evaluated the prognostic impact of peripheral blood monocytosis in patients with T-cell non Hodgkin lymphomas with "aggressive-typically nodal presentation". In this dataset monocytes >0.8×10(9)/L had a strong and statistically significant negative impact on overall survival (OS). In univariate analysis several parameters, including age >60 years, advanced stage, bone marrow involvement, ECOG PS >1, high LDH level, monocytes >0.8×10(9)/L, hemoglobin<120g/L, albumin<35g/L) had a negative influence on outcome, but in multivariate analysis, monocytosis alone had a stronger association with poor OS.

2013 - Prognostic role of gender in diffuse large B-cell lymphoma treated with rituximab containing regimens: a Fondazione Italiana Linfomi/Grupo de Estudos em Moléstias Onco-Hematológicas retrospective study [Articolo su rivista]
Carella, Angelo M; de Souza, Carmino A; Luminari, Stefano; Marcheselli, Luigi; Chiappella, Annalisa; di Rocco, Alice; Cesaretti, Marina; Rossi, Andrea; Rigacci, Luigi; Gaidano, Gianluca; Merli, Francesco; Spina, Michele; Stelitano, Caterina; Hohaus, Stefan; Barbui, Anna; Puccini, Benedetta; Miranda, Eliana C; Guida, Annalisa; Federico, Massimo
abstract

Male gender was recently reported as an adverse prognostic factor in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). We conducted a retrospective study of adult patients with DLBCL initially treated with rituximab containing regimens between 2001 and 2007. Patients were identified from the clinical archives of 43 Italian and Brazilian institutions. The principal endpoint was overall survival (OS). One thousand seven hundred and ninety-three patients were fully eligible for the study. Thirty-eight percent, 27%, 22% and 12% of patients had an International Prognostic Index (IPI) score of 0-1, 2, 3 and 4-5, respectively; 53% were males. After a median follow-up of 36 months (1-106), the 5-year OS was 76% (95% confidence interval 74-78%). In univariate analysis, male gender was an adverse prognostic factor with a hazard ratio of 1.52. In multivariate analysis, when adjusted by IPI, again gender maintained its prognostic relevance, showing an independent additive effect. In conclusion, in patients with DLBCL treated with rituximab containing regimens, gender may increase the predictive power of the IPI. Based on these results, given possible differences in blood clearance of rituximab between males and females, the benefit of higher doses of rituximab in males should be explored.

2013 - R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lmphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi [Articolo su rivista]
Federico, Massimo; Luminari, Stefano; Dondi, Alessandra; Tucci, Alessandra; Vitolo, Umberto; Rigacci, Luigi; Di Raimondo, Francesco; Carella, Angelo Michele; Pulsoni, Alessandro; Merli, Francesco; Arcaini, Luca; Angrilli, Francesco; Stelitano, Caterina; Gaidano, Gianluca; Dell'Olio, Matteo; Marcheselli, Luigi; Franco, Vito; Galimberti, Sara; Sacchi, Stefano; Brugiatelli, Maura
abstract

PURPOSE Although rituximab (R) is commonly used for patients with advanced follicular lymphoma (FL) requiring treatment, the optimal associated chemotherapy regimen has yet to be clarified. PATIENTS AND METHODS We conducted an open-label, multicenter, randomized trial among adult patients with previously untreated stages II to IV FL to compare efficacy of eight doses of R associated with eight cycles of cyclophosphamide, vincristine, and prednisone (CVP) or six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or six cycles of fludarabine and mitoxantrone (FM). The principal end point of the study was time to treatment failure (TTF). Results There were 534 patients enrolled onto the study. Overall response rates were 88%, 93%, and 91% for R-CVP, R-CHOP, and R-FM, respectively (P=.247). After a median follow-up of 34 months, 3-year TTFs were 46%, 62%, and 59% for the respective treatment groups (R-CHOP v R-CVP, P=.003; R-FM v R-CVP, P=.006; R-FM v R-CHOP, P=.763). Three-year progression-free survival (PFS) rates were 52%, 68%, and 63% (overall P=.011), respectively, and 3-year overall survival was 95% for the whole series. R-FM resulted in higher rates of grade 3 to 4 neutropenia (64%) compared with R-CVP (28%) and R-CHOP (50%; P< .001). Overall, 23 second malignancies were registered during follow-up: four in R-CVP, five in R-CHOP, and 14 in R-FM. CONCLUSION In this study, R-CHOP and R-FM were superior to R-CVP in terms of 3-year TTF and PFS. In addition, R-CHOP had a better risk-benefit ratio compared with R-FM.

2013 - Risk factors for impaired gonadal function in female Hodgkin lymphoma survivors: final analysis of a retrospective multicenter joint study from Italian and Brazilian Institutions. [Articolo su rivista]
Falorio, S; Biasoli, I; Luminari, Stefano; Quintana, G; Musso, M; Dell'Olio, M; Specchia, Mr; di Renzo, N; Cesaretti, Marina; Buda, G; Vallisa, D; Mannina, D; Andriani, A; Chiattone, Cs; Delamain, Mt; de Souza, Ca; Spector, N; Angrilli, F; Federico, Massimo
abstract

Hodgkin lymphoma (HL) is one of the most common types of cancer in the young and one of the most curable forms of cancer. Therefore, there has been an increasing interest in the study of long-term morbidities. The aims of the present study were to evaluate the prevalence and risk factors for impaired gonadal function in a retrospective cohort of 238 HL female survivors from Italy and Brazil and to analyse the role of oral contraceptives (OC) and GnRH-analogues. Besides data collection from HL databases, a specific questionnaire was administered to collect data on gonadal function. The median age at diagnosis was 25 years and the median follow-up was 7 years. Overall, 25% of the patients developed impaired gonadal function. Older age at diagnosis, front-line therapies containing alkylating agents and more than one treatment were independent risk factors, whereas the use of OC or GnRH-a reduced independently the risk of impaired gonadal function. The fertility rate among fertile survivors was low when compared with the general population. We confirmed that older age, type of front-line chemotherapy and a higher number of therapies are associated with gonadal function impairment in terms of infertility and premature menopause in female HL survivors. Also, the use of GnRH-a or OC was independently identified as a protective factor. Further prospective studies are needed to better understand the barriers to parenthood in HL survivors.

2013 - Role of radiotherapy in patients with early-stage diffuse large B-cell lymphoma of Waldeyer's ring in remission after anthracycline-containing chemotherapy [Articolo su rivista]
Mian, Michael; Ferreri, Andrés J. M; Rossi, Andrea; Conconi, Annarita; Tsang, Richard; Gospodarowicz, Mary K; Oldani, Elena; Federico, Massimo; Luminari, Stefano; Pogliani, Enrico M; Rossini, Fausto; Cabrera, Maria E; Martelli, Maurizio; Gutierrez Garcia, Gonzalo; Busetto, Mario; Cavalli, Franco; Zucca, Emanuele; Rambaldi, Alessandro; Cortelazzo, Sergio
abstract

Consolidation radiotherapy (cRT) in patients with stage I/II diffuse large B-cell lymphoma of the Waldeyer's ring (WR-DLBCL) in complete remission (CR) after induction chemotherapy (CHT) is often associated with relevant acute and chronic toxicity, and its impact on survival remains to be defined. A total of 184 patients in CR after anthracycline-based chemotherapy were retrospectively analyzed: 62 underwent CHT alone (CHT group), while 122 (66%) patients were referred to cRT (CHT + RT group). After a median follow-up of 54 months, 36 patients (20%) experienced relapse: 19% in the CHT group and 20% in the CHT + RT group. At the time of analysis 47 (76%) CHT patients and 97 (80%) CHT + RT patients were alive. Five-year overall survival (OS), disease-free survival (DFS) and lymphoma-specific survival (LSS) were 80%, 74% and 86%, respectively. Five-year OS was significantly prolonged in the CHT + RT group, while DFS and LSS were similar between groups. This discrepancy was attributed to a high percentage of deaths due to unrelated causes in CHT patients. cRT does not prolong LSS in patients with early-stage WR-DLBCL in CR after anthracycline-containing chemotherapy. An international confirmatory trial is warranted.

2013 - Survival of multiple myeloma patients in the era of novel therapies confirms the improvement in patients younger than 75 years: a population-based analysis [Articolo su rivista]
Pozzi, Samantha; Marcheselli, Luigi; Bari, Alessia; Liardo, ELIANA VALENTINA; Marcheselli, Raffaella; Luminari, Stefano; Quaresima, Micol; Cirilli, C.; Ferri, Paola; Federico, Massimo; Sacchi, Stefano
abstract

Novel treatments for multiple myeloma (MM) have shown promising results in clinical trials, but the advantage in unselected patients is still unclear. In order to evaluate whether novel therapies impact survival of MM patients, we performed a population-based analysis on data collected by the Modena Cancer Registry from 1989 to 2009. The analysis evaluated 1206 newly diagnosed MM patients collected in the years 1988-96 (conventional therapy), 1997-05 (high dose melphalan and autologous transplant), and 2006-09 (novel agents era). Both relative survival (RS) and overall survival (OS) improved over the years, but not equally in the three groups. For patients aged <65 years, RS improved in 1997-05 and 2006-09 compared with previous years and a trend to improvement was observed from 1997-05 to 2006-09. For patients aged 65-74 years, RS improved significantly in 2006-09 compared with 1988-96 and 1997-05. No amelioration was observed for patients 75+ years old. OS confirmed RS. In conclusion, the survival of MM patients aged <65 and, in particular, 65-74 years, has improved over time, especially after 2006. This observation provides circumstantial evidence that novel therapies might impact patient survival. Despite the limits of this study, these data refer to an unselected population, giving a picture of every day clinical practice.

2013 - The use of FDG-PET in the initial staging of 142 patients with follicular lymphoma: a retrospective study from the FOLL05 randomized trial of the Fondazione Italiana Linfomi [Articolo su rivista]
Luminari, Stefano; Biasoli, I.; Arcaini, L.; Versari, A.; Rusconi, C.; Merli, F.; Spina, M.; Ferreri, A. J.; Zinzani, P. L.; Gallamini, A.; Mastronardi, S.; Boccomini, C.; Gaidano, G.; D'Arco, A. M.; Di Raimondo, F.; Carella, A. M.; Santoro, A.; Musto, P.; Federico, Massimo
abstract

BACKGROUND: The role of [(18)F] fluorodeoxyglucose (FDG)-positron emission tomography (PET) in follicular lymphoma (FL) staging is not yet determined. PATIENTS AND METHODS: The aim of the present study was to investigate the role of PET in the initial staging of FL patients enrolled in the FOLL05-phase-III trial that compared first-line regimens (R-CVP, R-CHOP and R-FM). Patients should have undergone conventional staging and have available PET baseline to be included. RESULTS: A total of 142 patients were analysed. PET identified a higher number of nodal areas in 32% (46 of 142) of patients and more extranodal (EN) sites than computed tomography (CT) scan. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score increased in 18% (26 of 142) and decreased in 6% (9 of 142) of patients. Overall, the impact of PET on modifying the stage was highest in patients with limited stage. Actually, 62% (15 of 24) of cases with limited disease were upstaged with PET. CONCLUSIONS: The inclusion of PET among staging procedures makes the evaluation of patients with FL more accurate and has the potential to modify therapy decision and prognosis in a moderate proportion of patients. Further prospective clinical trials on FL should incorporate PET at different moments, and the therapeutic criteria to start therapy should be re-visited in the views of this new tool.

2012 - Cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab versus epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab for the initial treatment of elderly “fit” patients with diffuse large B-cell lymphoma: results from the ANZINTER3 trial of the Intergruppo Italiano Linfomi [Articolo su rivista]
Merli, F.; Luminari, Stefano; Rossi, G.; Mammi, Caterina; Marcheselli, Luigi; Tucci, A.; Ilariucci, F.; Chiappella, A.; Musso, M.; Di Rocco, A.; Stelitano, C.; Alvarez, I.; Baldini, L.; Mazza, P.; Salvi, F.; Arcari, A.; Fragasso, A.; Gobbi, P. G.; Liberati, A. M.; Federico, Massimo
abstract

We conducted a prospective study to compare epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab (R-miniCEOP) to cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (R-CHOP) for the treatment of “fit” elderly patients with diffuse large B-cell lymphoma (DLBCL). Patients over the age of 65 with stage II-IV DLBCL were screened with a comprehensive geriatric assessment. Patients were randomized to receive 6 courses of R-miniCEOP (114) or R-CHOP (110). Overall, the rate of complete remission was 70% (P=0.466). After a median follow-up of 42 months, 5-year EFS rates were 46% and 48% for R-miniCEOP and R-CHOP, respectively (P = 0.538). Patients older than 72 years and with low risk disease had a better outcome when treated with R-miniCEOP (P=0.011). Overall R-CHOP and R-miniCEOP are similarly effective for elderly “fit” patients with DLBCL. The less intense R-miniCEOP may be an acceptable option for the treatment of relatively older patients with low-risk disease.

2012 - Fertility in female survivors of hodgkin's lymphoma. [Articolo su rivista]
Biasoli, I.; Falorio, S.; Luminari, Stefano; Spector, N.; Federico, Massimo
abstract

Currently, Hodgkin's lymphoma is one of the most curable types of cancer. Patients are often young and so the long-term morbidities of treatment have become of increasing concern. Among these, infertility is one of the most challenging consequences for patients in reproductive age. Premature ovarian failure in premenopausal women is a serious long-term sequel of the toxicity of chemotherapy. The main consequence of this syndrome is infertility, but women also present other symptoms related to estrogen deprivation. Different rates of impaired gonadal function are reported, depending on the patient's age, stage of disease, dose and intensity of chemotherapy and the use of radiation therapy. The most established strategy in female infertility is cryopreservation of embryos after in vitro fertilization. Additionally, the use of oral contraceptives or gonadotropin-releasing hormone analogs (GnRH-a) during treatment is under study. This review will provide a general overview of the main studies conducted to evaluate the infertility rate among female Hodgkin's lymphoma survivors and risk factors associated to treatment, different end-pointg definitions for evaluating fertility and also a brief description of the available strategies for fertility preservation.

2012 - Follicular Lymphoma - treatment and prognostic factors. [Articolo su rivista]
Luminari, Stefano; Bellei, Monica; Biasoli, I.; Federico, Massimo
abstract

Follicular lymphoma is the second most frequent non-Hodgkin lymphoma accounting for about 10-20% of all lymphomas in western countries. The median age at diagnosis is 60 years old. The clinical presentation is usually characterized by asymptomatic peripheral adenopathy in cervical, axillary, inguinal and femoral regions. Treatment options for patients with naive or recurrent follicular lymphoma are still controversial, ranging from a "watch and wait" policy to hematopoietic stem cell transplantation. More recently, the availability of rituximab has substantially changed follicular lymphoma therapeutic approaches to such an extent that R-Chemo is now the standard induction first-line treatment. This review provides a general overview of the state of the art in the management of follicular lymphoma and also, a brief description regarding the the current prognostic tools available for treatment decisions.

2012 - Helicobacter pylori eradication as exclusive treatment for limited-stage gastric diffuse large B-cell lymphoma: results of a multicenter phase 2 trial. [Articolo su rivista]
Ferreri, Aj; Govi, S; Raderer, M; Mulè, A; Andriani, A; Caracciolo, D; Devizzi, L; Ilariucci, F; Luminari, Stefano; Viale, E; Müllauer, L; Dell'Oro, S; Arcidiacono, Pg; Ponzoni, M; Patti, C.
abstract

Helicobacter pylori eradication as exclusive treatment for limited-stage gastric diffuse large B-cell lymphoma: results of a multicenter phase 2 trial

2012 - Linking Drugs to Obscure Illnesses: Lessons from Pure Red Cell Aplasia, Nephrogenic Systemic Fibrosis, and Reye’s Syndrome. A Report From the Southern Network on Adverse Reactions (SONAR) [Articolo su rivista]
Charles L., Bennett; Karen M., Starko; Henrik S., Thomsen; Shawn, Cowper; Oliver, Sartor; Iain C., Macdougall; Zaina P., Qureshi; P., Brandon Bookstaver; April D., Miller; LeAnn B., Norris; Sudha, Xirasagar; Alyssa, Trenery; Isaac, Lopez; Adam, Kahn; Alanna, Murday; Luminari, Stefano; Denis, Cournoyer; Francesco, Locatelli; Paul, Ray; Donald R., Mattison
abstract

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye’s syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States’ NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

2012 - Prognostic assessment in patients with indolent B-cell lymphomas [Articolo su rivista]
Arcaini, Luca; Rattotti, Sara; Gotti, Manuel; Luminari, Stefano
abstract

Follicular lymphoma (FL) is an indolent lymphoma with long median survival. Many studies have been performed to build up prognostic scores potentially useful to identify patients with poorer outcome. In 2004, an international consortium coordinated by the International Follicular Lymphoma Prognostic Factor project was established and a new prognostic study was launched (FLIPI2) using progression-free survival (PFS) as main endpoint and integrating all the modern parameters prospectively collected. Low-grade non-Hodgkin lymphomas were once considered as a heterogenous group of lymphomas characterized by an indolent clinical course. Each entity is characterized by unique clinicobiologic features. Some studies have been focused on prognostic factors in single lymphoma subtypes, with the development of specific-entity scores based on retrospective series, for instance splenic marginal zone lymphoma (SMZL). A widely accepted prognostic tool for clinical usage for indolent non-follicular B-cell lymphomas is largely awaited. In this paper we summarized the current evidence regarding prognostic assessment of indolent follicular and non-follicular lymphomas.

2012 - Rituximab plus HyperCVAD alternating with high dose cytarabine and methotrexate for the initial treatment of patients with mantle cell lymphoma, a multicentre trial from Gruppo Italiano Studio Linfomi. [Articolo su rivista]
Merli, F; Luminari, Stefano; Ilariucci, F; Petrini, M; Visco, C; Ambrosetti, A; Stelitano, C; Caracciolo, F; Di Renzo, N; Angrilli, F; Carella, Am; Capodanno, I; Barbolini, E; Galimberti, S; Federico, Massimo
abstract

This study investigated the clinical activity and toxicity of R-HCVAD-AM [rituximab plus HyperCVAD (R-HCVAD) alternating with high-dose cytarabine and methotrexate (AM)] in patients with newly diagnosed Mantle Cell Lymphoma (MCL). Patients aged ≤70years with confirmed MCL received four alternating cycles each of R-HCVAD and AM. Patients who obtained a partial response proceeded to autologous stem cell transplant. Sixty-three patients were enrolled and 60 were fully eligible. Median age was 57years (22-66); 60%, 33% and 7% were classified at low (L)-, intermediate (I)- or high (H)-risk, respectively, according to the MCL International Prognostic Index (MIPI). Only 22 patients (37%) completed the four cycles and three patients died during therapy. Overall response and complete response rates were 83% and 72% respectively. After a median follow-up of 46months (range 1-72) the estimated 5-year overall survival (OS) and progression-free survival rates were 73% [95% confidence interval (CI) 59-83%], and 61% (95%CI 45-73%) respectively. MIPI maintained the prognostic value with an estimated 5-year OS of 89%, 80% and 24% for L, I, and H groups respectively (P<0·001). This multicentre study confirms that R-HCVAD-AM is an active regimen for the initial treatment of patients with MCL, but is associated with significant toxicity.

2012 - Role of Glutathione-S-Transferase (GST) polymorphisms in patients with advanced Hodgkin Lymphoma: results from the HD2000 GISL Trial [Articolo su rivista]
Morabito, F.; Hohaus, S.; Mammi, Caterina; Marcheselli, Luigi; Gentile, M.; Merli, F.; Montanini, Antonella; Stelitano, C.; La Sala, A.; Scalone, R.; Voso, M. T.; Luminari, Stefano; Iannitto, E.; Gobbi, P. G.; Federico, Massimo
abstract

Abstract Polymorphisms of the Glutathione-S Transferase (GST) family may influence the prognosis in lymphoma patients. We aimed to validate the impact of GSTT1 and GSTM1 deletions and of the GSTP1Ile105Val polymorphism on outcome and toxicity in 140 patients with advanced Hodgkin's lymphoma enrolled in the prospective multicenter HD2000-GISL trial, comparing ABVD, BEACOPP and CEC regimens. Carriers of the GSTP1Ile105Val polymorphism had a higher rate of grade 3-4 anemia following treatment. Overall, our study failed to validate GST genotyping as prognostic factor for progression-free survival (PFS). Only the small cohort of patients with an international prognostic score (IPS) >3 and undeleted GSTT1 and/or GSTM1, treated with ABVD had worse progression-free survival (PFS) (GSTT1+ vs GSTT1-: HR 5.02, 95% C.I., 1.16-21.8, P=0.031, GSTM1+/GSTT1+ vs GSTM1-and/or GSTT1-: HR 4.61, 95% C.I. 1.28-16.6, P=0.019, respectively). No differences were observed for patients treated with intensified regimens, as BEACOPP and CEC. In conclusion, the prognostic role of GST polymorphism, if at all, is limited to a small subgroup of patients treated with standard ABVD regimen.

2012 - T-cell lymphoma in South America and Europe. [Articolo su rivista]
Bellei, Monica; Chiattone, C. S.; Luminari, Stefano; Pesce, Emanuela Anna; Cabrera, M. E.; de Souza, A. C.; Gabùs, R.; Zoppegno, L.; Milone, J.; Pavlovsky, A.; Connors, J. M.; Foss, F. M.; Horwitz, S. M.; Liang, R.; Montolo, S.; Pileri, S. A.; Polliak, A.; Vose, J. M.; Zinzani, P. L.; Zucca, E.; Federico, Massimo
abstract

Peripheral T-cell lymphomas are a group of rare neoplasms originating from clonal proliferation of mature post-thymic lymphocytes with different entities having specific biological characteristics and clinical features. As natural killer cells are closely related to T-cell, natural killer-cell lymphomas are also part of the group. The current World Health Organization classification recognizes four categories of T/natural killer-cell lymphomas with respect to their presentation: disseminated (leukemic), nodal, extranodal and cutaneos. Geographic variations in the distribution of these diseases are well documented: nodal subtypes are more frequent in Europe and North America, while extranodal forms, including natural killer-cell lymphomas, occur almost exclusively in Asia and South America. On the whole, T-cell lymphomas are more common in asia than in western countries, usually affect adults, with a higher tendency in men, and, excluding a few subtypes, usually have an aggressive course and poor prognosis. Apart from anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, that have a good outcome, other nodal and extranodal forms have a 5-year oversall survival of about 30%. According to the principal prognostic indexes, the majority of patients are allocated to the unfavorable subset. In the past, the rarity of these diseases prevented progress in the understanding of their biology and improvements in the efficaciousness of therapy. Recently, international projects devoted to these diseases created networks promting investigations on T-cell lymphomas. These projects are the basis of forthcoming cooperative, large scale trials to detail biologic characteristics of each sub-entity and to possibly individuate targets for new therapies.

2012 - Tumour burden predicts treatment resistance in patients with early unfavourable or advanced stage Hodgkin lymphoma treated with ABVD and radiotherapy. [Articolo su rivista]
Gobbi, Pg; Bassi, E; Bergonzi, M; Merli, F; Coriani, C; Iannitto, E; Luminari, Stefano; Polimeno, G; Federico, Massimo
abstract

The purpose of the work was to investigate the factors predicting early resistance to treatment in Hodgkin lymphoma. Many staging parameters, including relative tumour burden (rTB), were analysed in 246 patients with Hodgkin lymphoma in relation to early failure, that is, less than complete remission (i.e. partial response, null response or progression) or occurrence of early relapse, as clinical expressions of resistance to treatment. Patients with early unfavourable disease were 129 and were treated with four to six cycles of ABVD + involved field radiotherapy; 117 patients with advanced stage disease received six cycles of ABVD + optional irradiation to no more than two sites. The rTB was volumetrically measured through the evaluation of staging computed tomography for all the lesions except bone marrow involvement, which was quantified by calculation. The relationship with early resistance was analysed with logistic regressions. The rTB demonstrated to be the best predictor of early failure in both patient subsets, being superior to the multiparameter International Prognostic Score. The rTB showed a significant exponential relationship with the relative risk of early failure, and with inclusion of the extranodal involvement into the model, a single equation became adequate to predict resistance in both early unfavourable and advanced stage patients. The conclusions are that the rTB is the best pretreatment factor related to the risk of resistance to combined ABVD + radiotherapy and that this relationship can be mathematically expressed in an easy way. A simplified assessment of rTB is highly desirable.

2012 - Watchful waiting in low-tumorburden follicular lymphoma in the Rituximab era. Results of a F2 observational [Articolo su rivista]
Solal Céligny, P.; Bellei, Monica; Marcheselli, Luigi; Pesce, Emanuela Anna; Pileri, S.; Mclaughlin, P.; Luminari, Stefano; Pro, B.; Montolo, S.; Ferreri, A. J. M.; Deconinck, E.; Milpied, N.; Gordon, L. I.; Federico, Massimo
abstract

PURPOSEPatients with follicular lymphoma (FL) registered in the F2-study and initially managed without treatment were analyzed to describe the presentation and outcome of a watch and wait (W&W) strategy in the rituximab era, to identify parameters for initiating treatment, and to evaluate whether initial W&W could have deleterious effects on treatment efficacy after progression or relapse. PATIENTS AND METHODSBetween 2003 and 2005, 120 patients selected from the 1,093 treatment-naive patients with FL in the F2-study cohort were initially managed expectantly (W&W), and 107 patients were assessed. Most of these patients (80%) had disseminated disease with a low tumor burden according to Groupe d'Etudes des Lymphomes Folliculaires criteria.ResultsAfter a median follow-up of 64 months, treatment was initiated in 54 patients (50%), with a median delay of 55 months for the entire cohort. In a univariate analysis, involvement of more than four nodal areas (hazard ratio [HR], 2.26) and serum albumin less than 3.5 g/dL (HR, 3.51) were predictive of a shorter time to lymphoma treatment initiation. In a multivariate analysis, only involvement of more than four nodal areas remained significant (HR, 2.32). The 4-year freedom from treatment failure (FFTF) rate of W&W patients (79%; 95% CI, 69% to 85%) was not inferior to that of a subgroup of 242 patients from the F2-study cohort with good prognosis characteristics who were initially treated with a rituximab-based regimen (69%; 95% CI, 61% to 76%; P = .103). CONCLUSIONIn the rituximab era, patients with FL in a selected prognostically favorable group can still be managed with W&W. W&W does not seem to have detrimental effects on FFTF and overall survival rates after treatment.

2011 - Anthracyclines: a cornerstone in the management of non-Hodgkin's lymphoma. [Articolo su rivista]
Luminari, Stefano; Montanini, Antonella; Federico, Massimo
abstract

Since anthracyclines were introduced in the treatment of non-Hodgkin's lymphoma in the late 1960s, they have been acknowledged as a cornerstone in the management of the disease and, in particular, of aggressive lymphomas. The high efficacy of anthracycline-containing regimens must, however, be balanced against the drug-related toxicity, which mainly affects the cardiovascular system and represents a major concern for clinicians, especially in the treatment of elderly patients. Patients' outcomes could be further improved, particularly for those at high risk of cardiotoxicity, by substituting liposomal doxorubicin for conventional doxorubicin. This approach has already been tested and shown to be effective in several cancers, especially in different subsets of patients with diffuse large B-cell lymphoma. The use of liposomal doxorubicin in combination regimens for other conditions, such as follicular lymphoma and splenic marginal zone lymphoma, is also under investigation, and early results are promising.

2011 - CLIPI: a new prognostic index for indolent cutaneos B cell lymphoma proposed by the International Extranodal Lymphoma Study Group (IELSG 11) [Articolo su rivista]
Mian, M.; Marcheselli, Luigi; Luminari, Stefano; Federico, Massimo; Cantonetti, M.; Sarris, A. H.; Rossi, A.; Rambaldi, A.; Frontani, M.; Devizzi, L.; Gianni, A. M.; Busetto, M.; Berti, E.; Martinelli, G.; Tsang, R. W.; Ferreri, A. J. M.; Pinotti, G.; Pogliani, E.; Zucca, E.; Cortelazzo, S.
abstract

Indolent primary cutaneous B cell lymphomas (PCBCL) generally have a good prognosis, but they often relapse leading in some cases to extracutaneous disease and therefore, to poor survival. We developed a prognostic model to improve the therapeutic approach to these lymphomas. Two hundred and seventeen patients with diagnosis of indolent PCBCL stage IE or IIE were assessed retrospectively. The prognostic model was built to fit a Cox proportional hazard model using all the covariates affecting progression-free survival (PFS) at p < 0.1 in the univariate analysis, and the final model was selected based on the Bayes Information Criteria. Elevated serum lactate dehydrogenase, morphology of the lesion (nodule vs. other), and >2 lesions were independent predictors for PFS. To each prognostic factor was assigned a value of 1. Patients were then stratified to three risk groups: score 0 (28%), low risk; score 1 (55%), intermediate risk; score 2 and 3 (17%), high risk with a 5-year PFS of 91%, 64%, and 48%, respectively (p < 0.001). The CLIPI is an easily applicable prognostic index and represents a promising tool for risk-adapted treatment strategies. However, it needs to be addressed in prospective clinical studies.

2011 - Case studies of elderly patients with non-Hodgkin's lymphoma. [Articolo su rivista]
Luminari, Stefano; Federico, Massimo
abstract

No abstract available

2011 - High response rate and improvement of long-term survival with combined treatment modalities in patients with poor-risk primary thyroid diffuse large B-cell lymphoma: an International Extranodal Lymphoma Study Group and Intergruppo Italiano Linfomi Study [Articolo su rivista]
Mian, M.; Gaidano, G.; Conconi, A.; Tsang, R.; Gospodarowicz, M. K.; Rambaldi, A.; Rossi, A.; Oldani, E.; Federico, Massimo; Luminari, Stefano; Bellei, Monica; Pogliani, E. M.; Rossini, F.; Cabrera, M. E.; Martelli, M.; Lopez Guillermo, A.; Busetto, M.; Cavalli, F.; Zucca, E.; Cortelazzo, S.
abstract

The impact of different treatment modalities and prognostic factors on the clinical course of primary thyroid diffuse large B-cell lymphoma (PTDLBCL) is still the subject of research. This study was conducted to clarify these clinical aspects of this disorder. The clinical parameters of 48 patients with PTDLBCL at time of diagnosis were comparable to those of previous studies. Patients underwent either radiotherapy (RT) ± surgery (SX), chemotherapy (CHT) alone or in combination with local treatments (RT or SX), or SX followed by CHT and RT. A 90% complete remission (CR) rate was observed among patients who underwent combined treatment modalities (CTM), compared to 76% among the others. The 5-year progression-free survival differed significantly between both groups (p = 0.028). Poor performance status and advanced age correlated with decreased survival. PTDLBCL is a curable disease prevalent in elderly patients. Combined treatment modalities were able to induce an elevated rate of CR, improving long-term survival in younger patients. However, the outcome in elderly patients still remains unsatisfactory.

2011 - I tumori in Italia. Rapporto 2011: La sopravvivenza dei pazienti oncologici in Italia [Articolo su rivista]
Fusco M, AIRTUM Working G. r. o. u. p.; Buzzoni, C; Coviello, E; Rashid, I; Bianconi, F; Cuccaro, F; Castaing, M; De Angelis, R; Giacomin, A; Guzzinati, S; Mosso, Ml; Pisani, P; Quaglia, A; Randi, G; Ramazzotti, V; Russo, A; Senatore, G; Stracci, F; Traina, A; Vercelli, M; Zarcone, M; Ferretti, S; Mazzoleni, G; Bellú, F; Tschugguel, B; De Valiere, E; Facchinelli, G; Falk, M; Dal Cappello, T; Vercellino, Pc; Andreone, S; Busato, A; Marzola, L; Migliari, E; Carletti, N; Nenci, I; Crocetti, E; Caldarella, A; Corbinelli, A; Giusti, F; Intrieri, T; Manneschi, G; Nemcova, L; Romeo, G; Sacchettini, C; Zappa, M; Paci, E; Serraino, D; Angelin, T; Bidoli, E; Dal Maso, L; de Dottori, M; De Paoli, A; De Santis, E; Forgiarini, O; Lise, M; Zucchetto, A; Zanier, L; Orengo, Ma; Casella, C; Marani, E; Puppo, A; Celesia, Mv; Cogno, R; Manenti, S; Garrone, E; Pannozzo, F; Busco, S; Cercato, Mc; Battisti, W; Sperduti, I; Macci, L; Bugliarello, E; Bernazza, E; Tamburo, L; Rossi, M; Curatella, S; De Francesco, C; Tamburrino, S; Bisanti, L; Autelitano, M; Ghilardi, S; Leone, R; Filipazzi, L; Bonini, A; Giubelli, C; Federico, Massimo; Artioli, Me; Valla, K; Braghiroli, B; Cirilli, C; Luminari, Stefano; Pirani, M; Ferrari, L; Bellatalla, C; Fusco, M; Panico, M; Perrotta, C; Vassante, B; Vitale, Mf; Michiara, M; Bozzani, F; Sgargi, P; Tumino, R; La Rosa, Mg; Cascone, G; Frasca, G; Giurdanella, Mc; Martorana, C; Morana, G; Nicita, C; Rollo, Pc; Ruggeri, Mg; Sigona, A; Spata, E; Vacirca, S; Mangone, L; Di Felice, E; Pezzarossi, A; Caroli, S; Pellegri, C; Vicentini, M; Storchi, C; Cavuto, S; Costa, J; Falcini, F; Colamartini, A; Bucchi, L; Balducci, C; Ravegnani, M; Vitali, B; Cordaro, C; Caprara, L; Giuliani, O; Giorgetti, S; Salvatore, S; Palumbo, M; Vattiato, R; Ravaioli, A; Foca, F; Rinaldi, E; Mancini, S; Tonelli, C; Amadori, M; Cremone, L; Iannelli, A; Zevola, A; Budroni, M; Cesaraccio, R; Pirino, D; Carboni, D; Fiori, G; Soddu, M; Mameli, G; Mura, F; Contrino, Ml; Madeddu, A; Tisano, F; Sciacca, S; Muni, A; Mizzi, M; Russo, M; Sacco, G; Aletta, P; Colanino Ziino, A; Tessandori, R; Fanetti, Ac; Maspero, S; Annulli, Ml; Moroni, E; Sanoja Gonzalez, Me; Zanetti, R; Rosso, S; Patriarca, S; Prandi, R; Sobrato, I; Gilardi, F; Busso, P; Piffer, S; Gentilini, Ma; Battisti, L; Rizzello, R; Cappelletti, M; Moser, M; La Rosa, F; D'Alò, D; Scheibel, M; Costarelli, D; Spano, F; Rossini, S; Santucci, C; Petrinelli, Am; Solimene, C; Brunori, V; Crosignani, P; Tagliabue, G; Contiero, P; Preto, L; Tittarelli, A; Maghini, A; Codazzi, T; Frassoldi, E; Gada, D; Costa, E; di Grazia, L; Zambon, P; Baracco, M; Bovo, E; Dal Cin, A; Fiore, Ar; Greco, A; Monetti, D; Rosano, A; Stocco, C; Tognazzo, S; Donato, F; Limina, Rm; Adorni, A; Andreis, P; Zani, G; Piovani, F; Salvi, O; Puleio, M; Vitarelli, S; Antonini, S; Candela, G; Pappalardo, G; Scuderi, T; Lottero, B; Ribaudo, M; Ricci, P; Guarda, L; Gatti, L; Bozzeda, A; Dall'Acqua, M; Pironi, V; Sutera Sardo, A; Mazzei, A; Sirianni, N; Lavecchia, Am; Mancuso, P; Usala, M; Pala, F; Sini, Gm; Pintori, N; Canu, L; Demurtas, G; Doa, N; PONZ DE LEON, Maurizio; Domati, Federica; Rossi, Giuseppina; Goldoni, Ca; Rossi, F; De Gaetani, C; Benatti, Piero; Roncucci, Luca; Di Gregorio, C; Pedroni, Monica; Pezzi, A; Maffei, Stefania; Mariani, Francesco; Borsi, E; Carruba, G; Cusimano, R; Amodio, R; Dolcemascolo, C; Staiti, R; Pastore, G; Magnani, C; Terracini, B; Cena, T; Alessi, D; Baussano, I; Merletti, F; Maule, M; Macerata, V; Cocchioni, M; Pascucci, C; Gennaro, V; Lazzarotto, A; Benfatto, L; Mazzucco, G; Montanaro, F.
abstract

INTRODUCTION: population-based survival analyses are fundamental to assess the impact of public health interventions and new therapies in cancer control. This monograph updates previous reports on cancer patient survival in Italy up to the year 2007. MATERIAL AND METHODS: we extracted from the Network of Italian Cancer Registries (AIRTUM) database over 1,490,000 records of tumours diagnosed during 1990-2007 and followed up to the end of 2008, including all multiple tumours. We used the Ederer II method to estimate relative survival (RS) for 29 different types of neoplasm. Five-year relative survival rates were analysed by gender and macroarea. Trends in 5-, 10- and 15-year RS were studied by gender over six 3-year diagnostic periods, from 1990 to 2007. Conditional 5-year RS was also computed by gender and macroarea. Hybrid approaches were applied to exploit the recent survival experiences of cases diagnosed up to 2007. Adjustment for age was performed using EUROCARE weights. Additional sections describe cancer patient survival in childhood and in elderly patients and provide a comparison of cancer patient survival rates in Italy with those of other countries. RESULTS: Standardized 5-year RS for all tumours but skin in 52% for men and 61% for women. Patient survival has improved for almost all types of cancer: from 1990 to 2007 5-year RS has increased by 15% for all cancers but skin; the exceptions are some cancers with poor prognosis, where patient survival has remained basically unchanged. In males, RS was usually lower than in females, but trend analysis shows that the gap is narrowing. We also report persisting lower RS in southern Italy: 5-year RS in the South is usually from 4% to 10% lower than in the North and Centre. CONCLUSION: this study provides valuable information for all stakeholders in cancer control, both in Italy and elsewhere. Increasing survival reflects improvements in various areas of cancer control. On the other hand, delayed diagnosis and suboptimal management are consistent with the reported differences in survival within the country.

2011 - Long-term follow-up analysis of HD9601 trial comparing ABVD versus Stanford V versus MOPP/EBV/CAD in patients with newly diagnosed advanced-stage Hodgkin's lymphoma: a study from the Intergruppo Italiano Linfom [Articolo su rivista]
Chisesi, T.; Bellei, Monica; Luminari, Stefano; Montanini, Antonella; Marcheselli, Luigi; Levis, A.; Gobbi, P. G.; Vitolo, U.; Stelitano, C.; Pavone, V.; Merli, F.; Liberati, A. M.; Baldini, L.; Bordonaro, R.; Pesce, Emanuela Anna; Federico, Massimo
abstract

PURPOSEThe Intergruppo Italiano Linfomi HD9601 trial compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) versus doxorubicin, vinblastine, mechloretamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V [StV]) versus the combination of mechlorethamine, vincristine, procarbazine, prednisone (MOPP) with epidoxorubicin, bleomycin, vinblastine (EBV), lomustine, doxorubicin, and vindesine (CAD) (MOPP/EBV/CAD [MEC]) for the initial treatment of advanced-stage Hodgkin's lymphoma to select which regimen would best support a reduced radiotherapy program (limited to two or fewer sites of either previous bulky or partially remitting disease). Superiority of ABVD and MEC to StV was demonstrated. We report analysis of long-term outcome and toxicity. PATIENTS AND METHODSPatients with stage IIB, III, or IV were randomly assigned among six cycles of ABVD, three cycles of StV, and six cycles of MEC; radiotherapy was administered in 76, 71, and 50 patients in the three arms, respectively.ResultsCurrently, the median follow-up is 86 months; in the prolonged observation period, eight additional failures, including two relapses, both in the StV arm, and six additional deaths in complete response were recorded. The 10-year overall survival rates were 87%, 80%, and 78% for ABVD, MEC, and StV, respectively (P = .4). The 10-year failure-free survival was 75%, 74%, and 49% in the ABVD, MEC, and StV arms, respectively (P < .001). The 10-year disease-free survival of patients treated or not with radiotherapy (RT) showed no difference for ABVD or MEC (85% v 80% and 93% v 68%), and a statistically significant difference for StV (76% v 33%; P = .004). No significant long-term toxicity was recorded. CONCLUSIONThe long-term analysis confirmed ABVD and MEC superiority to StV. The use of RT after StV was established as mandatory. ABVD is still to be considered as the standard treatment with a good balance between efficacy and toxicity.

2011 - Survival of European patients diagnosed with lymphoid neoplasms in 2000-2002: results of the HAEMACARE project [Articolo su rivista]
Marcos Gragera, Rafael; Allemani, Claudia; Tereanu, Carmen; De Angelis, Roberta; Capocaccia, Riccardo; Maynadie, Marc; Luminari, Stefano; Ferretti, Stefano; Johannesen, Tom Børge; Sankila, Risto; Karjalainen Lindsberg, Marja Liisa; Simonetti, Arianna; Martos, Maria Carmen; Raphaël, Martine; Giraldo, Pilar; Sant, Milena
abstract

The European Cancer Registry-based project on hematologic malignancies (HAEMACARE), set up to improve the availability and standardization of data on hematologic malignancies in Europe, used the European Cancer Registry-based project on survival and care of cancer patients (EUROCARE-4) database to produce a new grouping of hematologic neoplasms (defined by the International Classification of Diseases for Oncology, Third Edition and the 2001/2008 World Health Organization classifications) for epidemiological and public health purposes. We analyzed survival for lymphoid neoplasms in Europe by disease group, comparing survival between different European regions by age and sex.

2011 - Use of 2-(18F)fluoro-2-deoxy-D-glucose positron emission tomography in patients with Hodgkin lymphoma in daily practice: a population-based study from Northern Italy [Articolo su rivista]
Luminari, Stefano; Cesaretti, Marina; Tomasello, Chiara; Guida, Annalisa; Bagni, Bruno; Merli, F.; Postiglione, Raffaella; Mangone, L.; Versari, A.; Re, F.; De Lisi, V.; Ruffini, L.; Ferretti, S.; Cuneo, A.; Federico, Massimo
abstract

We conducted a population-based study to assess how positron emission tomography (PET) is currently used in patients with Hodgkin lymphoma (HL). Four cancer registries from northern Italy were used to identify patients with HL diagnosed from 2006 to 2008. Computed tomography (CT) and PET scans were collected before treatment start (B), at the end (F), and during treatment (I). One hundred and thirty-six patients were identified as the study population. B-PET, I-PET, and F-PET were performed in 82%, 65%, and 85% of patients, respectively. Overall, I-PET was coded as positive in 16% of cases. F-PET was positive in 13% of cases. The I-PET result was a prognostic factor for failure-free survival (FFS) (hazard ratio [HR] 5.33); the F-PET result was the only prognostic factor for overall survival (OS) (HR 14.2). This population-based study confirms the prognostic role of I-PET for FFS also in daily practice; the results of F-PET can be used to predict OS.

2010 - Cancer incidence in people with AIDS in Italy [Articolo su rivista]
Jerry, Polesel; Silvia, Franceschi; Barbara, Suligoi; Emanuele, Crocetti; Fabio, Falcini; Stefano, Guzzinati; Marina, Vercelli; Roberto, Zanetti; Giovanna, Tagliabue; Antonio, Russo; Luminari, Stefano; Fabrizio, Stracci; Vincenzo De, Lisi; Stefano, Ferretti; Lucia, Mangone; Mario, Budroni; Rosa Maria, Limina; Silvano, Piffer; Diego, Serraino; Francesco, Bellù; Adriano, Giacomin; Andrea, Donato; Anselmo, Madeddu; Susanna, Vitarelli; Mario, Fusco; Roberto, Tessandori; Rosario, Tumino; Pierluca, Piselli; Luigino Dal, Maso
abstract

People with HIV/AIDS (PWHA) have increased risk of some cancers. The introduction of highly active antiretroviral therapies (HAART) has improved their life expectancy, exposing them to the combined consequences of aging and of a prolonged exposure to cancer risk factors. The aim of this study was to estimate incidence rates (IR) in PWHA in Italy, before and after the introduction of HAART, after adjusting for sex and age through direct standardization. An anonymous record linkage between Italian AIDS Registry (21,951 cases) and Cancer Registries (17.3 million, 30% of Italian population) was performed. In PWHA, crude IR, sex- and age-standardized IR and age-specific IR were estimated. The standardized IR for Kaposi sarcoma and non-Hodgkin lymphoma greatly declined in the HAART period. Although the crude IR for all non-AIDS-defining cancers increased in the HAART period, standardized IR did not significantly differ in the 2 periods (352 and 379/100,000, respectively). Increases were seen only for cancer of the liver (IR ratio = 4.6, 95% CI: 1.3-17.0) and lung (IR ratio = 1.8, 95% CI: 1.0-3.2). Age-specific IRs for liver and lung cancers, however, largely overlapped in the 2 periods pointing to the strong influence of the shift in the age distribution of PWHA on the observed upward trends. In conclusion, standardized IRs for non-AIDS-defining cancers have not risen in the HAART period, even if crude IRs of these cancers increased. This scenario calls, however, for the intensification of cancer-prevention strategies, notably smoking cessation and screening programs, in middle-aged HIV-patients. © 2010 UICC.

2010 - Clinical activity of bortezomib in relapsed/refractory MALT lymphomas: results of a phase II study of the International Extranodal Lymphoma Study Group (IELSG) [Articolo su rivista]
Conconi, A; Martinelli, G; Lopez Guillermo, A; Zinzani, P. L; Ferreri, A. J. M; Rigacci, L; Devizzi, L; Vitolo, U; Luminari, Stefano; Cavalli, F; Zucca, E.
abstract

The nuclear factor-kappa B activation in mucosa-associated lymphoid tissue (MALT) lymphoma pathogenesis provided the rationale for the evaluation of bortezomib in this malignancy.

2010 - Decreasing incidence of gastric MALT lymphomas in the era of anti-Helicobacter pilori interventions: results from a population-based study on extranodal marginal zone lymphomas [Articolo su rivista]
Luminari, Stefano; Cesaretti, Marina; Marcheselli, Luigi; Rashid, I.; Madrigali, Stefano; Maiorana, Antonino; Federico, Massimo
abstract

BACKGROUND: Few studies have been carried out to date that have addressed the epidemiology of extranodal marginal zone lymphomas (EN-MZLs). PATIENTS AND METHODS: We carried out a population-based study to investigate incidence rates (IRs) and time trends of EN-MZL diagnosed in the province of Modena (Italy) from 1997 to 2007. RESULTS: One hundred and sixty-five cases were identified from the Modena Cancer Registry that corresponded to an age-standardized IR of 2.3 cases per 100 000. A bimodal distribution of age was shown with the group of young patients mostly represented by males with cutaneous lymphoma. No time trends were observed for the IR; the incidence of gastric mucosa-associated lymphoid tissue (g-MALT) lymphomas (N = 51) markedly declined during the study period, dropping from 1.4 in 1997 to 0.2 in 2002 and then remaining stable until 2007; the calculated annual percent change for g-MALT was -17.0% (95% confidence interval -26.6% to -6.2%). We also observed a significant decrease in the rate of g-MALT associated with Helicobacter pylori (HP) infection from 61% to 17% of patients diagnosed before and after 2002 (P = 0.007; P for trend = 0.016). CONCLUSION: This population-based study provides new insights into recent changes in the epidemiology of EN-MZL, mainly represented by the sharp reduced incidence of HP-positive g-MALT lymphomas.

2010 - GMP-manufactured density gradient media for optimized mesenchymal stromal/stem cell isolation and expansion. [Articolo su rivista]
Grisendi, Giulia; Annerén, C; Sternieri, R; Veronesi, Elena; Cervo, Gl; Luminari, Stefano; Maur, M; Frassoldati, A; Palazzi, G; Otsuru, S; Bambi, F; Paolucci, Paolo; Conte, Pierfranco; Horwitz, E; Dominici, Massimo; Cafarelli, Luigi
abstract

BACKGROUND AIMS: Bone marrow (BM) mesenchymal stromal/stem cells (MSC) are therapeutic tools in regenerative medicine and oncology. MSC isolation is often performed starting from a separation step based on research-grade 1.077 g/mL density gradient media (DGM). However, MSC clinical application should require the introduction of good manufacturing practice (GMP) reagents. We took advantage of two novel GMP DGM with densities of 1.077 and 1.073 g/mL (Ficoll-Paque PREMIUM and Ficoll-Paque PREMIUM 1.073, respectively) to test whether these reagents could isolate MSC efficiently while simultaneously comparing their performance.METHODS: BM samples were processed using either 1.077 or 1.073 g/mL GMP DGM. BM mononucleated cell (MNC) fractions were analyzed for viability, immunophenotype, clonogenic potential, ex vivo expansion and differentiation potential.RESULTS: No differences were noticed in cell recovery and viability between the groups. Fluorescence-activated cell-sorting (FACS) analyzes on freshly isolated cells indicated that the 1.073 g/mL GMP DGM more efficiently depleted the CD45(+) fraction in comparison with 1.077 GMP DGM. Moreover, in the 1.073 group, fibroblastic colony-forming units (CFU-F) were 1.5 times higher and the final MSC yield 1.8 times increased after four passages. Both reagents isolated MSC with the expected phenotype; however, 1.073-isolated MSC showed a higher expression of CD90, CD146 and GD2. Additionally, MSC from both groups were capable of fully differentiating into bone, adipose cells and cartilage.CONCLUSIONS: Both GMP DGM enriched MSC from BM samples, suggesting that these reagents would be suitable for clinical-grade expansions. In addition, the density of 1.073 g/mL provides a significant advantage over 1.077 g/mL GMP DGM, impacting the quantity of MSC obtained and reducing the ex vivo expansion time for optimized cell-based clinical applications.

2010 - Long term outcome of patients with localized aggressive non-Hodgkin lymphoma treated with PROMECE-CYTABOM plus involved-field radiation therapy: a study by the Gruppo Italiano Studio Linfomi. [Articolo su rivista]
Mannina, D.; Luminari, Stefano; Dondi, Alessandra; Polimeno, G.; Baldini, L.; Stelitano, C.; Merli, F.; Del'Olio, M.; Gobbi, P. G.; Giglio, G.; Barblini, E.; Brugiatelli, M.; Federico, Massimo
abstract

We conducted a retrospective analysis on 168 adult patients with newly diagnosed, limited-stage (I and II) diffuse large B-cell lymphoma (DLBCL) treated from 1988 to 2004 with PROMECE-CYTABOM (P-C) plus involved-field radiation therapy (IF-RT). At the end of P-C, the overall response rate was 92%. Radiotherapy (RT) was delivered to 84% of cases. With a median follow-up of 95 months, overall survival (OS), relapse free survival (RFS), and failure free survival at 5 and 10 years was 84% and 77%, 81% and 75%, 71% and 67%, respectively. Age (>60 years, p = 0.002), serum albumin (<3.5 g/dL; p = 0.015), and RT (p < 0.001) were independent predictors of OS. For patients in complete remission the administration of RT didn't improve both RFS and OS. This study confirms that patients with localized aggressive lymphoma have a high chance of cure with anthracycline containing regimens. Though the regimen used to treat these patients does not contain rituximab, results are considered excellent both in terms of efficacy and safety

2010 - Nonpegylated liposomal doxorubicin (Myocet) combination (R-COMP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL): results from the phase II EURO 18 trial [Articolo su rivista]
Luminari, Stefano; Montanini, Antonella; Caballero, D.; Bologna, S.; Notter, M.; Dyer, M. J. S.; Chiappella, A.; Briones, J.; Petrini, M.; Barbato, A.; Kayitalire, L.; Federico, Massimo
abstract

BACKGROUND: To evaluate the activity and safety of nonpegylated liposomal doxorubicin (Myocet) when substituted for doxorubicin in the R-CHOP regimen (R-COMP). PATIENTS AND METHODS: Seventy-five elderly patients with diffuse large B-cell lymphoma (DLBCL) were studied. Only patients with left ventricular ejection fraction (LVEF) >/=50% were allowed. R-COMP regimen was administered every 3 weeks for three cycles, followed by additional five cycles in case of complete response (CR) or partial response. RESULTS: From November 2002 to April 2005, 75 patients were registered, of which 72 were evaluated. Median age was 72 years (range 61-83); 56% of patients had high or high-intermediate International Prognostic Index score. Median LVEF at baseline was 61%. Thirty-eight patients had history of abnormal cardiovascular conditions. The overall response rate was 71%, with a CR rate of 57%. After a median follow-up of 33 months, the 3-year overall survival, failure-free survival, and progression-free survival rates were 72%, 39%, and 69%, respectively. Neutropenia (54%) was the most frequent grade 3-4 adverse event (AE); 21% of patients experienced cardiac AEs, graded as 3-4 in 4% of the cases. CONCLUSION: R-COMP is an effective regimen for the treatment of DLBCL in elderly patients, with an acceptable tolerability profile.

2010 - Other peripheral T-cell Lymphomas [Capitolo/Saggio]
Luminari, Stefano; Federico, Massimo
abstract

2008

2010 - Phase II Fludarabine and Cyclophosphamide for the treatment of indolent cell non-follicular lymphomas: final results of the LL02 trial of the Gruppo Italiano per lo Studio dei Linfomi. [Articolo su rivista]
Ferrario, A.; Merli, F.; Luminari, Stefano; Stelitano, C.; Mannina, D.; Russo, M.; Mazza, P.; Marcheselli, Luigi; Goldaniga, M. C.; Federico, Massimo; Baldini, L.
abstract

Indolent non-follicular non-Hodgkin lymphomas (INFL) are a heterogenous subset whose treatment has been poorly investigated. In this context we have evaluated the efficacy and safety of combined fludarabine and cyclophosphamide (FC) upfront therapy. Sixty-three patients with advanced INFL were enrolled in the study. Therapy consisted in FC combination (25 and 250 mg/m(2), i.v., respectively, for three consecutive days) every 28 days for six courses. After histological review, 61 patients (36 men, median age 64 years, range 40-70 years) were evaluated (22 small lymphocytic, 11 lymphoplasmacytic, 25 marginal zone and 3 CD5-negative non-Hodgkin lymphomas not otherwise specified). Further two patients were excluded for lack of essential data; six patients were withdrawn before the third cycle because of WHO grade III and IV toxicity. At the final evaluation, the overall response rate was 83% with 40.7% of complete remission. Intention-to-treat analysis showed that at the median follow-up of 36 months, overall survival, progression-free survival and failure-free survival were respectively 78%, 60% and 46%; remission duration among the 49 patients achieving complete remission/partial remission at the end of treatment was 65% (44-78) without significant differences between the main histotypes. The most frequent grade III and IV toxic events were haematological (neutropaenia 34%, anaemia 18% and thrombocytopaenia 11%) and infectious (10%). FC is effective for advanced untreated INFL. Early deaths and haematological toxicity suggest careful patient selection and monitoring.

2010 - Phase II Study of Velcade (R) Plus Mabthera (R) In Relapsed Follicular Lymphomas. [Abstract in Rivista]
Sacchi, Stefano; Marcheselli, Raffaella; Bari, Alessia; Liardo, ELIANA VALENTINA; Luminari, Stefano; F., Merli; A., Lazzaro; S., Neri; A. M., Carella; A., Fragasso; S., Falorio; G., Buda; P., Musto; M., Dell'Olio; L., Baldini
abstract

Background: Velcade ® (V) and Mabthera ® (M) have demonstrated an individual considerable efficacy in the treatment of non Hodgkin’s lymphoma. The aim of this study was to evaluate the efficacy and safety of the combination of V and M in patients with relapsed Follicular lymphoma (FL). Methods: Patients (pts) with histologic documentation of CD20+ FL , measurable and active disease, received : 1.3 mg/m2 of V on days 1-4-8-11 every 21 days for 6 cycle and M 375 mg/m2 on day 1 of each cycle from cycle III to VI. Two additional doses of M were administered alone after cycle VI, every 21 days (cycle VII and VIII). Response was assessed after 2 and 8 cycles using the NCI recommendations for Non-Hodgkin’s Lymphomas. Results: At the time of current analysis, initial planned accrual of 41 evaluable pts was not completed. From 2007 to now 37 pts entered into the trial. The pts characteristics at baseline were: median age 66 years (range: 46-84), male 51% , stage IV 43 % elevated values of LDH, 27%, and of Beta2microglobulin 41%. The FLIPI score was calculated in 34 pts (92%) and 11 pts (31%) had a poor prognostic score (> 3). The median number of previous immuno/chemotherapy regimens was 2 (range:1-3), and the median duration of last remission before registration into trial was 23 months (range: 3-67). In four out of the 37 pts who entered into the trial, the treatment is ongoing and thirty-three pts were evaluable for response. The overall response rate in the intent to treat analysis was 58% (19 pts ), of which 16 pts (49%) obtained complete response (CR) and 3 (9%) partial response (PR). Stable disease was seen in 1 pt (3%). Eight pts (24%) had progressive disease and 2 (6%) pts were lost at follow-up. Three pts (9%) had to stop the treatment: one pt (3%) for grade IV peripheral neuropathy, one pt (3%) refused to continue the treatment after 2 cycle and one pt (3%) died during the treatment for toxicity . After a median follow up of 14 month (0-44), the median overall survival and the event free survival were not reached. Overall, 2 pts relapsed (10 %) and 1 pt (5 %) showed a progression of disease. A total of five pts died, four because of lymphoma progression, and one for toxicity during treatment. Complete response are ongoing in 14 pts . Toxicity was evaluable in 33 patients. We observed the following grade 1/2 adverse events: neuropathy (10 pts), neutropenia (2 pts), infection (5 pts), constipation (4 pts), rash (2 pts), fatigue (1 pt). Further we saw the following grade 3/4 adverse events: thrombocytopenia (5 pts), neuropathy (5 pts), neutropenia (1 pt) and infection with fever(1 pt). Three patient interrupted the treatment due to severe neuropathy. Conclusions: The combination of V+M is associated with acceptable toxicity and a promising percentage of response. Further follow-up is required to evaluate the response duration and survival in the whole group of patients

2010 - Reassessments of ESAs for cancer treatment in the US and Europe [Articolo su rivista]
Bennett, Charles L; Mckoy, June M; Henke, Michael; Silver, Samuel M; Macdougall, Iain C; Birgegård, Gunnar; Luminari, Stefano; Casadevall, Nicole; Schellekens, Huub; Sartor, Oliver; Lai, Stephen Y; Armitage, James O.
abstract

Anemia is a widely prevalent complication among cancer patients. At the time of diagnosis, 30% to 40% of patients with non-Hodgkin lymphoma or Hodgkin lymphoma and up to 70% of patients with multiple myeloma are anemic; rates are higher among persons with myelodysplastic syndromes. Among patients with solid cancers or lymphomas, up to half develop anemia following chemotherapy. For almost 2 decades, erythropoiesis-stimulating agents (ESAs) were the primary treatment for cancer-related anemia. However, reassessments of benefits and risks of ESAs for cancer-associated anemia have occurred internationally. We reviewed guidelines and notifications from regulatory agencies and manufacturers, reimbursement policies, and utilization for ESAs in the cancer and chronic kidney disease settings within the United States, Europe, and Canada. In 2008 the US Food and Drug Administration (FDA) restricted ESAs from cancer patients seeking cure. Reimbursement is limited to hemoglobin levels < 10 g/dL. In the United States, ESA usage increased 340% between 2001 and 2006, and decreased 60% since 2007. The European Medicines Agency (EMEA) recommended that ESA benefits do not outweigh risks. In Europe between 2001 and 2006, ESA use increased 51%; since 2006, use decreased by 10%. In 2009, Canadian manufacturers recommended usage based on patient preferences. In Canada in 2007, approximately 20% of anemic cancer patients received ESAs, a 20% increase since 2004. In contrast to Europe, where ESA use has increased over time, reassessments of ESA-associated safety concerns in the United States have resulted in marked decrements in ESA use among cancer patients.

2010 - [Italian cancer figures, report 2010: Cancer prevalence in Italy. Patients living with cancer, long-term survivors and cured patients] [Articolo su rivista]
AIRTUM Working, Group; Guzzinati, S.; Dal Maso, L.; De Angelis, R.; De Paoli, A.; Buzzoni, C.; Crocetti, E.; Bucchi, L.; Casella, C.; Cuccaro, F.; Fusco, M.; Luminari, Stefano; Madeddu, A.; Mangone, L.; Patriarca, S.; Piffer, S.; Stracci, F.; Tagliabue, G.; Tumino, R.; Zappa, M.; Capocaccia, R.; Ferretti, S.; Mazzoleni, G.; Bellú, F.; Tschugguel, B.; De Valiere, E.; Facchinelli, G.; Falk, M.; Dal Cappello, T.; Giacomin, A.; Vercellino, P. C.; Andreone, S.; Busato, A.; Marzola, L.; Migliari, E.; Carletti, N.; Nenci, I.; Caldarella, A.; Corbinelli, A.; Giusti, F.; Intrieri, T.; Manneschi, G.; Nemcova, L.; Romeo, G.; Sacchettini, C.; Paci, E.; Serraino, D.; Angelin, T.; Bidoli, E.; de Dottori, M.; De Santis, E.; Forgiarini, O.; Zucchetto, A.; Zanier, L.; Vercelli, M.; Orengo, M. A.; Marani, E.; Puppo, A.; Celesia, M. V.; Cogno, R.; Manenti, S.; Garrone, E.; Quaglia, A.; Pannozzo, F.; Busco, S.; Rashid, I.; Ramazzotti, V.; Cercato, M. C.; Battisti, W.; Sperduti, I.; Macci, L.; Bugliarello, E.; Bernazza, E.; Tamburo, L.; Rossi, M.; Curatella, S.; De Francesco, C.; Tamburrino, S.; Bisanti, L.; Autelitano, M.; Randi, G.; Ghilardi, S.; Leone, R.; Filipazzi, L.; Bonini, A.; Giubelli, C.; Federico, Massimo; Artioli, M. E.; Valla, K.; Braghiroli, B.; Cirilli, C.; Pirani, M.; Ferrari, L.; Bellatalla, C.; Fusco, M.; Panico, M.; Perrotta, C.; Vassante, B.; Traina, A.; Carruba, G.; Cusimano, R.; Amodio, R.; Dolcemascolo, C.; Staiti, R.; Zarcone, M.; Michiara, M.; Bozzani, F.; Sgargi, P.; Cilia, S.; La Rosa, M. G.; Cascone, G.; Frasca, G.; Giurdanella, M. C.; Martorana, C.; Morana, G.; Nicita, C.; Rollo, P.; Ruggeri, M. G.; Sigona, A.; Spata, E.; Vacirca, S.; Di Felice, E.; Pezzarossi, A.; Caroli, S.; Pellegri, C.; Vicentini, M.; Storchi, C.; Cavuto, S.; Costa, J.; Falcini, F.; Colamartini, A.; Balducci, C.; Ravegnani, M.; Vitali, B.; Cordaro, C.; Caprara, L.; Giuliani, O.; Giorgetti, S.; Salvatore, S.; Palumbo, M.; Vattiato, R.; Ravaioli, A.; Foca, F.; Rinaldi, E.; Donato, A.; Iannelli, A.; Senatore, G.; Zevola, A.; Budroni, M.; Cesaraccio, R.; Pirino, D.; Carboni, D.; Fiori, G.; Soddu, M.; Mameli, G.; Mura, F.; Contrino, M. L.; Tisano, F.; Sciacca, S.; Muni, A.; Mizzi, M.; Russo, M.; Tessandori, R.; Ardemagni, G.; Gianola, L.; Maspero, S.; Annulli, M. L.; Moroni, E.; Roberto, G.; Zanetti, R.; Rosso, S.; Prandi, R.; Sobrato, I.; Gilardi, F.; Busso, P.; Franchini, S.; Gentilini, M. A.; Battisti, L.; Cappelletti, M.; Moser, M.; La Rosa, F.; D'Alò, D.; Scheibel, M.; Costarelli, D.; Spano, F.; Rossini, S.; Santucci, C.; Petrinelli, A. M.; Solimene, C.; Bianconi, F.; Brunori, V.; Crosignani, P.; Contiero, P.; Preto, L.; Tittarelli, A.; Maghini, A.; Codazzi, T.; Frassoldi, E.; Gada, D.; Costa, E.; di Grazia, L.; Zambon, P.; Baracco, M.; Bovo, E.; Dal Cin, A.; Fiore, A. R.; Greco, A.; Monetti, D.; Rosano, A.; Stocco, C.; Tognazzo, S.; Donato, F.; Limina, R. M.; Adorni, A.; Andreis, P.; Zani, G.; Piovani, F.; Salvi, O.; Puleio, M.; Vitarelli, S.; Antonini, S.; Candela, G.; Pappalardo, G.; Scuderi, T.; Lottero, B.; Ribaudo, M.; Ricci, P.; Guarda, L.; Gatti, L.; Bozzeda, A.; Dall'Acqua, M.; Pironi, V.; Sutera Sardo, A.; Mazzei, A.; Sirianni, N.; Lavecchia, A. M.; Mancuso, P.; Usala, M.; Pala, F.; Sini, G. M.; Pintori, N.; Canu, L.; Demurtas, G.; Doa, N.; Pisani, P.; Pastore, G.; Magnani, C.; Terracini, B.; Cena, T.; Alessi, D.; Baussano, I.; Merletti, F.; Maule, M.; Mosso, M. L.; Nonnato, M.; Rasulo, A.; Richiardi, L.; Zuccolo, L.; Pivetta, E.; Dalmasso, P.; Macerata, V.; Ponz De Leon, Maurizio; Domati, F.; Rossi, G.; Goldoni, C. A.; Rossi, F.; De Gaetani, C.; Benatti, Piero; Roncucci, Luca; Di Gregorio, C.; Pedroni, Monica; Pezzi, A.; Maffei, S.; Mariani, F.; Borsi, E.; Cocchioni, M.; Pascucci, C.; Gennaro, V.; Lazzarotto, A.; Benfatto, L.; Mazzucco, G.; Montanaro, F.
abstract

OBJECTIVES: the aim of the present monograph is to update the estimation of the number of people living with cancer in Italy, to describe geographic variability, and estimate the number of long-term survivors, i.e., people living five years or more after a cancer diagnosis. MATERIALS AND METHODS: the study included the data of the AIRTUMdatabase. Twenty-four Cancer Registries (CRs) (covering 27% of the Italian population) collected information on the incidence and vital status of 1,275,353 cases diagnosed between 1978 and 2005. For each CR, the observed prevalence was calculated up to the maximum observable duration. To estimate the complete prevalence (all living patients, independently from time since diagnosis) and the prevalence for lengths of time exceeding the CR maximum duration of registration, the observed prevalence was corrected through a completeness index. Completeness indices, gender, age and site specific, were estimated by means of statistical regression models using cancer incidence and survival data available from CRs with more than 15 years of observation. As of 1 January 2006, the prevalence was estimated (as absolute numbers and as a proportion per 100,000 inhabitants) for 46 cancer sites, by gender, age class, years since diagnosis and geographic areas. RESULTS: as of 2006, 2,244,000 persons (4%of the Italian population) were alive with a cancer diagnosis. A relevant geographic variability emerged, with proportions between 4%-5% among CRs in the Centre and North of Italy, and proportions between 2%-3% in the South. Forty-four percent of prevalent subjects (988,000) were males and 56% (1,256,000) females. Fifty-seven percent (1,285,680 people, 2.2% of total population) of these patients was represented by long-term survivors. In patients aged 75 years or more, the proportions of prevalent cases were 19%in males and 13%in females, and 10%between 60 and 75 years of age in both genders.More than half a million Italian women were alive with a breast cancer diagnosis (42%of women with a neoplasm), followed by women with cancers of the colonrectum (12%), corpus uteri (7%), thyroid (5%), and cervix uteri (4%). In men, 22%of prevalent cases (216,716) included patients with prostate cancer, 18% with bladder cancer, and 15%with colon-rectum cancer. Percentages of long-term survivors higher than 70% were reported for cancers of the cervix uteri (82% at five years, and 55% at 15 years from diagnosis), Hodgkin lymphoma, testis, brain and central nervous system, bone and connective tissue. Many patients with these types of cancers (often occurring in young people) can be considered "cured", i.e., with a life expectancy overlapping that of the general population.The estimated proportions of prevalent cases emerging from this study in Italy were quite similar to those reported in Northern Europe, but at least 15%lower than those in the United States. CONCLUSIONS: in 2006, the number of prevalent cases nearly doubled compared to 1992. The increase over time in the proportion of elderly patients, related to population ageing, requires adequate health policies. Knowing the number of people alive many years after cancer diagnosis (either cured or long-term survivors) provides the scientific bases for the definition of health policies focusing on them. Furthermore, it promotes the conduction of studies aimed at improving the present knowledge on the quality of life of these patients during and after the active phase of treatments, in addition to studies on the long-term effects of treatments.

2009 - ABVD Compared With BEACOPP Compared With CEC for the Initial Treatment of Patients With Advanced Hodgkin's Lymphoma: Results From the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. [Articolo su rivista]
Federico, Massimo; Luminari, Stefano; Iannitto, E; Polimeno, G; Marcheselli, Luigi; Montanini, Antonella; LA SALA, A; Merli, F; Stelitano, C; Pozzi, Samantha; Scalone, R; DI RENZO, N; Musto, P; Baldini, L; Cervetti, G; Angrilli, F; Mazza, P; Brugiatelli, M; Gobbi, Pg
abstract

PURPOSE: To compare doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) versus bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) versus cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, and bleomycin (COPPEBVCAD; CEC) for advanced Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Three hundred seven patients with advanced HL (stage IIB, III, and IV) were randomly assigned to receive six courses of ABVD, four escalated plus two standard courses of BEACOPP, or six courses of CEC, plus a limited radiation therapy program. RESULTS: After a median follow-up of 41 months, BEACOPP resulted in a superior progression-free survival (PFS), with a significant reduction in risk of progression (hazard ratio [HR] = 0.50) compared with ABVD. No differences between BEACOPP and CEC, or CEC and ABVD were observed. The 5-year PFS was 68% (95% CI, 56% to 78%), 81% (95% CI, 70% to 89%), and 78% (95% CI, 68% to 86%), for ABVD, BEACOPP, and CEC, respectively (BEACOPP v ABVD, P = .038; CEC v ABVD and BEACOPP v CEC, P = not significant [NS]). The 5-year overall survival was 84% (95% CI, 69% to 92%), 92% (95% CI, 84% to 96%), and 91% (95% CI, 81% to 96%) for ABVD, BEACOPP, and CEC, respectively (P = NS). BEACOPP and CEC resulted in higher rates of grade 3-4 neutropenia than ABVD (P = .016); BEACOPP was associated with higher rates of severe infections than ABVD and CEC (P = .003). CONCLUSION: As adopted in this study BEACOPP is associated with a significantly improved PFS compared with ABVD, with a predictable higher acute toxicity.

2009 - Anthracycline-fludarabine-containing regimens with or without rituximab in the treatment of patients with advanced follicular lymphoma. [Articolo su rivista]
Luminari, Stefano; Marcheselli, Luigi; Sacchi, Stefano; Pozzi, Samantha; Bari, Alessia; F., Ilariucci; C., Stelitano; F., Angrilli; A., Lazzaro; L., Baldini
abstract

BACKGROUND:: Recent experience has suggested that there has been a stepwise improvement in the survival outcomes of patients who have follicular lymphoma with the introduction of new treatment options. In the current study, the authors report the results of 2 subsequent phase 2 trials of 238 previously untreated patients. METHODS:: In a trial of bleomycin, epidoxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP) plus fludarabine, mitoxantrone, and dexamethasone (FND), 144 patients received 2 BACOP treatments followed by 4 FND treatments. In a trial of BACOP plus fludarabine and rituximab (FR), 94 patients received 3 BACOP treatments followed by 4 FR treatments. RESULTS:: The complete remission (CR) rate for BACOP/FND was 62\%. After a median follow-up of 60 months, the failure-free survival (FFS) and overall survival (OS) rates at 4 years were 53\% and 77\%, respectively. The CR rate for BACOP/FR was 79\%. After a median follow-up of 36 months, the FFS and OS rates at 4 years were 56\% and 97\%, respectively, which were significant compared with the CR and OS rates achieved with BACOP/FND. Twenty-five of 42 bcl-2-positive patients attained a molecularly negative CR and had improved FFS. No significant differences were observed between the 2 trials in the percentage of infections or neutropenia. CONCLUSIONS:: The CR and OS rates achieved with BACOP/FR were better, and overall toxicity did not increase. Furthermore, patients who received rituximab had a better FFS compared with patients who received chemotherapy alone. Finally, although conclusions between nonrandomized groups may depend on differences in observed and unobserved prognostic features, the current results suggested that the addition of rituximab to anthracycline-fludarabine-containing regimens have a favorable effect on the prognosis of patients with advanced follicular lymphoma. Cancer 2009. (c) 2009 American Cancer Society.

2009 - Bisphosphonates-associated osteonecrosis of the jaw: A long-term follow-up of a series of 35 cases observed by GISL and evaluation of its frequency over time [Articolo su rivista]
Pozzi, Samantha; Marcheselli, Raffaella; Falorio, S; Masini, L; Stelitano, C; Falcone, A; Quarta, G; Ponchio, L; Pitini, V; Luminari, Stefano; Baldini, L; Gruppo Italiano Studio, Linfomi
abstract

NO abstract is available for this article.

2009 - Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone outside German Hodgkin Study Group: The Italian experience [Articolo su rivista]
Luminari, S.; Federico, M.; Montanini, A.; Iannitto, E.; Polimeno, G.; Gobbi, P. G.
abstract

2009 - Bone marrow stem cell damage after three different chemotherapy regimens for advanced Hodgkin's lymphoma [Articolo su rivista]
Gobbi, P. G.; Valentino, F.; Danova, M.; Morabito, F.; Rovati, B.; Mammi, Caterina; Gentile, M.; Merli, F.; Stelitano, C.; Luminari, Stefano; Quintana, G.; Iannitto, E.; Brugiatelli, M.; Federico, Massimo
abstract

The aim of this study was to evaluate the apoptotic damage to bone marrow cells caused by three chemotherapy regimens for advanced Hodgkin's lymphoma, ABVD, COPPEBVCAD and BEACOPP, which were randomly administered in the HD 2000 GISL trial. Bone marrow mononuclear cells (BMMCs) stained with anti-CD34 antibody and Annexin V, were evaluated by flow cytometry before starting chemotherapy, 30 days after completing chemotherapy and after 6 months. Results are expressed as the percentages of BMMCs positive to anti-CD34, to Annexin V or to both. Fourteen patients treated with ABVD, 11 with COPPEBVCAD and 13 with BEACOPP were evaluated before and 30 days after treatment. Late assessments were made in 6, 7 and 8 of them, respectively. No differences were found among the pretherapeutic flow cytometry findings in relation to the staging characteristics (marrow involvement included). All the regimens increased the apoptotic fraction of the whole mononuclear bone marrow cells (COPPEBVCAD did so significantly) and increased the CD34+ compartment (with significant early differences after ABVD and BEACOPP, tending to late persistence for ABVD, only). All the regimens increased the apoptotic CD34+ cells within the whole BMMC population (significantly after BEACOPP), although with a general trend to decrease in their percentage within the CD34+ compartment over time, even after the most dose-dense regimens. Based on the variations induced in the apoptotic fraction of all mononuclear and CD34+ cells, ABVD was the least toxic regimen and COPPEBVCAD the most toxic one.

2009 - Follicular Lymphoma International Prognostic Index 2: a new prognostic index for follicular lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project [Articolo su rivista]
Federico, Massimo; Bellei, Monica; Marcheselli, Luigi; Luminari, Stefano; Lopez Guillermo, A.; Vitolo, U.; Pro, B.; Pileri, S.; Pulsoni, A.; Soubeyran, P.; Cortelazzo, S.; Martinelli, G.; Martelli, M.; Rigacci, L.; Arcaini, L.; Di Raimondo, F.; Merli, F.; Sabattini, E.; McLaughlin, P.; Solal Céligny, P.
abstract

PURPOSE: The aim of the F2 study was to verify whether a prospective collection of data would enable the development of a more accurate prognostic index for follicular lymphoma (FL) by using parameters which could not be retrospectively studied before, and by choosing progression-free survival (PFS) as principal end point. PATIENTS AND METHODS: Between January 2003 and May 2005, 1,093 patients with a newly diagnosed FL were registered and 942 individuals receiving antilymphoma therapy were selected as the study population. The variables we used for score definition were selected by means of bootstrap resampling procedures on 832 patients with complete data. Procedures to select the model that would minimize errors were also performed. RESULTS: After a median follow-up of 38 months, 261 events for PFS evaluation were recorded. beta2-microglobulin higher than the upper limit of normal, longest diameter of the largest involved node longer than 6 cm, bone marrow involvement, hemoglobin level lower than 12 g/dL, and age older than 60 years were factors independently predictive for PFS. Using these variables, a prognostic model was devised to identify three groups at different levels of risk. The 3-year PFS rate was 91%, 69%, and 51% for patients at low, intermediate, and high risk, respectively (log-rank = 64.6; P < .00001). The 3-year survival rate was 99%, 96%, and 84% for patients at low, intermediate, and high risk, respectively (P < .0001). CONCLUSION: Follicular Lymphoma International Prognostic Index 2 is a simple prognostic index based on easily available clinical data and may represent a promising new tool for the identification of patients with FL at different risk in the era of immunochemotherapy.

2009 - High-dose therapy and autologous stem cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy: long-term results. [Articolo su rivista]
Carella, Am; Bellei, Monica; Brice, P; Gisselbrecht, C; Visani, G; Colombat, P; Fabbiano, F; Donelli, A; Luminari, Stefano; Feugier, P; Browett, P; Hagberg, H; Federico, Massimo
abstract

no abstract available

2009 - I tumori nelle provincie di Parma, Reggio Emilia, Modena [Monografia/Trattato scientifico]
De Lisi, V.; Bozzani, F.; Michiara, M.; Sgargi, P.; Mangone, L.; Caroli, S.; Di Felice, E.; Pellegri, C.; Pezzarossi, A.; Storchi, C.; Vicentini, M.; Federico, Massimo; Artioli, M. E.; Braghiroli, B.; Cirilli, C.; Luminari, Stefano; Marcheselli, Luigi; Orsini, Mirko; Pirani, Monica; Valla, K.
abstract

Volume contenente i dati di incidenza, mortalità e sopravvivenza dei tumori nelle provincie di Parma, Reggio Emilia e Modena nell'anno 2007.

2009 - Prognosis factors in low-grade Non-Hodgkin's lymphomas [Articolo su rivista]
Federico, Massimo; Molica, S.; Bellei, Monica; Luminari, Stefano
abstract

Low-grade non-Hodgkin lymphomas were once considered as a heterogenous group of lymphomas characterized by an indolent clinical course. Today, low-grade non-Hodgkin lymphomas are classified as a group of 10 distinct entities, each characterized by unique clinicobiologic features. Follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma, and marginal zone lymphoma are the most-investigated subtypes. Several studies have been performed to identify prognostic factors specific for each subtype in an effort to help clinicians in treatment decisions. The field of biologically specific associated parameters holds great potential but requires more research and work to produce translational results.

2009 - Prognostic tools in follicular lymphomas [Articolo su rivista]
Luminari, Stefano; Cox, M. C.; Montanini, Antonella; Federico, Massimo
abstract

Despite significant improvements in treatment modalities over the 10 years, the clinical course of patients with follicular lymphoma (FL) remains heterogeneous. Thus, prognostic indexes are still required to direct treatment choices and for the design of clinical trials. Investigators have conducted a variety of studies aimed at integrated assessment of biological and clinical features in order to identify novel prognostic factors and scoring systems. Genetic studies focused on tumor cells and the tumor microenvironment represent a step forward in understanding the biology of FL and are likely to provide new prognostic tools for future clinical use. Several prognostic factors have been identified and are currently used in combination to establish prognostic scores and to support therapeutic decisions. The FL International Prognostic Index (FLIPI) is currently used for defining individual risk of death. More recently, FLIPI2 was developed by the same group that built FLIPI as a new model for prognostic definition of patients with FL. The model was defined using prospectively collected data from patients who also received the monoclonal therapeutic antibody rituximab and stratifies patients into three risk categories for disease progression. Since many biological factors are not yet clinically validated or easily assessable, clinical data still represent the major source of prognostic information. The progressive development of new and more effective therapies for the treatment of FL makes the study of prognosis a dynamic and evolving area of clinical research.

2009 - Refining GMP-manufactured density gradient media for optimised mesenchymal stromal/stem cell isolation and expansion. [Abstract in Rivista]
Grisendi, Giulia; C., Anneren; L., Cafarelli; Veronesi, Elena; R., Sternieri; G. L., Cervo; Luminari, Stefano; A., Frassoldati; M., Maur; G., Palazzi; Paolucci, Paolo; Conte, Pierfranco; Dominici, Massimo
abstract

not available

2009 - Response-guided ABVD chemotherapy plus involved-field radiation therapy for intermediate-stage Hodgkin lymphoma in the pre-positron emission tomography era: a Gruppo Italiano Studio Linfomi (GISL) prospective trial. [Articolo su rivista]
E., Iannitto; V., Minardi; P. G., Gobbi; G., Calvaruso; C., Tripodo; Marcheselli, Luigi; Luminari, Stefano; F., Merli; L., Baldini; C., Stelitano; V., Callea; M., Petrini; F., Angrilli; G., Quarta; D., Vallisa; S., Molica; E., Liardo; G., Polimeno; M., Brugiatelli; Federico, Massimo
abstract

PURPOSE: In the pre-positron emission tomography era, the Gruppo Italiano Studio Linfomi (GISL) investigated the feasibility and efficacy of a treatment based on a response-tailored number of doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) courses in 218 intermediate-stage Hodgkin lymphoma patients. PATIENTS AND METHODS: Patients with stage I/II showing at least one adverse prognostic factor and stage IIIA without adverse prognostic factors were recruited. Treatment included a first step of 3 ABVD courses, followed by an early-restaging. Patients in CR/CRu received 1 additional ABVD cycle, patients in PR received 3 more ABVD, and nonresponder patients went off study. Involved-field radiation therapy (RT) was recommended on chemotherapy completion. RESULTS: The median age was 30 years (range, 15-68 years) and 131 patients (61\%) were female. Seven percent of patients were in stage I, 78\% in stage II, and 15\% in stage III; B-symptoms, bulky tumor and erythrocyte sedimentation rate > 30 were recorded in 20\%, 26\%, and 43\% of cases, respectively. The CR/CRu rate was 62\% at early restaging, 72\% at the end of chemotherapy, and 95\% following RT. With a median follow-up of 74 months (range, 6-193 months), 7-year overall survival, relapse-free survival, and freedom from treatment failure were 91.8\% (95\% CI, 86\%-95.5\%), 89.2\% (95\% CI, 82.8\%-93.3\%), and 81.8\% (95\% CI, 75.2\%-86.7\%), respectively. Patients in CR/CRu on early restaging, receiving 4 ABVD, had an excellent outcome with 7-year RFS and cause-specific survival similar to those of the late responders treated with 6 ABVD (RFS, 87.5\% vs. 90.5\% and CSS, 96.6\% vs. 92.7\%, respectively). CONCLUSION: The response-guided ABVD program we report, based on standard clinical staging procedures, proved to be feasible and safe in patients with intermediate-stage Hodgkin lymphoma.

2009 - The GISL HD2000 trial comparing ABVD with BEACOPP and with CEC as initial treatment of patients with advanced Hodgkin lymphoma [Articolo su rivista]
Luminari, S.; Federico, M.
abstract

2008 - A Case-Control Study on the Role of an Antiviral Treatment with Interferon and Ribavirin after Conventional Chemotherapy in Diffuse Large B-Cell Lymphomas with Hepatitis C Virus (HCV) Infection [Abstract in Rivista]
R., Guariglia; Luminari, Stefano; A., De Renzo; E., Iannitto; M., Dell'Olio; Pozzi, Samantha; T., Pierri; L., D'Amato; A., Traficante; Sacchi, Stefano; P., Musto
abstract

Antiviral therapy (AVT) with interferon +/- ribavirin can induce neoplastic regression without chemotherapy (CT) in low-grade non-Hodgkin’s lymphomas (in particular, immunocytomas and nodal/extranodal marginal lymphomas) with associated HCV infection (HCV+). High grade, diffuse large B-cell non- Hodgkin's lymphomas (DLBCL) are HCV+ in about 12% of cases in Italian population. These patients show peculiar clinical characteristics, such as older age, liver damage, presence of monoclonal gammopathy (often with no clinically relevant cryoglobulinemic and/or rheumatoid activity), increased rate of autoimmune disorders and extranodal localizations. Their clinical outcome, however, is generally considered not significantly different, in terms of response rate, progression free survival (PFS) and overall survival (OS), from that of subjects with HCV negative (HCV-) DLBCL when treated with standard or even high dose CT and if significant signs of liver dysfunction are absent. In the present study we aimed to determine the possible role of AVT, performed after a standard CT treatment, in HCV+ DLBCL. We evaluated 40 HCV+ DLBCL patients (male/female ratio 25/15; median age 63 years, range 39-71) who received AVT after first complete (27 patients) or partial (13 patients) remission was achieved by frontline standard CT. Classic or modified CHOP+/-rituximab regimens were generally employed. Twenty-two patients (55%) showed a higher (3-4) IPI score and twenty patients (50%) evidenced increased ALT/AST values. A favourable HCV genotype (type 2-3) and a low viral load (< 600.000 copies) were observed in 19 (47.5%) and 15 (37.5%) patients, respectively. In the large majoriry of cases AVT consisted of peg-interferon 1 mg/kg (1.5 mg/kg for genotype 1) s.c. once-a-week, plus ribavirin 1000/1200 mg/d p.o., according to body-weight < or > 70/kg. A small number of patients received interferon-alpha with or without ribavirin. The planned duration of AVT ranged from 3 to 12 months and was modulated according to viral genotype and molecular response (genotype 2: 3 months, if viral clearance obtained after 1 month, otherwise continued for 6 months; other genotypes: 3 months of treatment with following suspension if viral clearance not obtained, otherwise continued for 12 months). Sequential treatment (CT followed by AVT) was generally well tolerated. Six patients, however, interrupted AVT before three months, mainly because of general malaise or myelotoxicity. HCV clearance was obtained in 22 patients (55%). A case-control comparison was made with a similar cohort of 40 HCV+ DBLCL patients, who did not receive AVT, matched for age, sex, IPI score, liver function, type of prior CT and response, viral load and HCV genotype. Three-year PFS was not statistically different between the two groups (52.5% vs 57.5%, p n.s.) , while a trend in favour of AVT treated patients was observed in terms of three-year OS (67.5%% vs 57.5%, p=0.055). A weak correlation between viral clearance and longer OS duration was also observed (p=0.048). Interestingly, during the follow up period, severe hepatic failure developed in 5 (12.5%) out of patients who had not received AVT and in only one (2.5%) of those treated with AVT. Seventy-nine percent of relapsed patients not treated with AVT received salvage CT, compared to 100% of AVT treated patients. Our currently available data indicate that a sequential treatment with CT followed by AVT is feasible in HCV+ DLBCL and may induce complete virus clearance in more than half of these patients. We hypothesize that a better control of the viral infection, rather than a direct or indirect antineoplastic activity of AVT, could have positive effects on the clinical outcome of patients with HCV+ DLBCL and, possibly, on their survival, i.e. by allowing the possibility of further salvage therapies and reducing that of hepatic failure.

2008 - A Case-Control Study on the Role of an Antiviral Treatment with Interferon and Ribavirin after Conventional Chemotherapy in Diffuse Large B-Cell Lymphomas with Hepatitis C Virus (HCV) InfectionBlood (ASH Annual Meeting Abstracts), Nov 2008; 112: 3054 [Abstract in Rivista]
Roberto, Guariglia; Luminari, Stefano; Amalia De, Renzo; Emilio, Iannitto; Matteo, Dell’Olio; Pozzi, Samantha; Teresa, Pierri; Lucia, D’Amato; Antonio, Traficante; Sacchi, Stefano; Pellegrino, Musto
abstract

Antiviral therapy (AVT) with interferon +/– ribavirin can induce neoplastic regression without chemotherapy (CT) in low-grade non-Hodgkin’s lymphomas (in particular, immunocytomas and nodal/extranodal marginal lymphomas) with associated HCV infection (HCV+). High grade, diffuse large B-cell non- Hodgkin’s lymphomas (DLBCL) are HCV+ in about 12% of cases in Italian population. These patients show peculiar clinical characteristics, such as older age, liver damage, presence of monoclonal gammopathy (often with no clinically relevant cryoglobulinemic and/or rheumatoid activity), increased rate of autoimmune disorders and extranodal localizations. Their clinical outcome, however, is generally considered not significantly different, in terms of response rate, progression free survival (PFS) and overall survival (OS), from that of subjects with HCV negative (HCV–) DLBCL when treated with standard or even high dose CT and if significant signs of liver dysfunction are absent. In the present study we aimed to determine the possible role of AVT, performed after a standard CT treatment, in HCV+ DLBCL. We evaluated 40 HCV+ DLBCL patients (male/female ratio 25/15; median age 63 years, range 39–71) who received AVT after first complete (27 patients) or partial (13 patients) remission was achieved by frontline standard CT. Classic or modified CHOP+/– rituximab regimens were generally employed. Twenty-two patients (55%) showed a higher (3–4) IPI score and twenty patients (50%) evidenced increased ALT/AST values. A favourable HCV genotype (type 2–3) and a low viral load (< 600.000 copies) were observed in 19 (47.5%) and 15 (37.5%) patients, respectively. In the large majoriry of cases AVT consisted of peg-interferon 1 mg/kg (1.5 mg/kg for genotype 1) s.c. once-a-week, plus ribavirin 1000/1200 mg/d p.o., according to body-weight < or > 70/kg. A small number of patients received interferon-alpha with or without ribavirin. The planned duration of AVT ranged from 3 to 12 months and was modulated according to viral genotype and molecular response (genotype 2: 3 months, if viral clearance obtained after 1 month, otherwise continued for 6 months; other genotypes: 3 months of treatment with following suspension if viral clearance not obtained, otherwise continued for 12 months). Sequential treatment (CT followed by AVT) was generally well tolerated. Six patients, however, interrupted AVT before three months, mainly because of general malaise or myelotoxicity. HCV clearance was obtained in 22 patients (55%). A case-control comparison was made with a similar cohort of 40 HCV+ DBLCL patients, who did not receive AVT, matched for age, sex, IPI score, liver function, type of prior CT and response, viral load and HCV genotype. Three-year PFS was not statistically different between the two groups (52.5% vs 57.5%, p n.s.), while a trend in favour of AVT treated patients was observed in terms of three-year OS (67.5%% vs 57.5%, p=0.055). A weak correlation between viral clearance and longer OS duration was also observed (p=0.048). Interestingly, during the follow up period, severe hepatic failure developed in 5 (12.5%) out of patients who had not received AVT and in only one (2.5%) of those treated with AVT. Seventy-nine percent of relapsed patients not treated with AVT received salvage CT, compared to 100% of AVT treated patients. Our currently available data indicate that a sequential treatment with CT followed by AVT is feasible in HCV+ DLBCL and may induce complete virus clearance in more than half of these patients. We hypothesize that a better control of the viral infection, rather than a direct or indirect antineoplastic activity of AVT, could have positive effects on the clinical outcome of patients with HCV+ DLBCL and, possibly, on their survival, i.e. by allowing the possibility of further salvage therapies and reducing that of hepatic failure.

2008 - A multicenter retrospective clinical study of CD5/CD10-negative chronic B cell leukemias. [Articolo su rivista]
Goldaniga, M; Ferrario, A; Cortelazzo, S; Guffanti, A; Pavone, E; Ambrosetti, A; Marcheselli, Luigi; Rossi, F; Luminari, Stefano; Rossi, A; Cro, L; Federico, Massimo; LAMBERTENGHI DELILIERS, G; Baldini, L.
abstract

CD5-negative chronic B cell lymphoproliferative disorders in leukemic phase (B-CLPD) are heterogeneous and relatively uncommon pathologies that often lack a histopathological definition because of the absence of accessible pathological tissue. We describe the clinical features and evolution-related variables of 156 patients with CD5/CD10-negative B-CLPD (median age 66 years, range 25-86). The median follow-up was 51 months (range 6-216), and overall 3- and 5-year survival was respectively 87 and 76%; 50 patients needed therapy at diagnosis, 56 during follow-up, and 50 remained untreated until the last control. A combined clinical, histological, cytomorphological, immunophenotypical, and cytogenetic diagnostic approach allowed the complete classification of only a minority of patients as being affected by splenic marginal zone or lymphoplasmacytic lymphoma; the majority of cases remained unclassifiable. Multivariate analysis showed that the clinicohematological variables adversely related to overall survival were serum LDH levels and age, whereas high serum LDH levels, hemoglobin levels of <11 g/dl, and splenomegaly related to treatment-free time (in "wait and see" cases); only splenomegaly related to time to progression (in treated patients). In conclusion, our retrospective study describes the clinical features and variables related to evolution in a large group of patients with CD5/CD10-negative chronic B-cell lymphoid leukemias and underlines the fact that a probable lymphoplasmacytic or marginal zone normal cell origin can be supposed in such leukemic forms, but never surely demonstrated.

2008 - ABVD plus radiotherapy versus EVE plus radiotherapy in unfavorable stage IA and IIA Hodgkin's lymphoma: results from an Intergruppo Italiano Linfomi randomized study. [Articolo su rivista]
Pavone, V; Ricardi, U; Luminari, Stefano; Gobbi, P; Federico, Massimo; Baldini, L; Iannitto, E; Ucci, G; Marcheselli, Luigi; Orsucci, L; Angelucci, E; Liberati, M; Gavarotti, P; Levis, A; INTERGRUPPO ITALIANO LINFOMI, Iil
abstract

BACKGROUND: In 1997, the Intergruppo Italiano Linfomi started a randomized trial to evaluate, in unfavorable stage IA and IIA Hodgkin's lymphoma (HL) patients, the efficacy and toxicity of the low toxic epirubicin, vinblastine and etoposide (EVE) regimen followed by involved field radiotherapy in comparison to the gold standard doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) regimen followed by the same radiotherapy program. PATIENTS AND METHODS: Patients should be younger than 65 years with unfavorable stage IA and IIA HL (i.e. stage IA or IIA with bulky disease and/or subdiaphragmatic disease, erythrocyte sedimentation rate higher than 40, extranodal (E) involvement, hilar involvement and more than three involved lymph node areas). RESULTS: Ninety-two patients were allocated to the ABVD arm and 89 to the EVE arm. Complete remission (CR) rates at the end of treatment program [chemotherapy (CT) + RT] were 93% and 92% for ABVD and EVE arms, respectively (P = NS). The 5-year relapse-free survival (RFS) rate was 95% for ABVD and 78% for EVE (P < 0.05). As a consequence of the different relapse rate, the 5-year failure-free survival (FFS) rate was significantly better for ABVD (90%) than for EVE (73%) arm (P < 0.05). No differences in terms of overall survival (OS) were observed for the two study arms. CONCLUSIONS: In unfavorable stage IA and IIA HL patients, no differences were observed between ABVD and EVE arms in terms of CR rate and OS. EVE CT, however, was significantly worse than ABVD in terms of RFS and FFS and cannot be recommended as initial treatment for HL.

2008 - Anthracycline-Fludarabine Containing Regimens with or without Rituximab in the Treatment of Advanced Follicular Lymphoma Patients [Abstract in Rivista]
Sacchi, Stefano; Marcheselli, Luigi; Pozzi, Samantha; Bari, Alessia; Luminari, Stefano; F., Ilariucci; C., Stelitano; F., Angrilli; A., Lazzaro; L., Baldini; M., Spriano; G., Caparrotti; M., Musso; G., Quarta; M., Brugiatelli
abstract

Introduction Recent experiences suggest a stepwise improvement in survival outcomes for patients with follicular lymphoma with the introduction of new treatment options. Here we report the results of 2 subsequent phase II trials conducted by Gruppo Italiano Studio Linfomi (GISL) utilizing CHOP-like plus fludarabine regimens with or without rituximab. Our results confirm an improvement in CR rate and show better survival with the addition of rituximab.Materials and MethodsThe BACOP/FND study (bleomycin, epidoxorubicin, cyclophosphamide, vincristine, prednisone/ fludarabine, mitoxantrone, dexamethasone), registered 144 patients between 1997 and 2002. After 2 BACOP, patients received 4 cycles of FND. Then, responsive patients were randomized to observation or to receive alpha-IFN + dexamethasone. The BACOP/FR ( BACOP + fludarabine and rituximab) study registered 94 patients between 2002 and 2006. After 3 BACOP, patients in PR or in CR BCL2+ , received 4 cycles of FR. For both trials, eligible patients had histological documented, previously untreated, advanced follicular lymphoma. ResultsBACOP/FND. Response rates by intent to treat analysis were: ORR 90%, CR 62%. No differences were observed in FFS and OS between the 2 arms of maintenance. At the time of the last follow up, 35 patients had died, 5 lost at follow up, while 85 patients are still alive, 81 with ongoing response and 4 with progressive disease. After a median follow up of 60 months, FFS and OS were 53% and 77% at 4 years, respectively. BACOP/FR . Response rates by intent to treat analysis were: ORR 93%, CR 79%. At the time of the last follow up, 3 patients had died, 3 patients were lost at follow up, 60 are still alive with ongoing response and 14 with progressive disease. After a median follow up of 36 months , FFS and OS at 4 years were 56% and 97%, respectively. PCR assay for BCL2. Forty two of the 80 patients were found to be positive for BCL2 in the bone marrow obtained prior to treatment. Of these 42 patients, 25 obtained CR molecularly negative. We observed an improved FFS rate in patients who became BCL negative after treatment.Toxicity. The most common toxicities were infections and neutropenia. Overall, the haematological toxicities were transient and reversible. Comparison between the results of the two trials. We observed a CR rate of 62% and 79% and an OS at 4 years of 77% and 97%, respectively in BACOP/FND versus BACOP/FR, and the differences were statistically significant. Side effects were more frequent in BACOP/FND, however, no significant differences were observed between the 2 trials.DiscussionThe results obtained with BACOP/FR in comparison with those with BACOP/FND were better in terms of response and overall survival, while overall toxicity did not increase, remaining transient and tolerable. Patients who obtained BCL2 clearance in BACOP/FR showed a better FFS in comparison with patients treated with BACOP/FND. Further, patients treated with rituximab had a better FFS in comparison with all other patients treated only with chemotherapy. Finally, although conclusion between non randomized groups may depend in differences in observed and unobserved prognostic features, we believe that statistical analysis of our results, suggest that the addition of rituximab to anthracycline-fludarabine containing chemotherapy regimen has a favourable effect on prognosis of advanced follicular lymphoma

2008 - BISPHOSPHONATES (BP) RELATED OSTEONECROSIS OF THE JAW (ONJ): A LONG TERM FOLLOW UP (FU) OF A SERIES OF 35 CASES OBSERVED BY GISL [Abstract in Rivista]
Pozzi, S.; Marcheselli, Raffaella; Sacchi, Stefano; Baldini, L.; Angrilli, F.; Falorio, S.; Quarta, G.; Stelitano, C.; Caparotti, G.; Luminari, Stefano; Falcone, A.; Natale, D.; Broglia, C. h.; Cuoghi, A.; Dini, D.; Ditonno, P.; Leonardi, G.; Pianezze, G.; Pitini, V.; Polimeno, G.; Ponchio, L.; Masini, L.; Maurizio, M.; Spriano, M.; Musto, P.
abstract

Background. In 2007 we published a review of 35 cases of BP-associated ONJ observed in cancer patients during a multicenter study performed by the GISL (Gruppo Italiano Studio Linfomi e Mielomi) in the period 2002-2005. Our study strongly suggested an association between the use of BP and the occurrence of ONJ, although we were unable to identify any definitive risk factors with a retrospective study. The most frequently ONJ-associated clinical characteristics were chemotherapy treatment, advanced age, female sex, anemia, parodonthopaties/dental procedures and thalidomide (in the case of MM patients). Aims. To update the FU of these 35 patients, evaluating ONJ evolution and the interference with the quality of life. Methods. We asked to the 14 centers that participated in the previous study, and that reported cases of ONJ, to up-date the status of the primary disease, the evolution of ONJ, and the quality of life of their pts. Results. Five patients were lost to FU. Among the remaining 30 pts, 25 were affected by multiple myeloma, and 5 by other type of neoplasia. Nineteen pts are alive (63%) and 11 patients (37%) died for progression of the primary disease. In the deceased pts the follow-up referred to the status of the ONJ just before the decease. Twenty-two are females, 8 are males with a median FU of 30 months since the diagnosis of ONJ for all patients and a median FU of 34 months for alive patients. In one patient (3%) ONJ resolved, in 11 patients (37%) the lesion is stable, and in 13 cases (43%) the lesion improved, as a result of one or more procedures. Five patients (17%) showed progression of the lesion: in 4 cases due to a fistula and in 1 case of local infection. No recurrence of the event has been reported. ONJ interfered with the ability of eating in 13 pt (43%) determining an impairment of quality of life. In 29 out of 30 (97%) BP has been suspended indefinitely, and only in 1 case the pt went on with the treatment after the diagnosis of ONJ. Conclusions. In our population ONJ showed a various range of evolution: in the majority of the cases it was stable or even improved or healed (37%,43% and 3% respectively), but even if rarely it evolved in a even worst complication like fistula and local infection. No cases of recurrence has been reported. The complication doesn’t seem to interfere with the survival of the pts, and all patients deceased for progression of the primary disease. ONJ interfere with the quality of life in particular because the lesion reduce the ability of eating. The large majority of treating physicians preferred to indefinitely discontinue BP administration regardless of the bone involvement and this could explaining why we did not observe any recurrence.

2008 - Secondary malignancies after treatment for indolent non-Hodgkin's lymphoma: A 16-year follow-up study [Articolo su rivista]
Sacchi, Stefano; Marcheselli, Luigi; Bari, Alessia; Marcheselli, Raffaella; Pozzi, Samantha; Luminari, Stefano; Lombardo, M; Buda, G; Lazzaro, A; Gobbi, Pg; Stelitano, C; Morabito, F; Quarta, G; Brugiatelli, M.
abstract

Relatively little information is available on the incidence of secondary cancer in non-Hodgkin's lymphoma. The aim of this long-term follow-up study was to determine the incidence, the time free of second tumors, and risk factors for developing secondary cancer in a homogeneous group of patients with non-Hodgkin's lymphoma. DESIGN AND METHODS: We evaluated a total of 563 patients with indolent non-Hodgkin's lymphoma enrolled in Gruppo Italiano Studio Linfomi trials from 1988 to 2003. RESULTS: After a median follow-up of 62 months, 39 patients (6.9%) developed secondary cancer: 12 myelodysplastic syndromes/acute myeloid leukemia, and 27 solid tumors. The overall standardized incidence ratio of secondary malignancy in patients with non-Hodgkin's lymphoma was higher than the risk of malignancy in the general population. The standardized incidence ratio was elevated in male patients and in patients under 65 years old at first treatment. Overall, the cumulative incidence of secondary cancer at 12 years was 10.5%, after correction in a competing-risk model. Univariate and multivariate Cox regression analyses showed that older age at the time of diagnosis, male sex, and fludarabine-containing therapy had significant negative impacts on the time free of second tumors. CONCLUSIONS: We have identified subgroups of non-Hodgkin's lymphoma patients with increased standardized incidence ratios of secondary malignancy and variables that have a negative impact on the time free of second tumors. This information could help physicians to select the most appropriate treatments. Finally, taking into account the possible occurrence of secondary neoplasia, long-term monitoring must be considered.

2007 - Antiviral treatment with interferon +/- ribavirin after chemotherapy for diffuse large B-cell non-Hodgkin lymphomas with hepatitis C virus (HCV) infection [Abstract in Rivista]
P., Musto; R., Guariglia; G., Pietrantuono; O., Villani; F., D'Auria; Luminari, Stefano; A., De Renzo; E., Iannitto; Pozzi, Samantha; Sacchi, Stefano
abstract

Background. Antiviral therapy (AVT) with interferon ± ribavirin hasshown to be effective in inducing neoplastic regression withoutchemotherapy (CT) in low-grade non-Hodgkin’s lymphomas (mainlyimmunocytomas and nodal/extranodal marginal lymphomas) with associatedHCV infection (HCV+ve). We have previously shown that highgrade, Diffuse B-Large Cell Lymphomas (DBLCL) are HCV+ve in about12% of cases in Italian population (ASH 2006, abs. 2242). These patientsshow peculiar clinical characteristics and have an outcome generally notsignificantly different, in terms of response rate, progression free survival(PFS) and overall survival (OS), from that of subjects with HCV negative(HCV-ve) DBLCL, when treated with standard or even high dose CT andif significant signs of liver dysfunction are absent. Aims. In the presentstudy we aimed to determine the possible role of AVT, performed aftera standard CT treatment, in high grade, HCV+ve DBLCL. Methods. Weevaluated the clinical outcome of 28 HCV+ve DBLCL patients whoreceived AVT (a or pegylated interferon ± ribavirin, given at recommendeddoses and therapy duration for specific HCV genotypes andaccording to viral response) after first complete or partial remission wasachieved by frontline standard CT. Classic or modified CHOP ± rituximabor PROMACE-CytaBOM regimens were generally employed. Forcomparison, a historical cohort of 24 patients with HCV+ve DBLCL,receiving similar CT, but without AVT, was employed. The two groupswere similar for age, sex, clinical stage, liver function, type of prior CT,viral load and HCV genotype. Results. Sequential treatment (CT followedby AVT) was generally well tolerated. Four patients, however, interruptedAVT before three months, due to general malaise or myelotoxicity.HCV clearance was obtained in 54% of patients. An interim evaluationshowed a not statistically significant trend (67 vs 54%) in favour of AVTtreatedpatients in terms of PFS at two years. A weak correlationbetween viral clearance and longer PFS duration was also observed.Two-year OS, however, was not different between AVT-treated or nottreated patients (71 vs 68%, p n.s.). Conclusions. Our currently availabledata indicate that a sequential treatment with CT followed by AVT isfeasible in HCV+ve DBLCL, may induce complete virus clearance andcould have a positive impact on remission duration. A larger number ofpatients and a longer follow-up are required to establish the exact role(if any) of AVT in HCV+ve DLBCL patients.0724

2007 - Bisphosphonate-associated osteonecrosis of the jaw: a review of 35 cases and an evaluation of its frequency in multiple myeloma patients [Articolo su rivista]
Pozzi, Samantha; Marcheselli, Raffaella; Sacchi, Stefano; L., Baldini; F., Angrilli; E., Pennese; G., Quarta; C., Stelitano; G., Caparotti; Luminari, Stefano; P., Musto; D., Natale; C., Broglia; A., Cuoghi; D., Dini; P., DI TONNO; G., Leonardi; G., Pianezze; V., Pitini; G., Polimeno; L., Ponchio; L., Masini; M., Musso; M., Spriano; G., Pollastri
abstract

Over a period of 28 months, we observed five cases of osteonecrosis of the jaw (ONJ) in cancer patients treated with bisphosphonates (BP) at our institution. This prompted us to undertake a retrospective, multicenter study to analyse the characteristics of patients who exhibited ONJ and to define the frequency of ONJ in multiple myeloma (MM). We identified 35 cases in Gruppo Italiano Studio Linfomi centers during the period 2002-05. The median time from cancer diagnosis to the clinical onset of ONJ was 70 months. In these 35 cases of ONJ, 24 appeared 20-60 months after starting BP treatment. The time for the onset of ONJ was significantly shorter for patients treated with zoledronic acid alone than for those treated with pamidronate followed by zoledronic acid. The frequency of ONJ in the MM group during the study period was 1.9%, although the nature of the present study may have resulted in an underestimation of ONJ cases. Our analysis strongly suggested an association between the use of BP and the occurrence of ONJ, although we were unable to identify any definite risk factors with a retrospective study. The most frequently ONJ-associated clinical characteristics were chemotherapy treatment, steroid treatment, advanced age, female sex, anemia, parodonthopaties/dental procedures and thalidomide (in the case of MM patients).

2007 - Diffuse B-large cell lymphomas with hepatitis C virus (HCV) infection: An interim report of a comparative study with or without antiviral treatment after chemotherapy [Abstract in Rivista]
P., Musto; R., Guariglia; G., Pietrantuono; O., Villani; F., D'Auria; Luminari, Stefano; A., De Renzo; E., Iannitto; Pozzi, Samantha; Sacchi, Stefano
abstract

Background. Antiviral therapy (AVT) with interferon ± ribavirin has shown to be effective in inducing neoplastic regression without chemotherapy (CT) in low-grade non-Hodgkin’s lymphomas (mainly immunocytomas and nodal/extranodal marginal lymphomas) with associated HCV infection (HCV+ve). We have previously shown that high grade, Diffuse B-Large Cell Lymphomas (DBLCL) are HCV+ve in about 12% of cases in Italian population (ASH 2006, abs. 2242). These patients show peculiar clinical characteristics and have an outcome generally not significantly different, in terms of response rate, progression free survival (PFS) and overall survival (OS), from that of subjects with HCV negative (HCV-ve) DBLCL, when treated with standard or even high dose CT and if significant signs of liver dysfunction are absent. Aims. In the present study we aimed to determine the possible role of AVT, performed after a standard CT treatment, in high grade, HCV+ve DBLCL. Methods. We evaluated the clinical outcome of 28 HCV+ve DBLCL patients who received AVT (a or pegylated interferon ± ribavirin, given at recommended doses and therapy duration for specific HCV genotypes and according to viral response) after first complete or partial remission was achieved by frontline standard CT. Classic or modified CHOP ± rituximab or PROMACE-CytaBOM regimens were generally employed. For comparison, a historical cohort of 24 patients with HCV+ve DBLCL, receiving similar CT, but without AVT, was employed. The two groups were similar for age, sex, clinical stage, liver function, type of prior CT, viral load and HCV genotype. Results. Sequential treatment (CT followed by AVT) was generally well tolerated. Four patients, however, interrupted AVT before three months, due to general malaise or myelotoxicity. HCV clearance was obtained in 54% of patients. An interim evaluation showed a not statistically significant trend (67 vs 54%) in favour of AVT-treated patients in terms of PFS at two years. A weak correlation between viral clearance and longer PFS duration was also observed. Two-year OS, however, was not different between AVT-treated or not treated patients (71 vs 68%, p n.s.). Conclusions. Our currently available data indicate that a sequential treatment with CT followed by AVT is feasible in HCV+ve DBLCL, may induce complete virus clearance and could have a positive impact on remission duration. A larger number of patients and a longer follow-up are required to establish the exact role (if any) of AVT in HCV+ve DLBCL patients.

2007 - Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study. [Articolo su rivista]
Gallamini, A; Hutchings, M; Rigacci, L; Specht, L; Merli, F; Hansen, M; Patti, C; Loft, A; DI RAIMONDO, F; D'Amore, F; Biggi, A; Vitolo, U; Stelitano, C; Sancetta, R; Trentin, L; Luminari, Stefano; Iannitto, E; Viviani, S; Pierri, I; Levis, A.
abstract

PURPOSE: Starting from November 2001, 260 newly diagnosed patients with Hodgkin's lymphoma (HL) were consecutively enrolled in parallel Italian and Danish prospective trials to evaluate the prognostic role of an early interim 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scan and the International Prognostic Score (IPS) in advanced HL, treated with conventional ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy. PATIENTS AND METHODS: Most patients (n = 190) presented with advanced disease (stages IIB through IVB), whereas 70 presented in stage IIA with adverse prognostic factors. All but 11 patients were treated with standard ABVD therapy followed by consolidation radiotherapy in case of bulky presentation or residual tumor mass. Conventional radiologic staging was performed at baseline. FDG-PET scan was performed at baseline and after two courses of ABVD (PET-2). No treatment change was allowed on the basis of the PET-2 results. RESULTS: After a median follow-up of 2.19 years (range, 0.32 to 5.18 years), 205 patients were in continued complete remission and two patients were in partial remission. Forty-three patients progressed during therapy or immediately after, whereas 10 patients relapsed. The 2-year progression-free survival for patients with positive PET-2 results was 12.8% and for patients with negative PET-2 results was 95.0% (P < .0001). In univariate analysis, the treatment outcome was significantly associated with PET-2 (P < .0001), stage IV (P < .0001), WBC more than 15,000 (P < .0001), lymphopenia (P < .001), IPS as a continuous variable (P < .0001), extranodal involvement (P < .0001), and bulky disease (P = .012). In multivariate analyses, only PET-2 turned out to be significant (P < .0001). CONCLUSION: PET-2 overshadows the prognostic value of IPS and emerges as the single most important tool for planning of risk-adapted treatment in advanced HL.

2007 - Incidence, clinical characteristics and survival of malignant lymphomas: a population-based study from a cancer registry in northern Italy. [Articolo su rivista]
Luminari, Stefano; Cesaretti, Marina; I., Rashid; Mammi, Caterina; Montanini, Antonella; E., Barbolini; Bellei, Monica; E., Pennese; A., Sirotti; Marcheselli, Luigi; G., Partesotti; Bari, Alessia; Maiorana, Antonino; G., Bonacorsi; Federico, Massimo
abstract

We conducted a population-based study of peripheral lymphomas (PL) that had beendiagnosed between 1997 and 2003 in the province of Modena, Italy, with the aim ofproviding updated incidence, clinical and survival data for these cancers.We evaluated theincidence patterns and time trends of 1582 cases of PL that had been reclassified accordingto the WHO classification of hematological malignancies. Data regarding clinical characteristics,treatment and outcome were also collected for each case. The WorldAge-Standardized Rate (ASR) was calculated as 13.4, 2.2 and 3.4 per 100,000 peoplefor B-cell non-Hodgkin’s lymphoma (NHL), T-cell NHL and Hodgkin’s Lymphoma (HL),respectively, with an increase of 1.62% per year during the study period. The lymphomasubtype showing the highest incidence was found to be diffuse large B-cell lymphoma(DLBCL) with an ASR of 4.8. Compared with reports from other western countries, ourseries is characterized by a higher incidence of HL and indolent B-NHL in general, and ofCLL/SLL (ASR¼3.3) and marginal zone NHL (ASR¼1.5), in particular, and also by alower incidence of FL (ASR¼2). After a median follow-up of 54 months, the 5-year relativesurvival for the whole series was found to be 70% with a statistically significant improvementfor cases diagnosed during 2002–2003 (from 66 to 74%; p¼0.03). Survival improvementwithin the study period was also evident for patients with DLBCL, HL and T-NHL.Our study provides a comprehensive description of both the epidemiological and clinicalfeatures of PL cases in Modena and our data also reflect the major advances in thecurability of some histological subtypes of this disease. The usefulness of a populationbasedapproach to better characterizing different lymphoma subtypes is also demonstrated.

2007 - Introduction of rituximab in front-line and salvage therapies has improved outcome of advanced-stage follicular lymphoma patients [Articolo su rivista]
Sacchi, Stefano; Pozzi, Samantha; Marcheselli, Luigi; Bari, Alessia; Luminari, Stefano; F., Angrilli; F., Merli; D., Vallisa; L., Baldini; M., Brugiatelli; I. L., Study Group
abstract

BACKGROUND: It is unclear whether new treatment modalities have improved the survival of follicular lymphoma patients. Some data show that there has been no improvement in survival in the last 3 decades of the 20th century, whereas the results of recent retrospective studies suggest that evolving therapy has improved the outcome for follicular lymphoma patients. METHODS: To evaluate the impact of evolving therapies for follicular lymphoma, particularly the introduction of rituximab, the overall survival (OS), failure-free survival (FFS), and survival after recurrence (SAR) was analyzed in 438 advanced-stage follicular lymphoma patients enrolled in consecutive Gruppo Italiano Studio Linfomi (GISL) trials between 1988 and 2004. RESULTS: A stepwise improvement in FFS and a significant reduction in the hazard ratio was observed with succeeding studies. Cox regression analysis showed an improvement over time for OS, with a decline in the hazard ratio particularly evident in the group treated with rituximab. Furthermore, the SAR significantly improved in the group of patients treated with chemotherapy + rituximab. CONCLUSIONS: After adjusting for all parameters with an impact on FFS and OS, the results of multivariate analysis suggest that rituximab therapy has a favorable effect on the prognosis of follicular lymphoma. The data show that FFS and OS have significantly improved in advanced-stage follicular lymphoma patients treated on GISL protocols during the last 18 years. These improvements are related to evolving front-line and salvage therapies, particularly the introduction of rituximab in combination with chemotherapy.

2007 - Long term results of a randomized study performed by Intergruppo Italiano Linfomi comparing Mini-CEOP vs P-VEBEC in elderly patients with diffuse large B-cell lymphoma. [Articolo su rivista]
Merli, F; Bertini, M; Luminari, Stefano; Mozzana, R; Botto, B; Liberati, Am; Baldini, L; Cabras, G; DI VITO, F; Orsucci, L; Naglieri, E; Polimeno, G; Marcheselli, Luigi; Pennese, E; Vitolo, U; Federico, Massimo; Gallo, E.
abstract

The Intergruppo Italiano Linfomi started, in 1996, a randomized trial for the initial treatment of elderly patients (older than 65 years) with Diffuse Large B-Cell Lymphoma (B-DLCL) comparing 6 courses of Mini-CEOP vs 8 weeks of P-VEBEC chemotherapy. Study objectives were survival, response and Quality of Life (QoL). Two hundred and thirty-two patients were evaluable for final analysis. Complete Response (CR) and Overall Response Rates (ORR) were 54% vs 66% (p = 0.107) and 90% vs 78% (p = 0.021) for P-VEBEC and Mini-CEOP, respectively. With a median follow-up of 72 months, the 5-year Overall Survival (OS), Relapse Free Survival (RFS), and Failure Free Survival (FFS) were 32%, 52%, and 21%, respectively. Subjects achieving a CR showed improvement of QoL regardless of treatment arm. Both Mini-CEOP and P-VEBEC determined a similar outcome for elderly patients with B-DLCL, with a third of patients alive after more than 6 years of follow-up. Both regimens can be considered equally for combination treatment with anti-CD20 monoclonal antibody.

2007 - Prognostic relevance of serum beta2 microglobulin in patients with follicular lymphoma treated with anthracycline-containing regimens. A GISL study. [Articolo su rivista]
Federico, Massimo; C., Guglielmi; Luminari, Stefano; C., Mammi; Marcheselli, Luigi; U., Gianelli; Maiorana, Antonino; F., Merli; Bellei, Monica; Pozzi, Samantha; C., Stelitano; A., Lazzaro; P. G., Gobbi; L., Baldini; S., Bergantini; V., Fregoni; M., Brugiatelli
abstract

Background and ObjectivesAlthough serum b2 microglobulin (b2M) is an easy parameter to measure, and overexpressedin a large number of lymphoproliferative diseases, its prognostic value hasbeen largely underestimated. The present study examined the influence of b2M levelson overall survival (OS) of patients with follicular lymphoma (FL).Design and MethodsThe prognostic role of b2M was evaluated in 236 patients with FL identified from thedatabases of the Gruppo Italiano per lo Studio dei Linfomi (GISL) and treated withanthracycline-based regimens from 1993 to 2003.ResultsElevated serum b2M levels were found in 82 patients (35%). According to multivariatelogistic regression analysis, elevated b2M levels were associated with elevatedlactate dehydrogenase (LDH) (p=0.021), age (p=0.029), and number of involvednodal areas (p<0.001). The percentage of elevated b2M levels increased progressivelywith increasing FLIPI scores (17%, 38%, and 63% in the low-, intermediate-, andhigh-risk groups, respectively). Five-year OS was 61% (95% CI, 47-73%) and 89% (95%CI, 82-93%) for patients with elevated vs normal b2M levels respectively (p<0.001).Cox regression analysis showed that b2M level had an independent and stable prognosticvalue (HR=3.0; 95%CI, 1.6-5.7). In a multivariate analysis the impact of b2Mlevel on survival was independent of FLIPI score, with a HR of 2.94 (95% CI, 1.54-5.62).Interpretation and ConclusionsOur results demonstrate that in patients treated in the pre-rituximab era, b2M levelwas an independent prognostic marker in addition to FLIPI score. We thus suggestthat b2M be routinely assessed and tested in future prognostic studies of FL patientstreated with combination chemotherapy and anti-CD20 agents.

2007 - SECOND MALIGNANCIES AFTER TREATMENT FOR INDOLENT LYMPHOMA: A 16 YEARS FOLLOW-UP STUDY [Abstract in Rivista]
Sacchi, Stefano; Marcheselli, Luigi; Bari, Alessia; Marcheselli, Raffaella; Pozzi, Samantha; Luminari, Stefano; M., Lombardo; G., Buda; A., Lazzaro; P., Gobbi; C., Stelitano; M., Brugiatelli
abstract

Background. Second malignancies have been associated with NonHodgkin Lymphoma treatment. Most studies report a high risk of second cancers (2 to 8 fold increase), mainly due to high ncidence of MDS/AML and solid tumors, such as lung, bladder and gastro-intestinal cancers. Nevertheless few analyses have addressed this issue focusing on indolent lymphoma. Aims. Aims of this study are to determine the incidence and the risk factors for the development of second cancers during long term follow up of patients treated for indolent lymphoma. Methods. The Gruppo Italiano Studio Linfomi (GISL) maintains a database on clinical characteristics, treatment and follow up of all patients who entered clinical trials. To address a uniform patients population inthis study, we identified 563 previously untreated patients with histologically confirmed diagnosis of indolent lymphoma, enrolled in GISL trials between 1988 and 2003. The incidence (numbers of second neoplasia by person-years under analysis) of second cancers in the study population was compared to the incidence of solid cancers in the Italian population, utilizing age-, sex- and calendar period-specific incidence rates, derived from ISTAT database. Standardized incidence ratio (SIR, the observed/expected ratio) and absolute excess risk (AER, observedcases in our cohort minus numbers expected, divided by person-years at risk) were calculated after stratifying for age cohorts. Time Free to second Tumor (TF2T) was measured from the end of the first treatment to last follow-up or date of diagnosis of second tumor. TF2T was calculated with a Kaplan-Meier estimate. Effects of potential risk factors on second cancer rates were examined in a Cox proportional-hazard model. Results. After a median follow-up of 62 months , we observed 33 cases (6%) of second cancers, including hematologic malignancies (2%). Ten out of 33 patients developed MDS/AML and 23 solid tumors, including 6 lung cancer, 6 gastro-intestinal cancer and 11 other type of cancers. Overall, incidence rate (1000 person-years) was 11.5. Excess of risk forsecond solid cancer was detected in the cohort age 50-54 (SIR =4,2; 95% CI 1.9-9.40; AER =1.27). Median TF2T was 28 months for MDS/AML, 44 for lung cancer and 47 for gastro-intestinal cancer. By univariate and Cox regression analysis, after stratifying for histology, we observed a significant negative impact (all p<.05) on TF2T for age at first treatment, male sex and fludarabine-containing therapy. Further, we divided thelog(HR), estimated by Cox regression analysis based on age, male sex and fludarabine-containing therapy, at the 33° and the 66° percentiles. Based on this analysis, we observed three groups with significant difference in the risk of developing second cancers (p<0.0001). Conclusions. Patients treated for indolent lymphoma are at elevated risk of developing second primary malignancies. The SIR and AER are increased in patients who were younger at first treatment. Age, male sex and fludarabine-containing chemotherapy have a negative impact on TF2T. Finally,utilizing these parameters in a Cox regression model, we were able to identify groups with an increased risk of second malignancies.

2006 - A model for predicting the risk of developing mild anemia (MA) in patients with lymphoid malignancy. A study of the Gruppo Italiano Studio Linfomi (GISL) [Abstract in Rivista]
Luminari, Stefano; Marcheselli, Luigi; I., Mancarella; Bellei, Monica; Montanini, Antonella; C., Mammi; E., Barbolini; Cesaretti, Marina; Pozzi, Samantha; M., Lombardo; Sacchi, Stefano; Federico, Massimo
abstract

Background: So far no predictive model has been defined to predict the risk of developing MA in cancer patients.Methods and objectives: All cases registered from 1991 to 2005 in one of GISL clinical trials, with a confirmed diagnosis of Aggressive lymphoma (AL), Follicular lymphoma (FL) or Hodgkin’s lymphoma (HL), were selected for the study. Patients should have available data on clinical features at diagnosis, treatment details and hematological toxicity. MA was defined as the presence of baseline Hb levels below11 g/dl or grade 1–4 hemoglobin toxicity defined according to WHO criteria. Theaim of the study was to develop a model to predict the risk of developing MA forpatients with Lymphoid Malignancy (LM).Results: One thousand eight hundred and seventy four patients were included inthe study: AL, FL and HL was the diagnosis in 830, 218 and 687 case respectively;median age was 54, 57 and 32 years for AL, FL and HL respectively and thefrequency of female patients was 43%, 48% and 49% for the three groups. MedianHb level at diagnosis was 12.9 g/dl, 13.2 g/dl and 12.3 g/dl for AL, FL and HLrespectively with 20% of patients with showing MA. All patients received an adequateanthracycline based CT regimen. Overall 38% of patients with Hb baseline levels above 11 g/dl developed MA during chemotherapy. CT regimens were divided intothree groups based on MA risk (group 1: MA risk 0 to 25%; group 2: MA risk 26% to50%; group 3; MA risk above 50%). In the Logit multivariate analysis Age (above 55yrs), Female gender, CT groups (2–3 versus 1) Hb levels and bulky disease were factorsindependently correlated with the risk of developing MA. A prediction model wasdefined using previously defined parameters which allowed the identification of threegroups of patient with a different risk of MA. Patients at low, intermediate-Low,Low-High and high risk had a probability of MA of 5%, 25%, 38% and 52%respectively (P < 0.0001).Conclusion: The risk of developingMA in patients with LM undergoing chemotherapycan be predicted with a simple assessment of clinical and treatment features. Patientsat high risk of MA could be considered for anemia prevention programs.

2006 - Diffuse Large B-Cell Lymphomas (DLBCL) with Hepatitis-C Virus (HCV) Infection: Incidence, Clinical Outcome and Preliminary Results of Antiviral Treatments (AVT) after Chemotherapy. [Abstract in Rivista]
Pellegrino, Musto; Luminari, Stefano; Amalia De, Renzo; Marcello, Persico; Emilio, Iannitto; Matteo, Dell’Olio; Daniele, Vallisa; Pozzi, Samantha; Andres, Ferreri; Francesco, Angrilli; Patrizio, Mazza; Giovanni, Quarta; Roberto, Guariglia; Marialucia, Barone; Giuseppe, Pietrantuono; Fiorella, D’Auria; Fabiana, Perna; Vincenzo, Lamura; Alessandro, Pulsoni; Fabrizio, Marcucci; Alfonso, Mele; Sacchi, Stefano; Bruno, Rotoli
abstract

A possible relationship between HCV and some sub-types of low-grade lymphomas (in particular, immunocytomas and nodal/extranodal marginal lymphomas) has been suggested. In these patients, AVT has shown to be effective in inducing neoplastic regression without chemotherapy (CT). In the present study we aimed to define epidemiological, clinical and therapeutic issues in DLBCL with concomitant HCV infection. We evaluated the incidence of HCV infection in 881 consecutive Italian patients with DLBCL (676 of whom collected by GISL - Gruppo Italiano Studio Linfomi, and 205 by ISS - Istituto Superiore di Sanità), in whom HCV determination was available. We found that 105 out of them (11.9%) were HCV+ve. We also looked at the clinical outcome of 61 patients, who had complete clinical and laboratory work-up and long term follow-up. With respect to a cohort of comparable historical controls without HCV infection, HCV+ve DLBCL showed older age (62 vs 48 years, p < 0.03), more frequently signs of liver damage (59% vs 8%, p < 0.001) and presence of monoclonal gammopathy (17% vs 3%, p < 0.05), increased rate of autoimmune disorders (19% vs 3 %, p < 0.02) and extranodal localizations (65.3% vs 35%, p < 0.04), including, in particular, liver, spleen, and other unusual sites (esophagous, vagina), often as primitive disease. First line CT for HCV+ve DLBCL. mainly consisted of classic/modified CHOP+/–rituximab or PROMACE-CytaBOM regimens. Response rate (complete + partial remission) was not different, approaching 60% in both groups. Six-year overall survival (OS) was also similar (62% for HCV+ve and 65% for HCV–ve DLBCL, p 0.67). However, during the first two years, there was a worse trend for HCV+ve patients with increased ALT levels, high viral load (> 800.000 IU RNA viral copies) and evidence of active hepatitis or cirrhosis at liver biopsy. Finally, we evaluated the possible role of AVT given after standard CT in HCV+ve DLBCL. Preliminary data available from 37 patients who have received at least three months of interferon (alpha or pegylated) +/– ribavirin in remission phase, indicate that such a sequential treatment is feasible, may induce complete virus clearance and may be associated with prolonged remission duration, without affecting, however, OS. In conclusion, about 12% of Italian patients with DBLCL have concomitant HCV infection and show some distinctive clinical and biological characteristics. In absence of liver dysfunction, these subjects should receive standard treatments as their HCV–ve counterparts. Monitoring of viral load and liver biopsy appears also to be useful for an appropriate management. A sequence of standard CT followed by AVT is a feasible approach which warrants to be further investigated.

2006 - Introduction of Combined Chemotherapies Plus Rituximab (R) Has Improved Outcome of Previously Untreated and Relapsed Follicular Lymphoma (FL) Patients (pts).. [Abstract in Rivista]
Sacchi, Stefano; Pozzi, Samantha; Marcheselli, Luigi; Bari, Alessia; Luminari, Stefano; Federico, Massimo; Francesco, Angrilli; Marco, Lombardo; Chiara, Broglia; Giovanni, Quarta; Maura, Brugiatelli
abstract

Some data suggest that there are been no improvement in survival of FL Pts in the last three decades of the 20th century. However that review ended in 1992, before the introduction of R treatment. Most recently reported data, show that evolving chemotherapies, including the incorporation of R has led to outcome improvement. Between 1994 and 2004, 344 Pts with FL were enrolled in different GISL Trials. For the purpose of this study we considered 270 Pts with similar characteristics enrolled in trials including or not R. The first group accounts for 176 naive Pts treated with Antracycline plus Fludarabine containing regimens (Cohort #1: 125 Pts) or plus R (Cohort #2: 51Pts). The second group accounts for 99 relapsed Pts treated with Antracycline plus Fludarabine containing regimens (Cohort #3: 40 Pts) or plus R (Cohort #4: 59 Pts). To evaluate the impact of the incorporation of R in front line and salvage therapies we assessed the patients OS, FFS, TTF, SAR in these different Cohorts of Pts. Descriptive analysis of prognostic features showed differences in the distribution among groups. To compensate for these variations we also performed Cox regression analysis. Previously Untreated patients. Regarding group #1 and #2 that enrolled Pts with clinical stage IIB, III and IV, FFS and OS according to treatment did not show any statistical differences. The univariate analysis of baseline clinical features showed an impact on OS and FFS for clinical stage, LDH level, involvement of more than 4 nodal sites and presence of extranodal involvement. The prevalence of this characteristics were higher in group #2 than group #1. Thus the FFS from group #2 vs. group #1 was adjusted for variation in prognostic features by Cox regression analysis, that shows a failure Hazard Radio reduction (HR) of 40 % in Pts who received R. Because of difference in follow up (FU) (49 months in Cohort #1 vs 21 months in Cohort #2), to evaluate differences in OS we utilized exact Log Rank test for unequal FU. So far, a trend exists for better OS in R treated patients, although the difference is not statistically significant. Relapsed Patients. Clinical characteristics were similar in the two Cohorts of pts. TTF was better in R treated Pts and the difference was statistically significant (66% vs. 53% at 3 yrs, p=0.023) The analysis of SAR demonstrated a better result for R Cohort with a statistically significant difference (88% vs. 68% at 3 yrs, p=0.022). OS according to treatment protocol, showed advantage for patients in R Cohort and the difference was statistically significant (92% vs. 70% at 5 yrs, p=0.004). Conclusion. In naïve patients our retrospective analysis showed a reduction of HR for FFS and a trend toward better OS in R treated Pts. In relapsed Pts all outcome parameters as OS, TTF and SAR had significant improvement in the Cohort treated with R. Although any conclusions between nonrandomized groups maybe subject to differences in observed and unobserved prognostic features, we believe that improvement have occurred in the management of FL Pts with the introduction of combined chemotherapy with R.

2006 - Prognosis of follicular lymphomas [Articolo su rivista]
Luminari, Stefano; Federico, Massimo
abstract

Follicular lymphoma (FL) is as an indolent neoplasia with median survival measured in decades. Nevertheless, some patients have poor progression-free survival and overall survival. Several treatment approaches are proposed for patients with FL, however criteria to rationalize treatment decisions are lacking. Studies have been performed to build up prognostic indices that are useful for defining risk-adapted treatment recommendations. Available indices are based on parameters that have an independent role in predicting patient survival and that are variably correlated with the features of the disease, with the characteristics of the patient and with the effects of treatment. Two new prognostic indices have recently been proposed for FL: the Italian Lymphoma Intergroup (ILI) index and the Follicular Lymphoma International prognostic Index (FLIPI). Both indices are based on large series of patients and exhibit differences in their ability to discriminate between patients with different probabilities of survival. In recent years, with the advent of gene expression profile studies, our knowledge of the biology of FL is changing as novel data become available about the lymphoma cell and about the role of the microenvironment; these studies have already provided novel prognostic tools for identifying patients with more aggressive disease. Further data and large international cooperative studies are needed to translate into clinical practice the novel acquisitions of biology and therapeutics. Copyright

2006 - Rituximab (R) in Combination with Fludarabine (F) and Cyclophosphamide (C) in Relapsed Follicular Lymphoma (FL) Patients (pts).Final Results of FC + R Phase II Trial by the GISL. [Abstract in Rivista]
Sacchi, Stefano; Pozzi, Samantha; Marcheselli, Raffaella; Luminari, Stefano; Federico, Massimo; Alessandra, Tucci; Francesco, Merli; Loretta, Orsucci; Giulia, Cervetti; Ubaldo, Occhini; Marina, Liberati; Vincenzo, Callea; Maura, Brugiatelli; Luca, Baldini
abstract

Blood (ASH Annual Meeting Abstracts) 2006 108: Abstract 2763© 2006 American Society of HematologyThis Article Services Email this article to a friend Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sacchi, S. Articles by Baldini, L. Search for Related Content PubMed Articles by Sacchi, S. Articles by Baldini, L. Social Bookmarking What's this? Poster Board #-Session: 941-II Rituximab (R) in Combination with Fludarabine (F) and Cyclophosphamide (C) in Relapsed Follicular Lymphoma (FL) Patients (pts).Final Results of FC + R Phase II Trial by the GISL. Stefano Sacchi, MD1, Samantha Pozzi, MD1,*, Raffaella Marcheselli, BS1,*, Stefano Luminari, MD1,*, Massimo Federico, MD1, Alessandra Tucci, MD2,*, Francesco Merli, MD3,*, Loretta Orsucci, MD4,*, Giulia Cervetti, MD5,*, Ubaldo Occhini, MD6,*, Marina Liberati, MD7,*, Vincenzo Callea, MD8,*, Maura Brugiatelli, MD9 and Luca Baldini, MD10,* 1 Dipartimento di Oncologia ed Ematologia, Universita di Modena, Modena, Italy; 2 Dipartimento di Medicina Interna, Ospedale, Brescia, Italy; 3 Dipartimento di Ematologia, Ospedale, Reggio Emilia, Italy; 4 Dipartimento di Ematologia, Ospedale, Torino, Italy; 5 Dipartimento di Ematologia, Universita di Pisa, Pisa, Italy; 6 Servizio di Ematologia, Ospedale, Arezzo, Italy; 7 Ist. Scienze Oncologiche, Universita di Perugia, Perugia, Italy; 8 Dipartimento di Ematologia, Ospedale, Reggio Calabria, Italy; 9 Divisione di Ematologia, Ospedale, Messina, Italy and 10 Dipartimento di Scienze Mediche, Universita di Milano, Milano, Italy . AbstractFifty-four Pts entered this trial between January 2000 and December 2002. Eligible Pts had histologic documentation of CD 20+ relapsed FL, according to the revised European/American Lymphoma classification, that required treatment, measurable lesion, and an ECOG performance status of 0 or 1. Pts were further required to be aged 18–70 years, and to have undergone < 3 previous lines of chemotherapy. Pts received FC + R chemoimmunotherapy consisting of F 25 mg/m2 and C 300 mg/m2/day for 3 consecutive days every 3 weeks for 4 cycles. R 375 mg/m2 I.V. infusion was administered starting 2 weeks following the first FC course and then on day 1 of each cycle thereafter. Clinical response were defined according to the International Working Group recommendations. BCL 2 analysis was performed by PCR assay. DR, TTP and OS were analyzed by Kaplan-Meier method. Cox analysis was used to analyse the association of baseline prognostic factors with response to treatment, DR,TTP and OS. The overall response rate for all 54 Pts by ITT analysis was 90%; forty Pts (74%), obtained complete responses. Progression occurred in 3 Pts ( 6% ) and 2 Pts dropped out of the trial: 1 for toxicity and 1 refused to start with therapy. A univariate analysis of baseline prognostic factors demonstrated that none of these factors predicted for response to treatment. There were 29 Pts out of 45 tested, positive for BCL 2 before therapy. Among these, 22 Pts were evaluated after treatment and 19 ( 86%) converted to BCL negativity. At last follow up (FU), 40 Pts were alive, 31 with ongoing response and 9 with progressive disease. The median DR, TTP and OS have not been reached after a median FU time of 45 months ( range, 1 to 74 months ). The median DR in the 49 Pts who have reached CR or PR was 35 months ( range, 6 to 70 months). None of the baseline prognostic characteristics was significantly related to DR. The median TTP in all 54 Pts, was 36 months ( range, 1 to 74 months ).BCL2 positivity and < 2 previous treatments were related with better TTP (p<0.05 ) OS rate at 4 years was 75%. Toxicity was evaluable in 52 Pts. The most common severe side effects were hematologic, and included 21 cases of neutropenia, 3 cases of thrombocytopenia and 2 cases of anemia. Infectious complications manifested in 3 Pts and 1

2006 - The length of treatment of aggressive non-Hodgkin's lymphomas established according to the international prognostic index score: long-term results of the GISL LA03 study [Articolo su rivista]
Federico, Massimo; Luminari, Stefano; Pg, Gobbi; Sacchi, Stefano; N., Renzo; M., Lombardo; F., Merli; L., Baldini; C., Stelitano; G., Partesotti; G., Polimeno; Montanini, Antonella; C., Mammi; M., Brugiatelli
abstract

Objectives: To compare two different schedules of two different anthracycline-containing regimens, where length of treatment is modulated according to the international prognostic index (IPI) in patients with aggressive non-Hodgkin's Lymphoma (NHL). Methods: In 1993 the Gruppo Italiano per lo Studio dei Linfomi (GISL) started a randomized 2 x 2 factorial phase III clinical trial for patients with newly diagnosed aggressive NHL comparing ProME(Epidoxorubicin)CE-CytaBOM (PE-C) to ProMI(Idarubicin)CE-CytaBOM (PI-C) and a fixed to a flexible treatment schedule where anthracycline dose was to be modulated according to observed hematological toxicity. Patients with low or low-intermediate IPI (IPI 0-2) and those with intermediate-high or high IPI (IPI 3-5) should receive six or eight courses, respectively. Involved-field radiotherapy was allowed for patients with initial bulky disease or with residual masses. Results: Three hundred and fifty-six patients were registered into the study and randomized. Patients were well balanced among the four study arms in terms of clinical characteristics and prognostic factors. Three hundred and forty-five patients were available for evaluation of study endpoints. At the end of induction therapy complete remission rate was 61%, 5-year failure-free survival (FFS) rate was 40% and 5-year overall survival (OS) rate was 59%; no differences were observed according to treatment arms. Patients in the flexible arm received higher dose intensity of anthracycline (P < 0.001) with no apparent increase in toxicity. However, the flexible schedule was not superior to the fixed one. Patients with IPI 3-5 showed lower response rates (45% vs. 67%: P < 0.0001) and lower 5-year FFS (29% vs. 45%: P < 0.0001) compared to those with IPI 0-2. Conclusions: six courses of fixed or flexible PE-C or PI-C can determine a promising success rate in patients with advanced aggressive NHL with IPI 0-2, whereas the same regimens are less effective in patients with IPI 3-5, even if two additional courses are delivered. For the latter group of patients innovative approaches are warranted.

2006 - The predictive value of positron emission tomography scanning performed after two courses of standard therapy on treatment outcome in advanced stage Hodgkin's disease [Articolo su rivista]
Gallamini, A; Rigacci, L; Merli, F; Nassi, L; Bosi, A; Capodanno, I; Luminari, Stefano; Vitolo, U; Sancetta, R; Iannitto, E; Trentin, L; Stelitano, C; Tavera, S; Biggi, A; Castagnoli, A; Versari, A; Gregianin, M; Pelosi, E; Torchio, P; Levis, A.
abstract

Background and Objectives. We explored the predictive value on therapy outcome of an early evaluation of treatment response by F-18-fluorodeoxyglucose position emission tomography (F-18-FDG-PET) scan performed after two courses of conventional standard-dose chemotherapy in advanced-stage Hodgkin's disease. Design and Methods. One hundred and eight patients with newly-diagnosed Hodgkin's disease in stage IIA with adverse prognostic factors, or in stage 1113 through IVB, were restaged with FDG-PET after two cycles of ABVD (PET-2). The end-point of the study was the predictive value of PET-2 on 2-year progression-free survival and 2-year failure-free survival. No treatment variation based only on PET-2 results was allowed. Results. Eighty-eight patients attained complete remission (CR) while 20 showed disease progression during therapy or within 6 months after having reached CR; one patient relapsed. PET-2 was positive in 20 patients: 17 progressed during therapy, one relapsed and two remained in CR. By contrast, 85/88 (97%) patients with a negative PET-2 remained in CR; three progressed or relapsed early after the end of the chemotherapy. Thus, the positive predictive value of a PET-2 was 90% and the negative predictive value was 97%. The sensitivity, specificity and overall accuracy of PET-2 were 86%, 98% and 95%, respectively. The 2-year probability of failure-free survival for PET-2 negative and for PET-2 positive patients was 96% and 6%, respectively (log rank test = 116.7, p < 0.01). Interpretation and Conclusions. F-18-FDG-PET scan performed after two courses of conventional standard-dose chemotherapy in advanced-stage Hodgkin's disease was able to predict treatment outcome in 103/108 (95%) of the patients.

2006 - The prognosis of follicular lymphomas: The F2-project [Articolo su rivista]
Federico, Massimo; Bellei, Monica; Pro, B.; Lopez Guillermo, A.; Vitolo, U.; Luminari, Stefano; Pileri, S.; Solal Céligny, P.
abstract

Follicular lymphoma (FL) accounts for 10–15% of non-Hodgkin’s lymphomas in western countries. Although patients with FL experience a relatively indolent course and usually exhibit dramatic responses to initial therapy, they should be considered affected by a fatal malignancy. There is a tendency to relapse over time, the response to salvage treatments is of shorter duration after every relapse, and patients eventually die of disease-related causes. Several treatment approaches are offered to patients with FL; however, criteria to rationalize treatment decisions are still lacking in many instances.

2006 - The role of anthracyclines in follicular lymphomas [Articolo su rivista]
Luminari, Stefano; Federico, Massimo
abstract

This article does not have an abstract.

2006 - The role of dose size in a chemotherapy regimen (ProMECE-CytaBOM) for the first-line treatment of large B-cell lymphomas: a randomized trial by the Gruppo Italiano Studio Linfomi (GISL) [Articolo su rivista]
Gobbi, Pg; Broglia, C; Valentino, F; Mammi, C; Lombardo, M; Merli, F; Luminari, Stefano; Polimeno, G; Riezzo, A; Lambelet, P; Rovati, A; Corazza, Gr; Federico, Massimo
abstract

Background: It is still unclear the actual contribute of dose intensity (DI), dose size (DS) and dose density (DD) in the conventional chemotherapy of large, B-cell non-Hodgkin lymphomas. Methods: A prospective, randomized trial compared the cyclic schedule of ProMECE-CytaBOM chemotherapy (cyc-PC, 6 cycles) with a modified version of it, which administered the same drugs sequentially (seq-PC), with the same planned cumulative DI and an 83% DD, within the same time frame (113 days), but with three times higher DS of all the drugs except vincristine. Results: Fifty-six patients received cyc-PC and 52 seq-PC. The actual mean cumulative DI was 0.79 +/- 0.15 with cyc-PC, 0.78 +/- 0.17 with seq-PC. Response was complete in 59% and 52%, partial in 20% and 21%, null in 5% and 6%, respectively. There were four toxic deaths (two per arm). Relapses occurred in 36% and 37%, respectively. Toxicity was similar in both arms. Overall, failure-free, progression-free and disease-free survival (median follow-up: 54 months) were statistically indifferent. Conclusions: The very similar DI actually delivered in both arm seems to be the main common determinant of the indifferent results recorded. Increasing DS - at least within the limits clinically attainable without stem cell rescue - does not improve results.

2006 - The role of high-dose therapy and autologous stem cell transplantation in patients with primary refractory Hodgkin's lymphoma: a report from the Gruppo Italiano per lo Studio dei Linfomi (GISL) [Articolo su rivista]
Morabito, F; Stelitano, C; Luminari, Stefano; Mammi, C; Marcheselli, Luigi; Callea, V; Gentile, M; Polimeno, G; Merli, F; Molica, S; Gobbi, P; Angrilli, F; Brugiatelli, M; Federico, Massimo
abstract

GISL recently conducted an exhaustive survey of 1078 patients with Hodgkin's Lymphoma (HL) enrolled between 1988 and 2002 in different prospective trials. Treatment failure was observed in 82 out of 1078 patients; of these 82 patients with refractory HL, complete information was available for 72, who form the evaluable population of the present study. After the initial therapy failure, 51 patients were treated with conventional salvage chemotherapy ( CC) (n = 24) or high-dose chemotherapy (HDC) (n = 27); 4-year overall survival ( OS) was 81% in the HDC group versus 38% in the CC group ( P = 0.019). The remaining 21 patients had rapidly progressive disease and died. After a median follow-up of 2.8 years, the projected OS for all 72 patients is 58 and 49% at 3 and 5 years, respectively. Age <45 years, the absence of systemic symptoms and a PS <1 predicted a significantly longer OS. Interestingly, the majority of patients with two or three negative prognostic factors did not receive potentially curative therapy. In conclusion, HDC seems to be a reasonable option for selected patients with refractory HL, although the majority of them did not receive a transplant. Finally, patients with a high-risk score had little chance of receiving potentially curative treatment.

2006 - Very high levels of soluble CD30 recognize the patients with classical Hodgkin's lymphoma retaining a very poor prognosis [Articolo su rivista]
Visco, C; Nadali, G; Vassilakopoulos, Tp; Bonfante, V; Viviani, S; Gianni, Am; Federico, Massimo; Luminari, Stefano; Peethambaram, P; Witzig, Te; Pangalis, G; Cabanillas, F; Medeiros, Lj; Sarris, Ah; Pizzolo, G.
abstract

Objectives: To evaluate the prognostic role of pretreatment serum levels of soluble CD30 (sCD30) in patients with advanced stage classical Hodgkin's lymphoma (cHL) treated with adriamycin, bleomycin, vinblastine, and dacarbazine or equivalent regimens. Methods: We identified 321 previously untreated patients with cHL who presented to the participating centers between 1985 and 2002, and had serum samples available for the determination of sCD30 levels. Results: With a median follow-up of 72 months, the actuarial 5-year overall survival was 82%, and failure-free survival (FFS) was 71%. The median serum level of sCD30 was 65 U/mL (range: 1-2230), and was significantly higher (P < 0.0001) when compared with a group of 113 healthy controls (4 U/mL, range: 0-20). Increasing level of sCD30 was associated with a continuous worsening of FFS and OS, and patients with sCD30 >= 200 U/mL had a 5-year FFS of 39%. With multivariate analysis, sCD30, Ann Arbor stage, and lactic acid dehydrogenase were significant independent factors in terms of FFS. The association of the above-mentioned three independent prognostic variables could discriminate 22% of patients with 5-year FFS of 40%. Conclusions: Our data confirm the independent prognostic role of sCD30 in identifying the patients with high risk of treatment failure, and show that its association with other variables can recognize patients with FFS considerably lower than 50%.

2006 - Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) as salvage therapy in relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL): Results of a phase II study conducted by the Gruppo Italiano per lo Studio dei Linfomi [Articolo su rivista]
Di Renzo, N; Brugiatelli, M; Montanini, Antonella; Vigliotti, Ml; Cervetti, G; Liberati, Am; Luminari, Stefano; Spedini, P; Giglio, G; Federico, Massimo
abstract

Patients with aggressive NHL who fail initial treatment or subsequently relapse have a very poor outcome and less than 20-25% achieve a prolonged disease-free interval with salvage therapies. To improve the outcome of patients with refractory aggressive NHL not suitable for High Dose Therapy (HDT) and Autologous Stem Cell Transplant (ASCT), the efficacy of a combination of gemcitabine, vinorelbine, procarbazine and prednisone (ViGePP) were tested. Between November 1999 and September 2002, 69 patients with relapsed or refractory aggressive NHL were treated with ViGePP regimen, every 4 weeks up to six courses. At the end of planned chemotherapy patients could receive additional radiotherapy on residual masses or on sites of previously bulky disease. Sixty-six patients were available for evaluation of study end-points. Thirty patients were refractory to therapy and 36 patients had relapsed after remission obtained with previous therapy. At the end of therapy, complete remission (CR) rate was 23%, 3-year relapse free survival rate was 40% and 3-year overall survival rate was 25% for the whole series (29% and 20% for relapsed and refractory patients, respectively). Patients achieving CR with ViGePP had a significantly better survival as compared with the remaining ones (p =0.0003). ViGePP as used in the present setting has demonstrated a promising activity, comparable to other conventional dose regimens. Although CR was achieved only in a minority of patients, this was durable in a significant proportion of them. This regimen should be tested in less heavily pretreated patients and probably in combination with new active agents such Rituximab. Further developments of this combination are warranted.

2005 - Aggressive non-Hodgkin's lymphoma in the elderly: A validated prognostic evaluation performed by the Gruppo Italiano per lo Studio dei Linfomi (GISL) [Articolo su rivista]
Mazza, P; Marcheselli, L; Specchia, M; Luminari, Stefano; Partesotti, G; Montanini, A; Fregoni, V; Federico, Massimo; Merli, F.
abstract

2005 - Analysis of Frequency and Risk Factors for Developing Bisphosphonate Associated Osteonecrosis of the Jaw. [Abstract in Rivista]
Pozzi, Samantha; Marcheselli, Raffaella; Sacchi, Stefano; Giovanni, Quarta; Pellegrino, Musto; Giuseppe, Caparrotti; Donato, Natale; Graziano, Pianezze; Giuseppe, Polimeno; Vincenzo, Pitini; Luisa, Ponchio; Chiara, Broglia; Mauro, Spriano; Maurizio, Musso; Luciano, Masini; Amedea, Donelli; Daniele, Dini; Giovanna, Leonardi; Luminari, Stefano; Giuseppe, Pollastri
abstract

Although the evidence available associating bisphosphonates (BP) with osteonecrosis of the jaw (ONJ) is far from conclusive, the growing literature reports strongly suggest a strict relationship between them. The real frequency of this complication is unknown because of the recent observation of this condition, the bias related to retrospective studies and the wide-spread use of this supportive therapy. Aims of this research were to look for additional risk factors for developing ONJ and to determine the frequency of this event in the subgroup of patients affected by Multiple Myeloma (MM) treated with BP. We asked 49 GISL centers to participate in a retrospective multicenter study filling out a form containing several queries, including sex and age, anamnesis for smoke habit, anemia and thrombotic events, type and time of neoplasia diagnosis, treatment and neoplasia status, odonthoiatric anamnesis, type and duration of therapy with BP, microbial isolation in site of lesion, specific treatment for osteonecrosis, number of patients (pts) affected by MM treated with BP from 2002 to 2005. Fifteen centers decided to participate in the study and 12 had cases of osteonecrosis. ONJ was reported in 19 pts. Sixty % were females and the median age was 65 ys. Sixteen had MM, 1 breast cancer, 1 prostatic cancer, 1 osteoporosis steroid related. Median time from diagnosis of cancer was 54 months and median duration of treatment with BP was 34 months. Thirteen events manifested between 20 and 60 months. Of the 19 pts, 8 had received zolendronate, 2 pamidronate and 9 both drugs. None had radiotherapy on head and neck, while two received total body irradiation. In these two cases, ONJ was associated with necrosis of the pelvis. The 2 solid tumors were treated with ormonal therapy. All MM pts had received one or more line of treatment including, VAD, MP, steroids and thalidomide alone or in combination, as well as high dose melphalan, as part of autologous bone marrow transplant. ONJ involved the mandible in 14 pts, the maxilla in 3 and both in 2. Symptoms included local pain and discomfort. In 17 cases CT scan was the strumental procedure used to identifiy the lesion. In 14 pts biopsy was performed excluding localization of neoplasia in 11 cases. Microbiological evaluation of the lesion was positive in 11 pts, with 6 cases of Actynomices. In 12 patients ONJ was apparently spontaneous; in 7 occurred after dental procedures. Parodonthopaties were present in 10 pts. In 11 cases ONJ was complicated by fistula, exposed bone or abscess. BP were stopped in 17 pts. Antibiothic therapy was administered in 17 cases; 7 pts underwent hyperbaric oxygen therapy and 8 surgical debridement. Several pts improved but none were cured. Considering only the MM subgroup 16 cases of ONJ were identified among 888 pts treated with BP between 2002 and 2005, with a frequency of 1.8%. Utilizing the data collected by our retrospective study a fine statistical analysis is not applicable. However, in MM pts the frequency of steroid treatment, parodonthopaties and anemia was particularly high, respectively 100%, 56%, and 56%, supporting the idea that these are additional risk factors for developing ONJ.

2005 - Centroblastic (CB) and immunoblastic (IB) subtypes of diffuse large B cell lymphomas (DLBCL) have such a different clinical outcome that should be considered as separate entities in the WHO classification of lymphomas. A GISL study [Articolo su rivista]
Federico, Massimo; Artusi, T; Luminari, Stefano; Brugiatelli, M; Ricciotti, M; Marcheselli, L; Molica, S; Lombardo, M; Angrilli, F; Polimeno, G; Gobbi, P.
abstract

2005 - Clinical characteristics of erythropoietin-associated pure red cell aplasia. [Articolo su rivista]
Carson, Kr; Evens, Am; Bennett, Cl; Luminari, Stefano
abstract

Recombinant human erythropoietin (epoetin) was first used for the treatment of anemia resulting from renal disease in 1986. During the first 10 years of its use, there were only three cases of epoetin-induced antibodies reported, which resulted in pure red cell aplasia (PRCA). Between 1998 and 2002, 191 chronic kidney disease patients developed PRCA during the course of epoetin treatment. Clinical characteristics of patients with PRCA include an absolute resistance to epoetin therapy, with a rapid development of severe anemia and very low reticulocyte count. In addition, patients developed high titre, high affinity neutralizing antibodies, which are detectable by immunoassays. The diagnosis of PRCA requires the onset of severe anemia, erythropoietin neutralizing antibodies in circulation, the lack of red cell precursors in the bone marrow aspirate, and normal to elevated transferrin saturation. Patients require blood transfusions to maintain an acceptable level of hemoglobin. Cessation of epoetin treatment alone does not improve PRCA. Patients have required immunosuppressive treatment. However, the most efficacious treatment has been kidney transplantation accompanied by immunosuppressive agents that prevent organ rejection. Evaluating patients receiving recombinant epeoetin therapy who experience a sudden loss of epoetin efficacy for the possibility of antibody-mediated PRCA is crucial. Timely identification and treatment of this rare syndrome can prevent the development of severe red blood cell transfusion requirements and the potential complications of iron overload, which results from these transfusions.

2005 - Epoetin-induced pure red-cell aplasia (PRCA): preliminary results from the research on adverse drug events and reports (RADAR) group. [Articolo su rivista]
A. M., Evens; C. L., Bennett; Luminari, Stefano
abstract

In 2002, investigators from France reported 13 patients in whom pure red cell aplasia developed during treatment with recombinant human erythropoietin (epoetin). We reviewed 208 cases of this syndrome reported worldwide. Adverse event reports describing suspected and confirmed cases of epoetin-associated PRCA in websites maintained by the manufacturers and distributors of epoetin products and other publicly available sources were reviewed. Cases were reported from countries in Europe, North America, Asia, Australia and the United States (US). For >95\% of the cases, EPREX had been administered subcutaneous to persons with chronic kidney disease (CKD) and anemia for a mean of nine months prior to diagnosis of PRCA. For 80\% of persons with the syndrome, reversal of antibody production and recovery of reticulocytes occurred with discontinuation of epoetin and treatment with immunosuppressive agents. Patients with anemia of CKD who developed neutralizing anti-erythropoietin antibodies and pure red cell aplasia during treatment with epoetin have been identified in a number of countries. In non-US countries, switching renal dialysis patients from subcutaneous to intravenous administration of epoetin alpha and improved handling of the drug appear to have been successful strategies for reducing the occurrence of this toxicity. The decrease in cases occurred coincident with these varied changes, although it is difficult to prove causality. PRCA is a rare, but important side effect of epoetin therapy.

2005 - Fludarabine and cyclophosphamide combination in the treatment of patients with indolent non-follicular B-cell non-Hodgkin's lymphomas. Results of a phase II trial of the Gruppo Italiano per lo Studio dei Linfomi (GISL). [Articolo su rivista]
Federico, Massimo; Luminari, Stefano; Brugiatelli, M; Goldaniga, M; Sacchi, Stefano; Merli, F; Stelitano, C; Bagnulo, A; Rizzo, M; Baldini, L.
abstract

2005 - Immunoglobulin M monoclonal gammopathies of undetermined significance and indolent Waldenstrom's macroglobulinemia recognize the same determinants of evolution into symptomatic lymphoid disorders: Proposal for a common prognostic scoring system [Articolo su rivista]
Baldini, L; Goldaniga, M; Guffanti, A; Broglia, C; Cortelazzo, S; Rossi, A; Morra, E; Colombi, M; Callea, V; Pogliani, E; Ilariucci, F; Luminari, Stefano; Morel, P; Merlini, G; Gobbi, P.
abstract

Purpose To evaluate the clinicohematologic variables at diagnosis that are prognostically related to neoplastic progression in patients with immunoglobulin M (IgM) monoclonal gammopathies of undetermined significance (MGUS), and indolent Waldenstrom's macroglobulinemia (IWM), and propose a scoring system to identify subsets of patients at different risk. Patients and Methods We evaluated 217 patients with IgM MGUS and 201 with IWM (male-female ratio, 131:86 and 117:84; mean ago, 63.7 and 63.6 years, respectively) diagnosed on the basis of serum monoclonal component (MC) levels and bone marrow lymphoplasmacytic infiltration degree. The variables selected by univariate analyses were multivariately investigated; on the basis of their individual relative hazards, a scoring system was devised to identify subsets of patients at different risk of evolution. Results After a median follow-up of 56.1 and 60.2 months, 15 of 217 MGUS and 45 of 201 IWM patients, respectively, required chemotherapy for symptomatic WM (13 and 36), non-Hodgkin's lymphoma (2 and 6) and amyloidosis (0 and 3). The median time to evolution (TTE) was not reached for MGUS and was 141.5 months for IWM. The variables adversely related to evolution were qualitatively the same in both groups: MC levels, Hb concentrations and sex. A scoring system based on these parameters identified three risk groups with highly significant differences in TTE in both groups (P <.0001). Conclusion MGUS and IWM identify disease entities with different propensities for symptomatic neoplastic evolution. As both have the same prognostic determinants of progression, we propose a practical scoring system that, identifying different risks of malignant evolution, may allow an individualized clinical approach.

2005 - Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: a follow-up report from the Research on Adverse Drug Events and Reports (RADAR) Project. [Articolo su rivista]
C. L., Bennett; D., Cournoyer; K. R., Carson; J., Rossert; Luminari, Stefano; A. M., Evens; F., Locatelli; S. M., Belknap; J. M., Mckoy; E. A., Lyons; B., Kim; R., Sharma; S., Costello; E. B., Toffelmire; G. A., Wells; H. A., Messner; P. R., Yarnold; S. M., Trifilio; D. W., Raisch; T. M., Kuzel; A., Nissenson; L., Lim; M. S., Tallman; N., Casadevall
abstract

Since its introduction in 1988, recombinant human erythropoietin (epoetin) has been standard treatment for patients with anemia due to chronic kidney disease. From 1998 to 2004, nearly 200 epoetin-treated persons with chronic kidney disease developed antibodies to epoetin, resulting in pure red cell aplasia (PRCA). The majority of these patients received Eprex, an epoetin alfa product marketed exclusively outside the United States. Herein, we report on the long-term outcome of these individuals. For 170 chronic kidney disease patients who developed epoetin-associated PRCA and had 3 months or more follow-up information available, case reports from the Food and Drug Administration and epoetin manufacturers were reviewed for information on clinical characteristics of the patients, immunosuppressive treatments, epoetin responsiveness, and hematologic recovery. Overall, 64\% of the PRCA patients received immunosuppressive therapy, including 19 who also underwent a renal transplantation. Thirty-seven percent experienced a hematologic recovery, with higher hematologic recovery rates among PRCA patients who received immunosuppressive therapy (57\% vs 2\%, P < .001). Among 34 patients who received epoetin after the onset of PRCA, 56\% regained epoetin responsiveness. The highest rates of epoetin responsiveness were observed among persons whose antierythropoietin antibodies were undetectable when epoetin was administered (89\%). Among chronic kidney disease patients with epoetin-associated PRCA, epoetin discontinuation and immunosuppressive therapy or renal transplantation is necessary for hematologic recovery. Reinitiation of epoetin therapy among individuals could be considered if antierythropoietin antibodies are undetectable.

2005 - The myocan phase II study of cyclophosphamide, oncovin, Myocet (TM) and prednisone plus rituximab (R-COMP) in elderly patients with diffuse large B-cell (DLBCL) non-Hodgkin lymphoma [Articolo su rivista]
Federico, Massimo; Caballero, M; Dyer, M; Luminari, Stefano; Thiel, E.
abstract

2005 - Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) regimen as salvage therapy in relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL): Results of a phase II study conducted by the Gruppo Italiano per lo Studio dei Linfomi (gisl) [Articolo su rivista]
Di Renzo, N; Brugiatelli, M; Montanini, A; Dell'Olio, M; Petrini, M; Stelitano, C; Liberati, Alessandro; Luminari, Stefano; Morandi, S; Giglio, G; Federico, Massimo
abstract

2004 - Erratum: Splenosis peritonei (British Journal of Heamatology 123:3 (378)) [Articolo su rivista]
Luminari, S.; De Santis, M.; Casolo, A.; Federico, M.
abstract

2004 - FLUDARABINE AND CYCLOPHOSPHAMIDE FOR THE TREATMENT OF PATIENTS WITH INDOLENT NON-FOLLICULAR (INFL) B-CELL NON-HODGKIN'S LYMPHOMAS. PRELIMINARY RESULTS OF A PHASE II TRIAL OF THE 'GRUPPO ITALIANO PER LO STUDIO DEI LINFOMI (GISL) [Abstract in Rivista]
Luminari, Stefano; L., Baldini; M., Brugiatelli; M., Goldaniga; Sacchi, Stefano; A., Bagnulo; F., Merli; C., Stelitano; G., Giglio; Federico, Massimo
abstract

Introduction: INFL comprises a rather heterogeneous subgroup of lymphomas,including small lymphocytic lymphoma (SLL), immunocytoma (IC) and marginalzone lymphomas (MZL). In April 2002, the GISL started a phase II trial to verifythe efficacy of fludarabine and cyclophosphamide (Flu–Cy) combination in this subsetof NHL, in terms of response, survival and toxicity.Patients and methods: Patients should have a diagnosis of SLL, IC, MZL or CD5negative mature B-cell leukemia (MBCL), supported by morphologic, phenotypicand molecular data; patients should also be untreated for lymphoma and have activedisease defined by the presence of anemia, thrombocytopenia, bulky disease, rapidlyincreasing lymphocytosis or enlarging masses. Treatment consisted of fludarabine25 mg/m2 i.v. day 1–3 and cyclophosphamide 250 mg/m2 i.v. days 1–3, to berepeated every 28 days for six cycles; an intermediate evaluation of response afterthree cycles was planned and an adequate anti-infective prophylaxis was mandatory.Results: As of March 2004, 44 patients were registered into the trial; one patientwas excluded from the study due to incorrect histology. Median age was 63 years(range 39–75), M/F ratio was 1.9. The diagnosis was SLL in 11 patients, IC in 7,MZL in 19 and MBCL in 5. All patients had stage IV disease. Anemia was presentin 32%, elevated b2 microglobulin in 56%, abnormal LDH in 32%. At the time ofthe present analysis, 24 patients completed the treatment program with 13 CR (52%)and 11 PRs (44%). Three patients died during treatment, one after the second cycledue to erosive pulmonary aspergillosis, the others due to bone marrow aplasiaoccurred after the 4th and 5th cycle, respectively. Overall, grade III or IV hematologicaltoxicity was observed in 44% of the patients. After a median follow-up of9 months, OS was 81%.Conclusion: The preliminary results of our study demonstrate that the Flu–Cycombination is effective in the treatment of patients with INFL but has also shown arelevant toxicity profile suggesting the need for extensive antimicrobial prophylaxis

2004 - I tumor in provincia di Modena nel 2002 [Monografia/Trattato scientifico]
Federico, Massimo; Artioli, M. E.; Rashid, I.; Fracca, A.; Cortesi, L.; Luminari, Stefano; Maiorana, Antonino; De Girolamo, G.
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena

2004 - Il linfoma mantellare [Capitolo/Saggio]
Federico, Massimo; Luminari, Stefano; Artusi, Tullio
abstract

Il linfoma mantellare (LM) è stato identificato per la prima volta come entità clinico-patologica distinta solo agli inizi degli anni 90 (1), con la scoperta della specifica traslocazione cromosomica t (11;14), ma era già stato ben descritto dal punto di vista morfologico nel 1982 da Denis Weisenburger che lo aveva definito com elinfoma della zona mantellare (2). L'esistenza di un linfoma costituito interamente da cellule clivate, con un comportamento clinico diverso dagli altri linfomi di origine centrofollicolare era stata postulata già negli anni 70 da Karl Lennert e dalla sua scuola di Kiel, che avevano coniato il termine di "linfoma centrocitico puro" (3). E' verosimile che casi di LM in passato siano stati classificati come linfomi linfocitici intermedi (4), a cellule clivate (5), centrocitici (6) o centrocitici diffusi a picocle cellule clivate (7).Il LM è stato riconosciuto definitivamente come una entità distinta nella recente classificazione dei linfomi della WHO ed ha una storia naturale ed una prognosi nettamente diversa dai linfomi di origine centrofollicolare e da quelli linfocitici che per molti anni sono stati inseriti nel gruppo ormai eterogeneo dei linfomi non-Hofgkin (LNH) indolenti.

2004 - Il linfoma mantellare. Linfomi non-Hodgkin [Monografia/Trattato scientifico]
Federico, Massimo; Luminari, Stefano; Artusi, Tullio
abstract

Monografia scientifica sul linfoma mantellare

2004 - Pure red-cell aplasia and epoetin therapy [Articolo su rivista]
Bennett, Cl; Luminari, Stefano; Nissenson, Ar; Tallman, Ms; Klinge, Sa; Mcwilliams, N; Mckoy, Jm; Kim, B; Lyons, Ea; Trifilio, Sm; Raisch, Dw; Evens, Am; Kuzel, Tm; Schumock, Gt; Belknap, Sm; Locatelli, F; Rossert, J; Casadevall, N.
abstract

BACKGROUND: Between 1988 and 1998, antibody-associated pure red-cell aplasia was reported in three patients who had undergone treatment with recombinant human erythropoietin (epoetin). Between 1998 and 2000, 13 such cases were reported from France -- 12 in patients who had received the Eprex formulation of epoetin alfa and 1 in a patient who had received Neorecormon (a formulation of epoetin beta); both are products that are marketed outside the United States. METHODS: We obtained reports of epoetin-associated pure red-cell aplasia from the Food and Drug Administration and from the manufacturers of Eprex, Epogen (another formulation of epoetin alfa), and Neorecormon. The numbers of case reports and estimates of exposure-adjusted incidence were analyzed according to the product, the cause of anemia, the route of administration, the country in which pure red-cell aplasia was identified, and the date on which pure red-cell aplasia was reported. RESULTS: Between January 1998 and April 2004, 175 cases of epoetin-associated pure red-cell aplasia were reported for Eprex, 11 cases for Neorecormon, and 5 cases for Epogen. Over half these cases had occurred in France, Canada, the United Kingdom, and Spain. Between 2001 and 2003, the estimated exposure-adjusted incidence was 18 cases per 100,000 patient-years for the Eprex formulation without human serum albumin, 6 per 100,000 patient-years for the Eprex formulation with human serum albumin, 1 case per 100,000 patient-years for Neorecormon, and 0.2 case per 100,000 patient-years for Epogen. After procedures were adopted to ensure appropriate storage, handling, and administration of Eprex to patients with chronic kidney disease, the exposure-adjusted incidence decreased by 83 percent worldwide. CONCLUSIONS: After the peak incidence of Eprex-associated pure red-cell aplasia was reached in 2001, interventions designed in response to drug-monitoring programs worldwide resulted in a reduction of more than 80 percent in the incidence of pure red-cell aplasia due to Eprex.

2004 - Quality of life assessment in elderly patients with aggressive non-Hodgkin's Lymphoma treated with anthracycline-containing regimens. Report of a prospective study by the Intergruppo Italiano Linfomi [Articolo su rivista]
Merli, F; Bertini, M; Luminari, Stefano; Mozzana, R; Berte, R; Trottini, M; Stelitano, C; Botto, B; Pizzuti, M; Quintana, G; De Paoli, A; Federico, Massimo
abstract

Background and Objectives. The aim of this study was to evaluate quality of life (QOL) in a group of elderly patients ( > 65 years) with aggressive non-Hodgkin's lymphoma (NHL) treated with chemotherapy regimens containing anthracyclines. Design and Methods. QOL was evaluated in a population of elderly patients with aggressive NHL enrolled in a phase III clinical trial run by the Intergruppo Italiano Linfomi (11L) from 1996 to 1999 to compare two different anthracycline-containing regimens (mini-CEOP vs P-VEBEC). The EORTC-QLQ-C30 questionnaire, which has already been validated in oncology, was used. The questionnaire was administered at the time of diagnosis, half way through the chemotherapy and at the time of restaging. Results. Ninety-one patients completed pre-therapy and post-therapy questionnaires and they are the subject of this report. Baseline QOL assessment showed a strong correlation of poor values of QOL with anemia and high risk according to the International Prognostic Index (IPI). At the end of treatment no functional scales showed worse values. A significant improvement was observed for pain (p = 0.003), appetite (p = 0.006), sleep (p = 0.015) and global health (p = 0.027). Considering only the 50 patients who achieved a complete remission (CR), an improvement was also recorded for emotional state (p = 0.10), role (P = 0.05), constipation (p = 0.04) and global QOL (p = 0.05). Interpretation and Conclusions. The EORTC-QLQ-C30 is feasible even in a population of elderly patients, in whom it had never been tested before. The improvement of QOL at the end of the treatment demonstrated that the symptoms of the disease have a greater negative influence on the patient's life than do the side effects of the therapy.

2003 - Do we need high-dose therapy for initial treatment of high-risk Hodgkin's disease? Venezia New isights in Hematology [Articolo su rivista]
Federico, Massimo; Luminari, Stefano
abstract

no abstract

2003 - Efficacy Controls and Long-Term Follow-Up of Patients (Pts) Treated with FC Plus Rituximab for Relapsed Follicular NHL. Session Type: Publication Only [Abstract in Rivista]
Sacchi, Stefano; Alessandra, Tucci; Francesco, Merli; Loretta, Orsucci; Giulia, Cervetti; Ubaldo, Occhini; Marina, Liberati; Giuseppe, Tarantini; Vuncenzo, Callea; Maura, Brugiatelli; Vito Michele, Lauta; Luca, Baldini; Marcheselli, Raffaella; Luminari, Stefano; Federico, Massimo
abstract

Although treatment of follicular lymphomas (FL) with standard chemotherapy regimens generally yields a high initial response rate, the clinical course consists of a pattern of repeated relapses.Subsequent responses after every new line of treatment are of progressively shorter duration and the patients eventually die of disease-related causes. The ability of Rituximab to sensitize cell lines to fludarabine, doxorubicine, vinblastine, and cisplatin together with the synergism of Rituximab with CHOP in the treatment of DLBCL, was recently reported .We have completed in April 2003 a multicenter Phase II clinical trial in 52 pts with relapsed FL. Patients received chemotherapy consistent of Fludarabine 25 mg/sqm/die and Cyclofosfamide 30 mg/sqm/die for 3 consecutive days every 3 weeks for 4 cycles. Rituximab was infused on day 1 of every cycles at a dose of 375 mg/sqm. Patient characteristic: median age 62 years (range: 44-80); disease stage: I -II B 21%, III 30%, IV 49%; number of prior chemotherapy regimens:1- 43%, 2-43%, 3-12%, 4-3%. The response rates in the intent to treat analysis is: CR 75 % (39 pts), PR 19% (10 pts) and dropouts 6% (3 pts).Of note, 58% of the pts initially bcl-2 positive in the bone marrow became bcl-2 negative following treatment.At a median follow-up of 20 months, the restricted media duration of response in the 49 pts who have obtained a response was 26 months (95% CI, 22-29). Included in the group of this 49 pts assessed for duration of response were 6 pts who had achieved a PR and a CR but whose bone marrow remained bcl-2 positive. These pts were treated with a subsequent course of 4 doses of Rituximab plus IFN-a 3 MU t.i.w for 6 weeks.Approximately 93% experienced treatment-related toxicity; however, the majority of side effects were grade 1 / 2. The most common severe adverse events were hematologic, and included 20 cases of grade 3/ 4 neutropenia, 1 case of thrombocytopenia, and 3 cases of anemia as well as infection. Five patients died during the treatment period and follow-up: 1 of myelodysplastic syndrome, 2 of disease progression, 1 of progressive carcinoma, and 1 of pneumonitis.Treatment delays of 1-3 weeks were necessary in 12 pts. Treatment interruptions were necessary in 3 pts, 1 following cycle 2 and 2 following cycle 3.The results of our trial demonstrate that this regimen is active and relatively well tollerate although significant cytopenia with delay of subsequent treatment administration was observed in several pts.Finally, a DR of 26 months after a median follow-up of 20 months compare favorably with the results obtained in other trial in similar subset of pts and support the evidence for Rituximab plus chemotherapy as a new standard for treating relapsed FL

2003 - High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy [Articolo su rivista]
Federico, Massimo; Bellei, Monica; Brice, P; Brugiatelli, M; Nagler, A; Gisselbrecht, C; Moretti, L; Colombat, P; Luminari, Stefano; Fabbiano, F; Di Renzo, N; Goldstone, A; Carella, Am
abstract

To determine whether high-dose therapy (HDT) with autologous stem-cell transplantation (ASCT) should be included in the initial consolidative treatment of patients with advanced, unfavorable Hodgkin's lymphoma (HL). Patients and Methods: One hundred sixty-three patients achieving complete remission (CR) or partial remission (PR) with four initial courses of doxorubicin, bleomycin, vinblastine, and dacarbazine, or other doxorubicin-containing regimens, were randomly assigned to receive HDT plus ASCT (83 patients) versus four courses of conventional chemotherapy (80 patients). Unfavorable HL was defined as the presence of at least two of the following poor prognostic factors: high lactate dehydrogenase level, large mediastinal mass (greater then at least 33%. of the thoracic diameter), more than one extranodal site, low hematocrit level, and inguinal involvement. Results. At the end of the treatment program, 92% of patients in arm A and 89% in arm 8 achieved a CR (P = .6). After a median follow-up of 48 months, the 5-year failure-free survival rates were 75% (95% confidence interval [CI], 65 to 85) in arm A and 82% (95% CI, 73 to 90) in arm B (P = .4). The 5-year overall survival rates were 89% (95% CI, 90 to 96) in arm A and 88%. (95% CI, 79 to 96) in arm B (P = .99). The 5-year relapse-free survival rates were 88% in arm A (95% CI, 80 to 96) and 94% in arm 6 (95% CI, 88 to 100), and the difference was not significant (P = .3). Conclusion: Patients with advanced unfavorable HL achieving CR or PR after four courses of doxorubicin-containing regimens have a favorable outcome with conventional chemotherapy. No benefit from an early intensification with HDT and ASCT was shown.

2003 - Prevalence and prognostic significance of sMUC-1 levels in plasma cell dyscrasias [Articolo su rivista]
Luminari, Stefano; Goldaniga, M; Ceccherelli, F; Guffanti, A; Bombardieri, E; Marcheselli, R; Cro, L; Colombi, M; Federico, Massimo; Baldini, L.
abstract

High serum Mucin-1 (sMUC-1) levels have been shown in patients with adenocarcinoma and multiple myeloma (MM). We evaluated sMUC-1 levels in 76 patients with MM, 6 with plasma cells leukaemia (PCL) and 89 with monoclonal gammopathy of undetermined significance, to establish prevalence data and verify its possible prognostic role. Of the 171 patients, 27 [16%; 95% confidence interval (CI): 10-21%] had high sMUC-1 levels compared with healthy subjects (1.5%; 95% CI: 0-4%). Elevated sMUC-1 levels in MM and PCL patients correlated with anaemia and elevated serum lactate dehydrogenase levels; these patients showed a shorter survival than those with normal sMUC-1 levels (median overall survival: 25 vs. 49 months, P = 0.003).

2003 - Serum MUC-1 as a marker of disease status in multiple myeloma patients receiving thalidomide - Response to Mileshkin et al. [Articolo su rivista]
Luminari, Stefano; Federico, Massimo; Baldini, L.
abstract

no abstract

2003 - Splenosis peritonei. [Articolo su rivista]
Luminari, Stefano; M. D., Santis; A., Casolo; Federico, Massimo
abstract

this article does not have an abstract

2003 - Treatment of indolent B-Cell nonfollicular lymphomas: final results of the LL01 randomized trial of the Gruppo Italiano per lo Studio dei Linfomi. [Articolo su rivista]
L., Baldini; M., Brugiatelli; Luminari, Stefano; M., Lombardo; F., Merli; Sacchi, Stefano; S. P., Gobbi; M., Liberati; L., Cavanna; M., Colombi; C., Stelitano; M., Goldaniga; F., Morabito; Federico, Massimo; V., Silingardi
abstract

Purpose: To evaluate the effect of epirubicin on therapeutic response and survival in patients with indolent nonfollicular B-cell lymphomas (INFL) treated with pulsed high-dose chlorambucil. Patients and Methods: A total of 170 untreated patients with advanced/active INFL were randomly assigned to receive either eight cycles of high-dose chlorambucil (15 mg/m2/d) plus prednisone (100 mg/d) for 5 days (HD-CHL-P; arm A) or eight cycles of HD-CHL-P plus epirubicin 60 mg/m2 intravenous on day 1 (arm B). The responding patients were randomly assigned to either maintenance therapy with interferon alfa (IFN-2a; 3 MU, three times weekly) for 12 months or observation. Results: There were 160 assessable patients (82 males, 78 females; median age, 63 years; range, 33 to 77 years); 77 patients were assigned to arm A, and 83 were assigned to arm B. Induction therapy led to 47 complete responses (CRs; 29.4%) and 68 partial responses (PRs; 42.5%), with no significant difference between the two arms (60 CR + PR in arm A [77.9%] and 55 CR + PR in arm B [66.3%]; P = .07). After a median follow-up of 38 months (range, 2 to 103 months), there was no between-group difference in overall survival (OS; P = .45), failure-free survival (P = .07), or progression-free survival (PFS; P = .5). Eighty-eight patients were randomly assigned to either IFN-2a (n = 43) or observation (n = 45), without any difference in 3-year PFS (44% and 42%, respectively). Univariate analysis showed that OS was influenced by age, anemia, serum lactate dehydrogenase levels, and International Prognostic Index distribution; multivariate analysis identified age and anemia as having influence on OS. Conclusion: HD-CHL-P treatment outcome in INFL patients was good (50% 3-year PFS, minimal toxicity, and low costs); epirubicin did not add any advantage. One-year IFN maintenance treatment did not prolong response duration. Supported by a grant (Ricerca Corrente) from the Italian Ministry of Health to Ospedale Maggiore Istituto Ricovero Cura Carattere Scientifico, Milan, Italy, and a grant from Associazione Angela Serra, Modena, Italy.

2002 - ABVD versus Stanford V versus MEC in unfavourable Hodgkin's lymphoma: results of a randomised trial [Articolo su rivista]
Chisesi, T; Federico, Massimo; Levis, A; Deliliers, Gl; Gobbi, Pg; Santini, G; Luminari, Stefano; Brugiatelli, M.
abstract

Background: Between January 1996 and April 2000, 355 patients with advanced Hodgkin's disease (HD) (stage II bulky disease, III and IV) were enrolled in a prospective, multicentre, randomised trial aimed at comparing the efficacy of two new promising regimens: Stanford V and MEC hybrid. ABVD was chosen as the control arm. Radiotherapy was planned at the end of induction therapy on residual masses or on sites of previous bulky lesions. One hundred and seventeen, 123 and 115 patients were treated with Stanford V, MEC and ABVD, respectively. The records of 275 enrolled patients (89 Stanford V, 88 MEC, 98 ABVD) have been reviewed and are the subject of this report. Results: After induction therapy a complete response (CR) was observed in 93, 89 and 74% of patients treated with MEC, ABVD and Stanford V, respectively, with a statistically significant difference (P = 0.013) between the arms. After a median follow-up of 24 months, 16 relapses have been recorded among 196 patients who achieved a CR. Relapse rates are 16, 6 and 4% for Stanford V, ABVD and MEC, respectively (P = 0.042). The 3-year survival was 93%, without any significant difference among the arms. However, a significant difference emerged in terms of failure free survival (FFS). Patients treated with Stanford V did the worst compared with those treated with ABVD or MEC (P = 0.001). Toxicity was comparable in the three treatment arms. Conclusion: For this randomised study, both ABVD and MEC gave superior results to Stanford V in term of response and FFS; MEC seems to be the best regimen in terms of relapse-free survival, even if a significant difference has not yet been achieved. Notwithstanding the short follow-up, these results seem to be very impressive in defining the best standard treatment for HD for this subset of patients.

2002 - Bleomycin, epidoxorubicin, cyclophosphamide, vincristine and prednisone (BACOP) in patients with follicular non-Hodgkin's lymphoma: Results of a prospective, multicenter study of the Gruppo Italiano per lo Studio dei Linfomi (GISL) [Articolo su rivista]
M., Lombardo; F., Morabito; F., Merli; S., Molica; L., Cavanna; Sacchi, Stefano; C., Broglia; F., Angrilli; F., Ilariucci; C., Stelitano; D., Luisi; R., Berte; Luminari, Stefano; Federico, Massimo; M., Brugiatelli
abstract

At present we report the results of a prospective, non-randomized open trial, conducted on follicular lymphoma (FL) patients by the Gruppo Italiano per lo Studio dei Linfomi (GISL), after a median follow-up of 62.6 months. Seventy-three patients with FL were registered to the study and treated with combination chemotherapy consisting of cyclophosphamide, epidoxorubicin, vincristine, bleomycin and prednisone, weekly administered every 4 weeks. After chemotherapy, involved-field radiotherapy was delivered in case of either localized, bulky and extranodal disease at presentation or limited residual disease at the end of chemotherapy. Patient received four or eight chemotherapy courses in case of localized or advanced disease, respectively. The overall response rate at the end of the treatment program was 97.3%, with 78.1% CR and 19.2% PR. CR rate was 94.3 and 63.1% in stage I-II and III-IV, respectively (p = 0.006). Beside the stage, response rate was significantly influenced by bone mar-row involvement, and the number of extranodal sites. Relapse free survival was 60.8% at 5 years in the whole series; in localized disease it was 70.3 vs. 44.8% in advanced disease (p = 0.044). Relapse free survival was significantly influenced by stage, bone marrow involvement, number of extranodal sites and International Prognostic Index (IPI) score. The overall 5-year survival rate was 90.2%; being 95.6% for patients with stage I-II and 85.1% for those III-IV (p = 0, 0133). In addition, both IPI and Italian Lymphoma Intergroup (ILI) score had a significant impact on survival. The toxicity profile of the treatment was acceptable. From the results of this prospective study it is possible to conclude that this regimen and the whole treatment program is effective as first line therapy for the general population of FL. In particular the BACOP schedule is a valid anthracycline-containing regimen, and in this respect suitable to be considered as a treatment option.

2002 - Follicular lymphomas: is there a chance for cure? [Articolo su rivista]
Federico, Massimo; Sacchi, Stefano; Bellei, Monica; Luminari, Stefano; Baldini, L.; Vitolo, U.; Rigacci, L.; Brugiatelli, M.
abstract

no abstract

2002 - Phase II Study with Fludarabine and Cyclophosphamide Plus Rituximab (FC+R) in Relapsed Follicular Lymphoma Patients. [Abstract in Rivista]
Sacchi, Stefano; Alessandra, Tucci; Francesco, Merli; Loretta, Orsucci; Giulia, Cervetti; Ubaldo, Occhini; Marina, Liberati; Giuseppe, Tarantini; Vicenzo, Callea; Maura, Brugiatelli; Vito Michele, Lauta; Luca, Baldini; Luminari, Stefano; Federico, Massimo
abstract

Both Cyclophsphamide (C) and Fludarabine (F) have individual anti-lymphoma activity and the combination Rituximab (R) + F has been shown to have a synergistic activity against resistant lymphoma cell lines in vitro. In march 2000, we started a Phase II multicenter clinical trial to test safety and efficacy of FC+R combination in patients with relapsed follicular lymphoma. We have recently completed the enrollment of 48 pts in the trial. Patients received 4 doses of R (375 mg/sqm/d) in combination with 4 cycles of F (30 mg/sqm/d for 3 days) and C (300mg/sqm/d for 3 days) every 28 days. Patients characteristic: 45% males, 55% females; median age: 62 years (range 44-71); stage IV 47% pts; Systemic Symptoms 8,5% pts; elevated LDH 15% pts. Rearrangement of BCL2 gene was evaluated with PCR in 38pts (79%) on bone marrow or peripheral blood mononucleated cells; 22 patients showed BCL2 rearrangement (58%). Medium number of previous chemotherapy regimens was 1,7 (range 1-4); median duration of last remission before registration into the trial was 12 months (range 1-68). Thirty-nine patients were available for evaluation at the time of current analysis. One patient did not complete therapy due to severe cytopenia. The response rate in the intent-to-treat analysis was 97%, with 74%, Complete Responses (CR) and 23% Partial Responses (PR). Out of 18 patients with molecular monitoring of disease before and after chemotherapy, 15 patients (83%) obtained molecular remission in the bone marrow (BM) .After a median follow-up of 12 months (1-25), median duration of remission was 13 months; twenty percent of patients were only recently registered into the trial and had a short follow-up (less than 4 months). Overall, 8 patients relapsed (21%). One patient died due to severe neutropenia occurred during chemoterapy; two patients died due to lymphoma progression. Complete responses are ongoing in 28 patients. As far as toxicity is concerned WHO grade III-IV leukopenia was observed in 10 patients, with 4 patients presentig a WHO grade IV granulocytopenia. WHO grade IV infections were observed in only one patient who had a pulmonary infection after third cycle. Non-ematologic toxicity was minimal. During follow up, one patient had a renal cell tumor and one patient had myelodisplasia, 3 and 6 months after the end of treatment, respectively. In conclusion the combination FC+R is associated with acceptable toxicity and with an excellent response rate in this group of heavily pre-treated patients with relapsed follicular lymphoma. Furhter follow-up is required to evaluate response duration and survival in the whole group of patients.

2002 - Prospective study of indolent non-follicular non-Hodgkin's lymphoma: validation of Gruppo Italiano per lo studio dei linfomi (GISL) prognostic criteria for watch and wait policy. [Articolo su rivista]
F., Morabito; L., Baldini; C., Stelitano; Luminari, Stefano; A., Frassoldati; F., Merli; M., Colombi; R., Sabbatini; M., Brugiatelli; Federico, Massimo; G. I., per lo studio dei linfomi
abstract

Only recently both the Revised European American Lymphoma (REAL) and World Health Organization (WHO) classifications clearly identified indolent non-follicular non-Hodgkin's lymphoma (NHL) as a distinct group of precise histological entities. Therefore, prognostic models, specifically designed for this NHL subset, are still lacking. In this study, we prospectically evaluated the prognostic criteria proposed by the Gruppo Italiano per lo studio dei linfomi (GISL) to identify patients with an indolent non-progressive clinical course, eligible for a watch and wait policy within this histological subset defined according to stringent criteria of histomorphology and immunophenotype. Fifty-three patients affected with small lymphocytic, marginal zone, lymphoplasmacytic lymphoma and lacking at presentation the following: B symptoms, bulky disease, anemia, thrombocytopenia, diffuse pattern of bone marrow infiltration and short tumor doubling time, were registered in a prospective therapeutic GISL trial and addressed to a watch and wait program. After 41.3 months of median follow-up, the median progression free survival (PFS) was not reached and 73% of cases did not progress. When additional variables were considered, in order to improve the prognostic model, it was evident that LDH level and the number of extranodal sites were of statistical significance in the multivariate analysis. Based on this finding, a prognostic score was devised which was able to further identify a small group of patients more likely to undergo early progression, and thus suitable for immediate treatment. In conclusion, the GISL definition of indolent disease is a reliable tool to design the appropriate therapeutic strategy in this histological setting.

2001 - Nodal marginal zone B-cell lymphomas may arise from different subsets of marginal zone B lymphocytes. [Articolo su rivista]
A., Conconi; F., Bertoni; E., Pedrinis; T., Motta; E., Roggero; Luminari, Stefano; C., Capella; M., Bonato; F., Cavalli; E., Zucca
abstract

Nodal marginal zone B-cell lymphoma (MZL) is a rare and not extensively studied entity that accounts for approximately 2% of all non-Hodgkin lymphomas. Complementarity-determining regions 2 and 3 (CDR2, CDR3) of the immunoglobulin heavy-chain variable region (V(H)) genes were amplified by polymerase chain reaction (PCR), cloned, and sequenced in 8 patients with nodal MZL. All showed a potentially functional V(H) rearrangement. The use of V(H) gene families was unbiased and without overrepresentation of any particular V(H) gene or gene family. The presence of somatic V(H) mutations was detected, with a deviation from the closest germ line sequence ranging from 4% to 17% in 6 of 8 patients. In 3 mutations, the replacement-to-silent mutation ratio suggested the presence of an antigen-selected process. Sequencing different subclones of the same cloned PCR products allowed the detection of intraclonal variability in 4 analyzed patients. The observed pattern of V(H) mutations suggested that nodal MZL, formerly deemed a malignancy of memory B cells, may arise from different subsets of marginal zone B cells-the naive B cells that express unmutated V(H) genes-from memory B cells showing somatic mutations without intraclonal variation, and from germinal center B cells defined by their capacity to undergo the somatic hypermutation process.

2000 - BCL10 gene mutations rarely occur in lymphoid malignancies [Articolo su rivista]
Luminari, Stefano; D., Intini; L., Baldini; E., Berti; F., Bertoni; E., Zucca; L., Cro; A. T., Maiolo; F., Cavalli; A., Neri
abstract

BCL10, a gene involved in apoptosis signalling, has recently been identified through the cloning of chromosomal breakpoints in extranodal (MALT-type) marginal zone lymphomas carrying the t(1;14)(p22;q32) translocation. BCL10 was also found mutated in these cases as well as in other types of lymphoid and solid tumors, suggesting that its inactivation may play an important pathogenetic role; however, this has been questioned by recent studies showing a lack of somatic mutations in human cancers. We report the mutation analysis of exons 1-3 of the BCL10 gene in DNAs from 228 cases of lymphoid malignancies (30 B cell chronic lymphocytic leukemias, 123 B and 45 T non-Hodgkin's lymphomas and 30 multiple myelomas). Somatic mutations were detected in four cases (approximately 2\%): one small lymphocytic, one follicular and two diffuse large cell lymphomas. The mutations were all within exon 3 and have not been previously reported. Our data suggest that BCL10 mutations may play only a limited role in the pathogenesis of lymphoid neoplasms.

2000 - Lack of CD95/FAS gene somatic mutations in extranodal, nodal and splenic marginal zone B cell lymphomas. [Articolo su rivista]
F., Bertoni; A., Conconi; Luminari, Stefano; C., Realini; E., Roggero; L., Baldini; S., Carobbio; F., Cavalli; A., Neri; E., Zucca
abstract

Germline CD95 (also known as FAS, APT1 and APO1) gene mutations have been associated with benign lymphoproliferative diseases and autoimmune processes. Somatic mutations have been reported in human tumours, including lymphomas. Since marginal zone B cell lymphomas usually arise in a background of chronic inflammation, often of autoimmune origin, we searched for CD95 gene mutations in an unselected series of marginal zone B cell lymphomas. The CD95/FAS full coding region, comprising exon-intron junctions, was amplified from genomic DNA by polymerase chain reaction (PCR) in 10 separate reactions. PCR products were analysed by single-strand conformation polymorphism (SSCP) and visualised by silver staining. Bands exhibiting an altered electrophoretic mobility were sequenced. Twenty-seven cases of marginal zone B cell lymphomas of whom fresh or frozen tumour material was available (18 extranodal, five splenic and four nodal) were studied. Previously described silent polymorphisms in exons 7 (C836T) and 3 (T416C) were detected in 42\% and in 19\% of the cases, respectively. One silent T-to-A substitution at bp 431, within exon 3, was found in one case. Our results did not reveal the presence of CD95 somatic mutations in unselected cases of marginal zone B cell lymphomas. On the basis of our data, we cannot rule out that other genes coding for proteins involved in the CD95-induced apoptotic pathway might be altered. However, this pathway does not seem to play an important role in the pathogenesis of these lymphoma subtypes.

1999 - Analysis of BCL-10 gene mutations in ovarian cancer cell lines. [Articolo su rivista]
F., Bertoni; Luminari, Stefano; D., Intini; S., Carobbio; A. M., Codegoni; V., Spataro; A., Neri
abstract

no abstract available

1998 - FGFR3 gene mutations associated with human skeletal disorders occur rarely in multiple myeloma. [Articolo su rivista]
N. S., Fracchiolla; Luminari, Stefano; L., Baldini; L., Lombardi; A. T., Maiolo; A., Neri
abstract

no abstract available

1998 - Low-grade MALT lymphoma involving multiple mucosal sites and bone marrow. [Articolo su rivista]
G., Graziadei; G., Pruneri; N., Carboni; Luminari, Stefano; M. L., Targia; A., Neri; M., Colombi; R., Buffa; L., Baldini
abstract

Mucosa-associated lymphoid tissue (MALT) lymphomas are indolent neoplasms which tend to remain localized for a long time before spreading. We describe here the case of a 36-year-old woman with a low-grade MALT lymphoma involving the lung, stomach, lingual tonsil, and bone marrow at the time of diagnosis. The clonal origin of the pulmonary and bone marrow neoplastic infiltrates was assessed by means of gene rearrangement analysis. All of the involved sites were infiltrated by centrocyte- and monocytoid-like cells expressing the B-cell-associated antigens CD19 and CD20 and showed IgM lambda chain restriction; no CD5, CD10, or CD43 expression was detectable. As the patient had a history of recurrent bronchitis, and computed tomography performed 3 years before the lymphoma diagnosis had already revealed a lesion of the left lung, we conclude that the present case probably represents a pulmonary low-grade MALT lymphoma characterized by an early and unusual involvement of different mucosal sites and bone marrow.

1997 - MDM-2 oncoprotein overexpression in laryngeal squamous cell carcinoma: association with wild-type p53 accumulation. [Articolo su rivista]
G., Pruneri; L., Pignataro; N., Carboni; Luminari, Stefano; P., Capaccio; A., Neri; R., Buffa
abstract

The MDM-2 gene encodes for a nuclear phosphoprotein that binds p53 and inhibits its ability to activate transcription by concealing the p53 activation domain. It has been suggested that MDM-2 overexpression might represent an alternative mechanism by which p53-mediated pathways are inactivated in human tumors. MDM-2 overexpression can be detected by immunohistochemical analysis as a result of gene amplification and/or increased mRNA expression. We studied MDM-2 gene amplification and protein overexpression in 46 and 50 cases, respectively, of laryngeal squamous cell carcinomas previously analyzed for p53 gene alterations. Not one of the cases showed MDM-2 gene amplification, whereas MDM-2 nuclear immunoreactivity was found in 17 tumors (34\%). In 10 of these, coexpression of p53 protein was detectable in the absence of gene mutations in exons 5 through 9 (P = .03). Likewise, MDM-2 was also overexpressed in 18 (46\%) of 39 morphologically normal mucosa samples, 15 (50\%) of 30 preneoplastic lesions, and 9 (40\%) of 22 cases of severe dysplasia. Finally, we found no significant correlations between MDM-2 expression (neither per se nor in association with wild-type or mutated p53), and the evaluated clinicopathologic parameters of histologic grade, lymph node status, or clinical stage. Our results suggest that MDM-2 gene amplification might not occur in laryngeal carcinomas and that MDM-2 protein overexpression might represent an alternative mechanism by which p53 is inactivated in the early stages of laryngeal cancer tumorigenesis.

Università degli studi di Modena e Reggio Emilia

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