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Samantha POZZI
Professore Associato
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto
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Pubblicazioni
2023
- Clinicopathological, cytogenetic, and molecular profiles of primary cutaneous diffuse large B-cell lymphomas
[Articolo su rivista]
Uccella, Silvia; Goteri, Gaia; Maiorana, Antonino; Donati, Valentina; Tibiletti, Maria Grazia; Magnoli, Francesca; Facchi, Sofia; Merchiori, Deborah; Morsia, Erika; Papotti, Robel; Bettelli, Stefania; Forti, Elisa; Galimberti, Sara; Rupoli, Serena; Filosa, Alessandra; Dardanis, Dimitri; Bomben, Riccardo; Braglia, Luca; Pozzi, Samantha; Sacchi, Stefano
abstract
We analyzed the clinicopathological, cytogenetic, and molecular features of 18 primary cuta-neous diffuse large B-cell lymphomas (PCDLBCLs) and 15 DLBCLs secondarily localized to the skin (SCDLBCLs), highlighting biological similarities and differences between the 2 groups.PCDLBCLs were subclassified after histopathological review as PCDLBCL-leg type (PCDLBCL-LT, 10 cases) and the PCDLBCL-not otherwise specified (PCDLBCL-NOS, 8 cases). Immunohisto-chemistry for Hans' algorithm markers, BCL2, and MYC was performed. The molecular study included the determination of the cell of origin (COO) by Lymph2Cx assay on NanoString platform, FISH analysis of IgH, BCL2, BCL6, and MYC genes, as well as the mutation analysis of MYD88 gene.In immunohistochemistry analysis, BCL2 and MYC hyperexpression was more frequent in LT than in NOS cases and, according to Hans' algorithm, PCDLBCL-LTs were mostly of the non-GC type (8/ 10), whereas in PCDLBCL-NOS, the GC type prevailed (6/8). The determination of COO using Lymph2Cx supported and further confirmed these results. In FISH analysis, all but one LT cases versus 5 of 8 PCDLBCL-NOS showed at least one gene rearrangement among IgH, BCL2, MYC, or BCL6. In addition, MYD88 mutations were more frequently present in LT than in NOS subtypes. Interestingly, MYD88-mutated patients were older, with a non-GC phenotype and had worse OS, compared to MYD88 WT cases. Overall, SCDLBCL did not show, at the genetic and expression level, different pro-files than PCDLBCL, even if they bear a significantly worse prognosis. At survival analysis, the most important prognostic factors in patients with PCDLBCL were age and MYD88 mutation, whereas relapse and high Ki-67 expression were relevant in patients with SCDLBCL.Our study comprehensively analyzed the clinicopathological and molecular features of PCDLBCL-LT, PCDLBCL-NOS, and SCDLBCL, underlining the differences among them and the importance of properly identifying these entities at the time of diagnosis.(c) 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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
- PEG-Asparaginase Single-Agent Rescue in an Advanced Case of Monomorphic Epitheliotropic Intestinal T Cell Lymphoma
[Articolo su rivista]
Barbieri, E.; Pozzi, S.; Gelmini, R.; Roncati, L.; Maccaferri, M.; Potenza, L.; Marasca, R.; Luppi, M.; Leonardi, G.
abstract
Purpose: MEITL is a very rare and highly aggressive peripheral T cell lymphoma with poor prognosis and for which there is no standard treatment. Treatment options for patients patients with relapsed/refractory disease are scarce and the choice of an appropriate rescue still represents an unmet need. Methods: Here, we report the case of a 65-year-old woman affected by MEITL, progressing after initial treatment with an anthracycline-based chemotherapy and surgery, who received single-agent PEG-asparaginase salvage therapy at our institution. Results: PEG-asparaginase single-agent rescue proved to be rapidly effective in controlling the disease and its associated paraneoplastic features. Nevertheless, toxicity was high and the patient died due to a treatment-related complication. Conclusion: The case we described brings new evidences on the effectiveness of PEG-asparaginase therapy in MEITL patients. Whether PEG-asparaginase should be included in the treatment course of MEITL patients could be the subject of future studies.
2022
- An 81-Year-Old Man with a 6-Year History of Chronic Lymphocytic Leukemia Presenting with Disease Flare Following Ibrutinib Discontinuation
[Articolo su rivista]
Pozzi, S.; Potenza, L.; Giusti, D.; Colaci, E.; Pioli, V.; Leonardi, G.; Maccaferri, M.; Luppi, M.; Marasca, R.
abstract
Patient: Male, 81-year-old Final Diagnosis: Chronic lymphocytic leukemia Symptoms: Fever Medication: — Clinical Procedure: — Specialty: Hematology Objective: Background: Case Report: Conclusions: Unusual clinical course Chronic lymphocytic leukemia (CLL) is a mature B-cell neoplasm and the most common leukemia in adults in Western countries. Novel agents, including BTK inhibitors and the BCL2 inhibitor venetoclax, have dramati-cally changed the treatment landscape. Moreover, a disease flare, characterized by sudden worsening of clinical symptoms, radiographic findings of rapidly worsening splenomegaly or lymphadenopathy, and laboratory changes (increased absolute lymphocyte count or lactate dehydrogenase), is a phenomenon described in up to 25% of patients with CLL after ibrutinib discontinuation. We describe a patient with CLL with disease flare after ibrutinib discontinuation due to disease progression and describe the subsequent management of vene-toclax initial treatment in the course of the disease flare. We describe the case of an 81-year-old man with a 6-year history of CLL who was treated with multiple lines of therapy and developed worsening of disease-related signs and symptoms with fever, marked increase of lym-phocyte count, acute worsening of renal function, and increase in lymph nodes and spleen size following ces-sation of targeted therapy with ibrutinib at the time of disease progression. There was subsequent overlap-ping of ibrutinib during the venetoclax dose escalation period to prevent disease flare recurrence. Our report highlights the problem of disease flare after ibrutinib discontinuation in order to avoid associated patient morbidity, underscoring the importance of awareness of this phenomenon and focusing on the addition of venetoclax at time of progression in ibrutinib-treated patients, as a temporary overlap strategy, to prevent disease flare.
2022
- Obinutuzumab does not improve complete methabolic response but does not compromise mobilization or engraftment of autologous peripheral blood stem cells in diffuse large B cell lymphoma: Results from a fondazione italiana linfomi prospective phase II study (the GIOTTO study)
[Articolo su rivista]
Rigacci, L.; Battistini, R.; Kovalchuk, S.; Zoli, V.; Puccini, B.; Evangelista, A.; Arcaini, L.; Flenghi, L.; Visco, C.; Mian, M.; Di Rocco, A.; Peracchio, C.; Gotti, M.; Tisi, M. C.; Palombi, F.; Pozzi, S.; Gioia, D.; Viero, P.; Martelli, M.
abstract
Salvage immunochemotherapy and transplant consolidation is the standard treatment for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We tested a combination of Obinutuzumab and DHAP for treating R/R DLBCL. The primary end point was the rate of complete metabolic response (CMR). Secondary end points were stem cell mobilization, stem cell engraftment, overall survival, and feasibility. In this prospective, phase-2, single-arm trial (EudraCT 2014-004014-17) patients received the standard three doses of Obinutuzumab for the first cycle, and then one dose. Patients with CMR were consolidated with an autologous stem cell transplantation (ASCT). An interim analysis was provided after the first 29 patients to confirm the initial null hypothesis that at least 10/29 patients would achieve CMR. Among the 29 patients evaluated for the first stage only six patients (6/29, 21%) achieved CMR, thus, study enrollment was stopped. Nine patients exhibited extra-hematologic toxicities ≥ grade 3. Among the 19 patients that started stem cell mobilization, one failed (5%) and 18 achieved mobilization (95%). Of these 18 patients, nine were reinfused. Mobilization was observed in 16 patients (89%) after one or two apheresis rounds. The mean number of CD34 + cells mobilized was 5.8 × 106/Kg (median: 5.5, IQR: 5–6.75). The mean number of reinfused CD34 + cells in the nine patients was 4.1 × 106/Kg (median: 4.1, IQR: 3.5–5). Obinutuzumab combined with DHAP did not compromise stem cell mobilization or engraftment after ASCT in patients with DLBCL. However, Obinutuzumab + DHAP provided a lower CMR rate than expected.
2022
- Treatment with Idelalisib in Patients with Relapsed or Refractory Follicular Lymphoma: The Observational Italian Multicenter FolIdela Study
[Articolo su rivista]
Casadei, B.; Argnani, L.; Broccoli, A.; Patti, C.; Stefani, P. M.; Cuneo, A.; Casaluci, G. M.; Visco, C.; Gini, G.; Pane, F.; D'Alo, F.; Luzi, D.; Cantonetti, M.; Pozzi, S.; Musuraca, G.; Rosignoli, C.; Arcari, A.; Kovalchuk, S.; Tani, M.; Tisi, M. C.; Petrini, M.; Stefoni, V.; Zinzani, P. L.
abstract
Follicular lymphoma (FL) is an indolent hematological disease, often responsive to the first line of treatment, but characterized by repeated relapses. The therapeutic algorithm for relapsed/refractory FL patients comprises phosphatidylinositol 3-kinase inhibitors. Idelalisib showed anticancer activity, while inducing a significant rate of toxicities. Since the evidence in the literature on its use in normal clinical practice is scarce, a retrospective multicenter study was conducted to evaluate effectiveness and tolerability in a real-life context. Seventy-two patients with a median age at diagnosis of 57.2 years—mostly with an advanced stage (88.9%) and relapsed to the most recent therapy (79.1%)—were enrolled. The median number of prior therapies was three (20.8% refractory to the last therapy before idelalisib). With a median number of 4 months of treatment, the overall response rate was 41.7% (20.8% complete responses). Median disease-free survival and overall survival were achieved at 8.4 months and at 4 years, respectively. Forty-four percent of patients experienced at least one drug-related toxicity: 6.9% hematological ones and 43% non-hematological. The study confirmed that idelalisib has anticancer effectiveness and an acceptable safety profile in relapsed/refractory FL with unfavorable prognostic characteristics, even in the context of normal clinical practice.
2021
- Cell of origin (COO), BCL2/MYC status and IPI define a group of patients with Diffuse Large B-cell Lymphoma (DLBCL) with poor prognosis in a real-world clinical setting
[Articolo su rivista]
Bettelli, S.; Marcheselli, R.; Pozzi, S.; Marcheselli, L.; Papotti, R.; Forti, E.; Cox, M. C. C.; Di Napoli, A.; Tadmor, T.; Mansueto, G. R.; Musto, P.; Flenghi, L.; Quintini, M.; Galimberti, S.; Lalinga, V.; Donati, V.; Maiorana, A.; Polliack, A.; Sacchi, S.
abstract
2021
- Cytokine release syndrome associated with T-cell-based therapies for hematological malignancies: Pathophysiology, clinical presentation, and treatment
[Articolo su rivista]
Cosenza, M.; Sacchi, S.; Pozzi, S.
abstract
Cytokines are a broad group of small regulatory proteins with many biological functions involved in regulating the hematopoietic and immune systems. However, in pathological conditions, hyperactivation of the cytokine network constitutes the fundamental event in cytokine release syndrome (CRS). During the last few decades, the development of therapeutic monoclonal antibodies and T-cell therapies has rapidly evolved, and CRS can be a serious adverse event related to these treatments. CRS is a set of toxic adverse events that can be observed during infection or following the administration of antibodies for therapeutic purposes and, more recently, during T-cell-engaging therapies. CRS is triggered by on-target effects induced by binding of chimeric antigen receptor (CAR) T cells or bispecific antibody to its antigen and by subsequent activation of bystander immune and non-immune cells. CRS is associated with high circulating concentrations of several pro-inflammatory cytokines, including interleukins, interferons, tumor necrosis factors, colony-stimulating factors, and transforming growth factors. Recently, considerable developments have been achieved with regard to preventing and controlling CRS, but it remains an unmet clinical need. This review comprehensively summarizes the pathophysiology, clinical presentation, and treatment of CRS caused by T-cell-engaging therapies utilized in the treatment of hematological malignancies.
2021
- Management of adverse events and supportive therapy in relapsed/refractory multiple myeloma
[Articolo su rivista]
Pozzi, S.; Bari, A.; Pecherstorfer, M.; Vallet, S.
abstract
Relapsed/refractory (RR) multiple myeloma (MM) patients are a fragile population be-cause of prolonged drug exposure and advanced age. Preserving a good quality of life is of high priority for these patients and the treatment of disease-and treatment-related complications plays a key role in their management. By preventing and limiting MM-induced complications, supportive care improves patients’ outcome. Erythropoietin-stimulating agents and bisphosphonates are well-established supportive strategies, yet novel agents are under investigation, such as anabolic bone agents and activin receptor-like kinase (ALK) inhibitors. The recent dramatic changes in the treatment landscape of MM pose an additional challenge for the routine care of RRMM patients. Multi-drug combinations in first and later lines increase the risk for long-lasting toxicities, including adverse cardiovascular and neurological events. Moreover, recently approved first-in-class drugs have unique side-effect profiles, such as ocular toxicity of belantamab mafodotin or gastrointestinal toxicity of selinexor. This review discusses current standards in supportive treatment of RRMM patients, including recommendations in light of the recent SARS-CoV-19 pandemic, and critically looks at the incidence and management of side effects of standard as well as next generation anti-MM agents.
2021
- Pazopanib-related secondary polycythemia in metastatic myxofibrosarcoma: A case report and review of the literature
[Articolo su rivista]
Fanelli, M.; Caputo, F.; Cerma, K.; Gelsomino, F.; Bari, A.; Dominici, M.; Pozzi, S.
abstract
Introduction: Pazopanib, a tyrosine kinase inhibitor (TKI), is a standard treatment for various tumours, including metastatic non-adipocytic soft-tissue sarcomas. In literature, erythrocytosis has been described as a TKI-related condition. Case report: A 59-year-old man underwent surgical removal of a sub-scapular mass consistent with myxofibrosarcoma. After distant relapse, he first started chemotherapy, and then Pazopanib. He was found to have increased levels of hemoglobin (Hb) and hematocrit (Hct). He was asymphtomatic, with no history of pulmonary disease nor smoking habit. Erythropoietin (EPO) level was higher than normal. A polycythemia vera was ruled out. Management & outcome: The patient started a prophylactic therapy with lysine acetylsalicylate, and we observed a reduction of Hb, but not Hct. Due to disease progression, we interrupted Pazopanib. After a week from drug discontinuation, Hb levels got back to the normal range, Hct was lowering. We decided not to perform phlebotomy, considering the declining trend in Hb and Hct values and the absence of symptoms. Discussion: We postulated a Pazopanib-related secondary erythrocytosis, since Hb and Hct levels increased from baseline during treatment, then normalized when Pazopanib was discontinued. We used the Naranjo Nomogram to assess the correlation between the adverse effect and Pazopanib, the correlation was “Probable”, a score of 5. To the best of our knowledge, this is the first case report of Pazopanib-related secondary polycythemia in a patient with sarcoma. It is important to pay attention to blood count and to any symptoms potentially related to erythrocytosis in patients treated with TKIs.
2020
- Citarinostat and Momelotinib co-target HDAC6 and JAK2/STAT3 in lymphoid malignant cell lines: a potential new therapeutic combination
[Articolo su rivista]
Cosenza, M.; Civallero, M.; Marcheselli, L.; Sacchi, S.; Pozzi, S.
abstract
Histone deacetylase (HDAC) inhibitors represent an encouraging class of antitumor drugs. HDAC inhibitors induce a series of molecular and biological responses and minimal toxicity to normal cells. Citarinostat (Acy-241) is a second generation, orally administered, HDAC6-selective inhibitor. Momelotinib (CYT387) is an orally administered inhibitor of Janus kinase/signal transducer of transcription-3 (JAK/STAT3) signaling. Momelotinib showed efficacy in patients with myelofibrosis. We hypothesized that both HDAC and JAK/STAT pathways were important in lymphoproliferative disorders, and that inhibiting JAK/STAT3 and HDAC simultaneously might enhance the efficacy of momelotinib and citarinostat without increasing toxicity. Accordingly, we tested the citarinostat + momelotinib combination in lymphoid cell lines. Citarinostat + momelotinib showed strong cytotoxicity; it significantly reduced mitochondrial membrane potential, down-regulated Bcl-2 and Bcl-xL, and activated caspases 9 and 3. Caspase-8 was upregulated in only two lymphoid cell lines, which indicated activation of the extrinsic apoptotic pathway. We identified a lymphoid cell line that was only slightly sensitive to the combination treatment. We knocked down thioredoxin expression by transfecting with small interfering RNA that targeted thioredoxin. This knockdown increased cell sensitivity to the combination-induced cell death. The combination treatment reduced Bcl-2 expression, activated caspase 3, and significantly inhibited cell viability and clonogenic survival.
2020
- Improving the international prognostic index score using peripheral blood counts: Results of a large multicenter study involving 520 patients with diffuse large B cell lymphoma
[Articolo su rivista]
Marcheselli, Raffaella; Bari, Alessia; Tadmor, Tamar; Marcheselli, Luigi; Cox, Maria Christina; Papotti, Robel; Ferrari, Angela; Baldini, Luca; Gobbi, Paolo; Levy, Ilana; Pugliese, Giuseppe; Federico, Massimo; Polliack, Aaron; Pozzi, Samantha; Sacchi, Stefano
abstract
The main purpose of this study was to assess whether it is possible to improve the prognostic impact of international prognostic index (IPI) score by combining it with peripheral blood counts. Thus, we evaluated the prognostic power of lymphocyte, neutrophil, and monocyte counts in 520 patients with diffuse large B cell lymphoma treated with R-CHOP, confirming that these parameters have a strong impact on overall survival (OS). Using revised IPI (R-IPI), 44% of patients were categorized as poor-risk and showed an OS at 5 years of 46%. As OS at 5 years of the 520 patients is 67%, it is clearly evident that R-IPI tends to overestimate the proportion of patients with poor prognosis. Accordingly, in an attempt to improve the discriminating power of R-IPI, we evaluated and compared three different scores by combining the neutrophil lymphocyte ratio (NLR) and absolute monocyte count (AMC) with the following values: (a) IPI score 3-5, (b) age > 60 years and performance status, (c) age >= 65 years and LDH > ULN. The three indexes studied, had a similar 5 years OS for the high-risk group (46%-52%), but the proportion of patients classified as poor-risk were 37%, 20%, and 32%, respectively, which are lower than 44% identified with R-IPI. Thus, while R-IPI overestimates the number of high-risk patients, after applying our models, it is possible to recognize patients who are truly at high-risk. Of the three scores, the most accurate appears to be that based on NLR, AMC, LDH > ULN and age >= 65 years, which identifies 32% of high-risk patients, correlating well with what is seen in clinical practice.
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.
2019
- From Osteoclast Differentiation to Osteonecrosis
of the Jaw: Molecular and Clinical Insights
[Articolo su rivista]
Anesi, Alexandre; Generali, Luigi; Sandoni, Laura; Pozzi, Samantha; Grande, Alexis
abstract
Bone physiology relies on the delicate balance between resorption and formation of its tissue. Bone resorption depends on a process called osteoclastogenesis in which bone-resorbing cells, i.e., osteoclasts, are produced by the differentiation of more undifferentiated progenitors and precursors. This process is governed by two main factors, monocyte colony-stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL). While the former exerts a proliferating effect on progenitors/precursors, the latter triggers a differentiation effect on more mature cells of the same lineage. Bone homeostasis requires a perfect space–time coordination of the involved signals. When osteoclastogenesis is poorly balanced with the differentiation of the bone forming counterparts, i.e., osteoblasts, physiological bone remodelling can turn into a pathological state, causing the systematic disruption of bone tissue which results in osteopenia or osteolysis. Examples of these conditions are represented by osteoporosis, Paget’s disease, bone metastasis, and multiple myeloma. Therefore, drugs targeting osteoclastogenesis, such as bisphosphonates and an anti-RANKL monoclonal antibody, have been developed and are currently used in the treatment of such diseases. Despite their demonstrated therapeutic efficacy, these agents are unfortunately not devoid of side effects. In this regard, a condition called osteonecrosis of the jaw (ONJ) has been recently correlated with anti-resorptive therapy. In this review we will address the involvement of osteoclasts and osteoclast-related factors in the pathogenesis of ONJ. It is to be hoped that a better understanding of the biological mechanisms underlying bone remodelling will help in the design a medical therapeutic approach for ONJ as an alternative to surgical procedures.
2019
- The prognostic role of end of treatment FDG-PET-CT in patients with diffuse large B cell lymphoma can be improved by considering it with absolute monocyte count at diagnosis
[Articolo su rivista]
Marcheselli, R.; Franceschetto, A.; Sacchi, S.; Bari, A.; Levy, I.; Pizzichini, P.; Prosperi, D.; D'Apollo, R.; Massi, L.; Casolo, A.; Pozzi, S.; Marcheselli, L.; Tadmor, T.; Prandini, N.; Cox, M. C.
abstract
It is well established that some patients with diffuse large B-cell lymphoma (DLBCL) and the negative end of treatment PET-CT (EOT-PET-CT) will relapse, while a proportion with positive uptake can still obtain long-term EFS. We reviewed data of 200 consecutive, previously untreated patients with DLBCL recorded in Italy and Israel between 2007 and 2015. We found that patients with negative EOT-PET-CT with AMC > 630/mmc have a 3-years EFS of 72%, compared to those with AMC ≤ 630/mmc that have an EFS of 84%. Furthermore, considering patients with positive EOT-PET-CT, those with AMC > 630/mmc have a 3-years EFS of 8%, while those with AMC ≤ 630/mmc have an EFS of 38%. Thus, it appears that combining the gold standard for response evaluation EOT-PET-CT with a simple and inexpensive parameter like AMC at diagnosis, further improves prognostication in DLBCL. Applying this simple method can be useful for all doctors working in lymphoma clinical practice.
2018
- Absolute monocyte count at diagnosis could improve the prognostic role of early FDG-PET in classical Hodgkin lymphoma patients
[Articolo su rivista]
Bari, Alessia; Marcheselli, Luigi; Marcheselli, Raffaella; Pozzi, Samantha; Cox, Maria Christina; Baldessari, Cinzia; Ferri, Paola; Gobbi, Paolo; Baldini, Luca; Tadmor, Tamar; Musto, Pellegrino; Federico, Massimo; Sacchi, Stefano
abstract
Recently published international guidelines suggested that
positron emission tomography (PET)-computed tomography
(CT) could be utilized for response assessment using the
Deauville criteria in fluorodeoxyglucose (FDG)-avid lym-
phomas (Meignan et al, 2012). Interim PET (I-PET) scan-
ning seems highly predictive of treatment failure in Hodgkin
Lymphoma (HL) patients.
We recently showed that the absolute monocyte count
(AMC) has prognostic value in patients with classical HL
(cHL) (Tadmor et al, 2015). Here, we show that the com-
bined use of I-PET and AMC at diagnosis enables a more
accurate projection of patient outcome in cHL.
The present study is an ancillary branch of the analysis
reported by Tadmor et al, (2015). Patients with histopatho-
logical diagnosis of cHL previously enrolled in the Gruppo
Italiano Studio Linfomi trials were eligible if data on all clini-
cal and laboratory features and treatments, reported I-PET
results, treatment response and follow-up were available.
Response was defined according to the revised International
Working Group guidelines (Cheson et al, 1999). An absolute
lymphocyte count <06 9 10
9
/l and AMC > 075 9 10
9
/l
were used as cut-off points. I-PET was performed after 2
cycles of treatment. A positive or negative I-PET was defined
by the local investigators’ interpretation of the nuclear physi-
cian’s scan report, which was based on a visual qualitative
assessment.
The principal end-point of the study was the impact of
I-PET and AMC on progression-free survival (PFS); their
impact on overall survival (OS) was the secondary end-point.
Survival functions were estimated using the Kaplan–Meier
method. Statistical comparisons between curves were per-
formed with log-rank test, and the effect of the covariate was
reported as hazard ratios (HR), from Cox regression.
All patients had a diagnosis of cHL; 76% of cases had the
nodular sclerosis (NS) subtype. Seventy-six patients (64%)
were treated with classical ABVD (doxorubicin, bleomycin,
vincristine, dacarbazine), and 23 (19%) and 19 (16%) with
the more intensive BEACOPP (bleomycin, etoposide, doxoru-
bicin, cyclophosphamide, vincristine, procarbazine, pred-
nisone) and COPPEBVCAD (cyclophosphamide, lomustine,
vindesine, melphalan, prednisone, epidoxirubicin, vincristine,
procarbazine, vinblastine, bleomycin) regimens (Federico
et al, 2009), respectively. Of the entire cohort, 104 patients
(88%) achieved complete remission. Twenty-six patients had
a positive I-PET (22%) and 28 (24%) had AMC > 075 9
10
9
/l at diagnosis.
The median follow-up of the entire cohort was 88 months
(range 5–142 months). The estimated 5-year OS was 91%
(95% confidence interval [CI]: 84–95%). The 5-year PFS was
80% (95% CI: 71–86%). Patients with positive I-PET showed
a worse PFS compared to patients with negative I-PET (51%
and 88%, respectively; HR 587 [95% CI: 256–135]).
Patients with AMC > 075 9 10
9
/l at diagnosis had a worse
PFS compared to patients with AMC ≤ 075 9 10
9
/l (58%
and 87%, respectively; HR 373 [95% CI: 161–864]). Multi-
ple Cox proportional hazards (PH) regression, adjusted for
International Prognostic Score 3–7, confirmed the prognostic
role of I-PET (HR 532 [95% CI: 230–123]; P < 0001) and
AMC >075 9 10
9
/l (HR 319 [95% CI: 132–768];
P = 0010). Figure 1A, B shows the PFS for I-PET and AMC,
and Table I shows the uni- and multivariate Cox PH regres-
sion for PFS. The prognostic role of I-PET and AMC on OS
was also confirmed.
Given the strong predictive value of both I-PET and
AMC, we stratified patients by positive or negative I-PET
and AMC > 075 9 10
9
/l or ≤075 9 10
9
/l into 3 groups
with different levels of risk. The low risk level (negative I-
PET and AMC ≤ 075 9 10
9
/l; n = 73, 62%) had a 5-year
PFS of 90% (95% CI: 80–96%)
2018
- Cancer Treatment Induced Bone Loss (CTIBL) in breast cancer women: a multidisciplinary approach at the Modena Cancer Center screening over 600 patients.
[Abstract in Rivista]
Pozzi, S.; Belletti, L.; Cortesi, L.; Moscetti, L.; Omarini, C.; Piacentini, F.; Toss, A.; Caputo, Francesco; Greco, S.; Isca, C.; Napolitano, M.; Tarantino, V.; Malinverni, C.; Checchi, Eleonora; Mascia, Maria Teresa; Cascinu, S
abstract
Background: CTIBL in breast cancer (BC) women is well
know. It is commonly, but not exclusively, related to aromatase
inhibitors. The “Nota 79” by AIFA contemplates
the primary prevention of fracture risk in BC women in
adjuvant hormonal treatment with bisphosphonates or denosumab,
at osteoporosis dosage. At the Modena Cancer
Center we started a collaboration with oncologists hematologists
and bone specialists in order to offer the
best tailored treatment in high risk fracture patients.
Patients and Methods: patients newly diagnosed with BC
in hormonal treatment fill-out a form, in order to evaluate
the risk factors for osteoporosis, and based on the results
and the bone density they are referred to the osteoncology
unit along with serological and urinary markers of bone
turn-over.
Results: in over 18 months of activity, more than 600
patients have been screened by self-completed questionnaire.
From the analysis of the first 400 questionnaires
emerged that 61% had one or more risk factors, 20%
received supplement of vitamin D, and approximately 5%
were on bisphosphonates. At baseline, the measurement of
the height, the evaluation of the spine at the chest X ray or
by morphometry highlighted asymptomatic vertebral fractures
in few patients. Several patients presented with secondary
hyperparathyroidism, that required correction
before to start any treatment with antiresorptive agents.
Cases with hypercalciuria were also corrected along with
antiresorptive therapy. Few cases demonstrated high bone
turn-over with CTX levels above the limits. The treatment
has been individualized based on the medical history and
comorbidities, oncological treatment and the bone turnover.
All the patients have been informed of the possible
risk of osteonecrosis of the jaw; dental medical history was
collected for each patient, but orthopanthomography and
odontoiatric evaluation was prescribed in selected patients.
Vitamin D level was corrected before any therapy and
improvement of the dietary habits and physical activity
was highly recommended. Data analysis is still ongoing.
Conclusions: all the patients receiving AIs require the prevention
of CTIBL, but the limited resources pushed us to
select, at this time, the patients with special needs to be
evaluated in multidisciplinary group. The complexity of the
bone health requires attentive evaluation by bone specialists
in selected cases before to start antiresorptive agents.
Supplemental data will be presented at the meeting.
2018
- Cell-penetrating CaCO3nanocrystals for improved transport of NVP-BEZ235 across membrane barrier in T-cell lymphoma
[Articolo su rivista]
Vergaro, Viviana; Civallero, Monica; Citti, Cinzia; Cosenza, Maria; Baldassarre, Francesca; Cannazza, Giuseppe; Pozzi, Samantha; Sacchi, Stefano; Fanizzi, Francesco Paolo; Ciccarella, Giuseppe
abstract
Owing to their nano-sized porous structure, CaCO3nanocrystals (CaCO3NCs) hold the promise to be utilized as desired materials for encapsulating molecules which demonstrate wide promise in drug delivery. We evaluate the possibility to encapsulate and release NVP-BEZ235, a novel and potent dual PI3K/mTOR inhibitor that is currently in phase I/II clinical trials for advanced solid tumors, from the CaCO3NCs. Its chemical nature shows some intrinsic limitations which induce to administer high doses leading to toxicity; to overcome these problems, here we proposed a strategy to enhance its intracellular penetration and its biological activity. Pristine CaCO3NCs biocompatibility, cell interactions and internalization in in vitro experiments on T-cell lymphoma line, were studied. Confocal microscopy was used to monitor NCs-cell interactions and cellular uptake. We have further investigated the interaction nature and release mechanism of drug loaded/released within/from the NCs using an alternative approach based on liquid chromatography coupled to mass spectrometry. Our approach provides a good loading efficiency, therefore this drug delivery system was validated for biological activity in T-cell lymphoma: the anti-proliferative test and western blot results are very interesting because the proposed nano-formulation has an efficiency higher than free drug at the same nominal concentration.
2018
- The therapeutic strategy of HDAC6 inhibitors in lymphoproliferative disease
[Articolo su rivista]
Cosenza, M.; Pozzi, S.
abstract
Histone deacetylases (HDACs) are master regulators of chromatin remodeling, acting as epigenetic regulators of gene expression. In the last decade, inhibition of HDACs has become a target for specific epigenetic modifications related to cancer development. Overexpression of HDAC has been observed in several hematologic malignancies. Therefore, the observation that HDACs might play a role in various hematologic malignancies has brought to the development of HDAC inhibitors as potential antitumor agents. Recently, the class IIb, HDAC6, has emerged as one potential selective HDACi. This isoenzyme represents an important pharmacological target for selective inhibition. Its selectivity may reduce the toxicity related to the off-target effects of pan-HDAC inhibitors. HDAC6 has also been studied in cancer especially for its ability to coordinate a variety of cellular processes that are important for cancer pathogenesis. HDAC6 has been reported to be overexpressed in lymphoid cells and its inhibition has demonstrated activity in preclinical and clinical study of lymphoproliferative disease. Various studies of HDAC6 inhibitors alone and in combination with other agents provide strong scientific rationale for the evaluation of these new agents in the clinical setting of hematological malignancies. In this review, we describe the HDACs, their inhibitors, and the recent advances of HDAC6 inhibitors, their mechanisms of action and role in lymphoproliferative disorders.
2017
- A Multicenter Phase II Study of Twice-Weekly Bortezomib plus Rituximab in Patients with Relapsed Follicular Lymphoma: Long-Term Follow-Up
[Articolo su rivista]
Bari, Alessia; Marcheselli, Raffaella; Marcheselli, Luigi; Alvarez, Isabel; Pozzi, Samantha; Ferri, Paola; Lazzaro, Antonio; Fragasso, Alberto; Neri, Santo; Baldini, Luca; Carella, Angelo Michele; Angrilli, Francesco; Guariglia, Roberto; Buda, Gabriele; Stelitano, Caterina; Sacchi, Stefano
abstract
Single-agent bortezomib (B) has shown activity in heavily pretreated patients with relapsed/refractory indolent lymphoma. On the basis of these findings, we performed a phase II study of B combined with rituximab (R) in patients with relapsed follicular lymphoma (FL). Forty-five patients with fairly good prognostic profiles were enrolled from 2007 to 2011 and received a total of 6 cycles of the B+R combination. The endpoints were the overall response rate (ORR), progression-free survival (PFS), duration of remission (DoR), overall survival (OS), and toxicity evaluation. When considering all the enrolled patients the ORR was 64%. At 5 years, the estimated PFS, DoR, and OS were 34, 49, and 70%, respectively. After excluding the 7 R-naïve patients, the ORR was 58%, with a PFS of 19 months. The most common grade >2 toxicities were thrombocytopenia (18%), peripheral neuropathy (13%), and neutropenia (2%). Our study shows the feasibility, long-term efficacy, and excellent tolerability of the B+R combination. We are aware that our study has specific limitations, such as the small sample size consisting of patients with a relatively good prognostic profile. However, because FL patients will be treated with subsequent chemotherapy regimens, a well-tolerated and effective chemotherapy-free therapy could be considered an additional tool for long-term disease control.
2017
- A concise review of lenalidomide therapy for follicular lymphoma
[Articolo su rivista]
Bari, Alessia; Marcheselli, Raffaella; Barbolini, Monica; Ferri, Paola; Sacchi, Stefano; Pozzi, Samantha
abstract
Introduction: Lenalidomide, first introduced for the treatment of multiple myeloma in 2008, has been used in the treatment of various subtypes of non-Hodgkin lymphoma (NHL). Considering its mechanism of action, it has been associated with rituximab, showing strong activity in follicular lymphomas (FL). As the chemo-free treatments are a topic of great relevance we decided to prepare a concise review mainly directed to clinicians involved in the management of NHL patients. Areas covered: This article reviews the clinical trials published since 2008 utilizing lenalidomide alone or in combination for treating relapsed/refractory or treatment naïve patients with FL. Expert opinion: With current rituximab plus chemotherapy treatments, almost all patients will relapse from the disease over time. The introduction of lenalidomide in the management of FL showed good efficacy in particular in combination with rituximab (R2). The high rates of durable responses obtained with the R2 combination were similar to those previously observed with standard chemotherapy plus rituximab. If the results of the ongoing multicenter pivotal phase 3 trial (NCT01476787) are favorable for R2 combination, we may move towards a chemotherapy-free approach in the management of FL, which would finally turn a dream into reality.
2017
- Bendamustine, Low-dose dexamethasone, and lenalidomide (BdL) for the treatment of patients with relapsed/refractory multiple myeloma confirms very promising results in a phase I/II study.
[Articolo su rivista]
Pozzi, Samantha; Gentile, M; Sacchi, Stefano; Marcheselli, Raffaella; Corso, A; Cocito, F; Musto, P; Guarini, A; Minoia, C; Vincelli, I; Ria, R; Rivolti, E; Mele, G; Bari, Alessia; Mazzone, C; Badiali, S; Marcheselli, Luigi; Palumbo, A; Morabito, F.
abstract
Lenalidomide and dexamethasone are an effective treatment for naïve and relapsed multiple myeloma (MM) patients. Bendamustine is a good option for B-cell malignancies showing only partial cross resistance with alkylating agents used in MM patients. Based on these considerations, we proposed a phase I/II study testing escalating doses of bendamustine and lenalidomide and fixed low doses of dexamethasone (BdL). Fifteen patients were enrolled in phase I study. Maximum tolerated dose was established at dose "level 0": bendamustine 40 mg/m2 days 1,2; lenalidomide 10 mg days 1-21; d 40 mg days 1,8,15,22 every 28-day cycle, for six cycles. We enrolled 23 patients in the phase II study. BdL combination showed mainly hematological toxicities, fever and infections. Overall response rate was 47%. After median follow up of 22 months, median PFS was 10 months. Two-years OS rate was 65%. BdL combination confirmed to be a promising treatment for patients with relapsed/refractory MM.
2017
- Neutrophil-lymphocyte ratio at diagnosis is an independent prognostic factor in patients with nodular sclerosis Hodgkin lymphoma: Results of a large multicenter study involving 990 patients
[Articolo su rivista]
Marcheselli, Raffaella; Bari, Alessia; Tadmor, Tamar; Marcheselli, Luigi; Cox, Maria Christina; Pozzi, Samantha; Ferrari, Angela; Baldini, Luca; Gobbi, Paolo; Aviv, Ariel; Pugliese, Giuseppe; Federico, Massimo; Polliack, Aaron; Sacchi, Stefano
abstract
Several studies have demonstrated the prognostic value of neutrophil-lymphocyte ratio (NLR) in patients with solid tumors and non-Hodgkin lymphoma. In contrast, there is only sparse data on its prognostic role in patients with classical Hodgkin lymphoma (cHL). The aim of our study was to establish whether NLR could serve as an independent prognostic factor in a cohort of 990 patients with nodular sclerosis (NS)-cHL. After analysis of the log hazard ratio (HR) as a function of NLR, we chose the value 6 as cutoff. Patients with NLR >6 had a worse progression-free survival and overall survival compared to those with NLR ≤6; 84% vs 75% and 92% vs 88%, at 5 years, with an HR of 1.65 and 1.82, respectively. Multivariate analysis showed that the risk remained high with HR 1.44 and HR 1.54 in progression-free survival and overall survival, respectively. In summary, our study shows that NLR is a robust and independent prognostic parameter in NS-cHL, both in early and advanced disease. It is inexpensive and simple to apply. Thus, we conclude that NLR, possibly in combination with the international prognostic score and absolute monocyte count, is a useful guide for physicians treating NS-cHL patients.
2017
- Ricolinostat, a selective HDAC6 inhibitor, shows anti-lymphoma cell activity alone and in combination with bendamustine
[Articolo su rivista]
Cosenza, Maria; Civallero, Monica; Marcheselli, Luigi; Sacchi, Stefano; Pozzi, Samantha
abstract
Histone deacetylase inhibitors (HDACis) have emerged as a new class of anticancer agents, targeting the biological process including cell cycle and apoptosis. We investigated and explained the anticancer effects of an HDAC6 inhibitor, ricolinostat alone and in combination with bendamustine in lymphoma cell lines. Cell viability was measured by MTT assay. Apoptosis, reactive oxygen species (ROS) generation, Bcl-2 protein expression, cell cycle progression and tubuline expression were determined by flow cytometry. The effects of ricolinostat alone and in combination on the caspases, PI3K/Akt, Bcl-2 pathways, ER stress and UPR were assessed by immunoblotting. Ricolinostat shows anti lymphoma activity when used as single agent and its capability to induce apoptosis is synergistically potentiated by the bendamustine in lymphoma cell lines. Drug combination reduced the proportion of cells in the G0/G1and S phases and caused an increase of âsub-G0/G1â peak. The synergistic effect accompanied with the increased ROS, activation of caspase-8, -9, and -3, the cleavage of PARP and modulated by Bcl-2 proteins family. In addition, the exposure of ricolinostat induced the acetylation level of α-tubulin, the extend of which was not further modified by bendamustine. Finally, the apoptosis effect of ricolinostat/bendamustine may be mediated by a corresponding effect on microtubule stabilization. Our data suggest that ricolinostat in combination with bendamustine may be a novel combination with potential for use as an antitumor agent in lymphoma.
2017
- Ruxolitinib combined with vorinostat suppresses tumor growth and alters metabolic phenotype in hematological diseases
[Articolo su rivista]
Civallero, Monica; Cosenza, Maria; Pozzi, Samantha; Sacchi, Stefano
abstract
JAK-2 dysregulation plays an important role as an oncogenic driver, and is thus a promising therapeutic target in hematological malignancies. Ruxolitinib is a pyrrolo[2.3-d]pyrimidine derivative with inhibitory activity against JAK1 and JAK2, moderate activity against TYK2, and minor activity against JAK3. Vorinostat is an HDAC inhibitor that reduces JAK-2 expression, thus affecting JAK-2 mRNA expression and increasing JAK-2 proteasomal deterioration. Here we hypothesized that the combination of ruxolitinib and vorinostat could have synergistic effects against hematological disease. We tested combinations of low doses of ruxolitinib and vorinostat in 12 cell lines, and observed highly synergistic cytotoxic action in six cell lines, which was maintained for up to 120 h in the presence of stromal cells. The sensitivity of the six cell lines may be explained by the broad effects of the drug combination, which can affect various targets. Treatment with the combination of ruxolitinib and vorinostat appeared to induce a possible reversal of the Warburg effect, with associated ROS production, apoptotic events, and growth inhibition. Decreased glucose metabolism may have markedly sensitized the six more susceptible cell lines to combined treatment. Therapeutic inhibition of the JAK/STAT pathway seems to offer substantial anti-tumor benefit, and combined therapy with ruxolitinib and vorinostat may represent a promising novel therapeutic modality for hematological neoplasms.
2016
- Safety and efficacy of lenalidomide in combination with rituximab in recurrent indolent non-follicular lymphoma: Final results of a phase II study conducted by the Fondazione Italiana Linfomi
[Articolo su rivista]
Sacchi, Stefano; Marcheselli, Raffaella; Bari, Alessia; Buda, Gabriele; Molinari, Anna Lia; Baldini, Luca; Vallisa, Daniele; Cesaretti, Marina; Musto, Pellegrino; Ronconi, Sonia; Specchia, Giorgina; Silvestris, Franco; Guardigni, Luciano; Ferrari, Angela; Chiapella, Annalisa; Carella, Angelo Michele; Santoro, Armando; Di Raimondo, Francesco; Marcheselli, Luigi; Pozzi, Samantha
abstract
Safety and efficacy of lenalidomide in combination
with rituximab in recurrent indolent non-follicular
lymphoma: final results of a phase II study
conducted by the Fondazione Italiana Linfomi
2016
- The histone deacetylase inhibitor romidepsin synergizes with lenalidomide and enhances tumor cell death in T-cell lymphoma cell lines
[Articolo su rivista]
Cosenza, Maria; Civallero, Monica; Fiorcari, Stefania; Pozzi, Samantha; Marcheselli, Luigi; Bari, Alessia; Ferri, Paola; Sacchi, Stefano
abstract
We investigated the cytotoxic interactions of romidepsin, a histone deacetylase inhibitor, and lenalidomide, an immunomodulatory agent, in a T-cell lymphoma preclinical model. Hut-78 and Karpas-299 cells were treated with romidepsin and lenalidomide alone and in combination. The interaction between romidepsin and lenalidomide was evaluated by the Chou–Talalay method, and cell viability and clonogenicity were also evaluated. Apoptosis, reactive oxygen species (ROS) levels, and cell cycle distribution were determined by flow cytometry. ER stress, caspase activation, and the AKT, MAPK/ERK, and STAT-3 pathways were analyzed by Western blot. Combination treatment with romidepsin and lenalidomide had a synergistic effect in Hut-78 cells and an additive effect in Karpas-299 cells at 24 hours and did not decrease the viability of normal peripheral blood mononuclear cells. This drug combination induced apoptosis, increased ROS production, and activated caspase-8, −9, −3 and PARP. Apoptosis was associated with increased hallmarks of ER stress and activation of UPR sensors and was mediated by dephosphorylation of the AKT, MAPK/ERK, and STAT3 pathways.The combination of romidepsin and lenalidomide shows promise as a possible treatment for T-cell lymphoma. This work provides a basis for further studies.
2015
- Absolute monocyte count and lymphocyte-monocyte ratio predict outcome in nodular sclerosis Hodgkin lymphoma: Evaluation based on data from 1450 patients
[Articolo su rivista]
Tadmor, Tamar; Bari, Alessia; Marcheselli, Luigi; Sacchi, Stefano; Aviv, Ariel; Baldini, Luca; Gobbi, Paolo G.; Pozzi, Samantha; Ferri, Paola; Cox, Maria Christina; Cascavilla, Nicola; Iannitto, Emilio; Federico, Massimo; Polliack, Aaron
abstract
Objective: To verify whether absolute monocyte count (AMC) and lymphocyte-monocyte ratio (LMR) at diagnosis are valid prognostic parameters in classical Hodgkin lymphoma (cHL).
Patients and Methods: Data were collected from 1450 patients with cHL treated in Israel and Italy from January 1, 1988, through December 31, 2007.
Results: The median age of the patients was 33 years (range, 17-72 years), and 70% (1017) of the patients had nodular sclerosis (NS); the median follow-up duration was 87 months. The best cutoff value for AMC was 750 cells/mm3, and the best ratio for LMR was 2.1. The adverse prognostic impact of an AMC of more than 750 cells/mm(3) was confirmed for the entire cohort, and its clinical significance was particularly evident in patients with NS histology. The progression-free survival (PFS) at 10 years for an AMC of more than 750 cells/mm(3) was 65% (56%-72%), and the PFS at 10 years for an AMC of 750 cells/mm(3) or less was 81% (76%-84%; P<.001). The overall survival (OS) at 10 years for an AMC of more than 750 cells/mm3 was 78% (70%-85%), and the OS at 10 years for an AMC of 750 cells/mm(3) or less was 88% (84%-90%; P=.01). In multivariate analysis, both AMC and LMR maintained prognostic significance for PFS (hazard ratio [HR], 1.54, P=.006, and HR, 1.50, P=.006) after adjusting for the international prognostic score, whereas the impact on OS was confirmed (HR, 1.56; P=.04) only in patients with NS and an AMC of more than 750 cells/mm(3).
Conclusion: This study confirms that AMC has prognostic value in cHL that is particularly significant in patients with NS subtype histology. This finding links the known impact of macrophages and monocytes in Hodgkin lymphoma with routine clinical practice.
2015
- Activity of BKM120 and BEZ235 against lymphoma cells
[Articolo su rivista]
Civallero, Monica; Cosenza, Maria; Pozzi, Samantha; Bari, Alessia; Ferri, Paola; Sacchi, Stefano
abstract
Non-Hodgkin lymphomas encompass a heterogeneous group of cancers, with 85-90% arising from B lymphocytes and the remainder deriving from T lymphocytes or NK lymphocytes. These tumors are molecularly and clinically heterogeneous, showing dramatically different responses and outcomes with standard therapies. Deregulated PI3K signaling is linked to oncogenesis and disease progression in hematologic malignancies and in a variety of solid tumors and apparently enhances resistance to antineoplastic therapy, resulting in a poor prognosis. Here, we have evaluated and compared the effects of the pan-PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitor BEZ235 onmantle, follicular, and T-cell lymphomas. Our results suggest that BKM120 and BEZ235 can effectively inhibit lymphoma cell proliferation by causing cell cycle arrest and can lead to cell death by inducing apoptosis and autophagy mediated by ROS accumulation. Despite great advances in lymphoma therapy after the introduction of monoclonal antibodies, many patients still die from disease progression. Therefore, novel treatment approaches are needed. BKM120 and BEZ235 alone and in combination are very effective against lymphoma cells in vitro. If further studies confirm their effectiveness in animal models, they may be promising candidates for development as new drugs.
2015
- Calcium-Carbonate Nanocapsules Improve the Efficacy of BEZ235 in Lymphoma a Cell Line: A Promising New Technology of Drug Delivery
[Abstract in Rivista]
Civallero, Monica; Vergaro, Viviana; Citti, Cinzia; Cosenza, Maria; Cannazza, Giuseppe; Parenti, Carlo; Bari, Alessia; Ciccarella, Giuseppe; Sacchi, Stefano; Pozzi, Samantha
abstract
Nanotechnology is a promising branch of the medical field, directed to improve diagnostic and therapeutics strategies, applying nanovectors as drug delivery systems. Efficient encapsulation of anticancer drugs in nanocolloids and microcapsules was recently developed by G. Ciccarella research group (1). Based on our collaboration with the Nantional Nanotechnology Laboratory of the University of Salento and our previous experience with target therapies, we encapsulated BEZ235, a phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR). BEZ235 efficiently blocks the dysfunctional activation of the PI3K/mTOR pathway in cellular and in vivo settings, thus inhibiting the growth and proliferation of various cancer cells, and phase I/II clinical trials were open in solid cancer. However the scarse solubility limited further development of this promising compound. In order to overcome the solubility issue BEZ235-loaded nanocapsules were generated by the stepwise adsorption of oppositely charged polyelectrolytes into biocompatible CaCO3 cores. First nanocapsules were tested for biocompatibility. The exposition of lymphoma cell lines to empty nanocapsules up to 48 hours, did not induce any cititoxicity, confirming their biocompatibility. Second, encapsulated BEZ235 was compared with free-drug to test the cytotoxicity in a T lymphoma cell line (HUT78) by MTT assay. The results suggested that nanoencapsulated-BEZ235 was extremely efficient compared with free-BEZ235, reaching IC50 just after 5 hours of exposure compared with an IC65% at 48 hours with the free drug. A validated LC-MS/MS method was developed in order to quantify intracellular concentration of BEZ235 over time. Intracellular concentration of BEZ235 in the lymphoma cell line was consistent with biological results since the internalization kinetic and efficiency was increased by the coating. In order to confirm that the encapsuled-BEZ235 was still effective on cell apoptosis, we tested free BEZ and encapsulated BEZ235 at a concentration of 1µM in T cell lymphoma cell lines. Encapsulated-BEZ235 induced apoptosis evidenced by the cleavage of caspase 8, 9 and 3 at an earlier time point compared with free BEZ235 and at significantly lower concentration.
We also confirmed that the encapsulated-BEZ235 maintained its effect on the target mTOR/AKT pathway: p-AKT was dephosphorylated at 5h while the free BEZ235 operates at least after 24 hours at concentrations 100 times higher, as previously demonstrated.
Keeping in mind a future clinical application of these polymeric particles/capsules, our data can be regarded as a promising new nanotechnology-based strategy to improve the efficacy and bioavailability of old and new drugs. Functional biological studies of BEZ235-encapsulated carrier and its mechanism of internalization are already under way, and animal in vivo studies to evaluated toxicity and distribution of the nanocapsuled compound are ongoing.
2015
- Risk of second primary malignancy in breast cancer survivors: A nested population-based case-control study
[Articolo su rivista]
Marcheselli, Raffaella; Marcheselli, Luigi; Cortesi, Laura; Bari, Alessia; Cirilli, Claudia; Pozzi, Samantha; Ferri, Paola; Napolitano, Martina; Federico, Massimo; Sacchi, Stefano
abstract
Purpose: Evolving therapies have improved the prognoses of patients with breast cancer; and currently, the number of long-term survivors is continuously increasing. However, these patients are at increased risk of developing a second cancer. Thus, late side effects are becoming an important issue. In this study, we aimed to investigate whether patient and tumor characteristics, and treatment type correlate with secondary tumor risk. Methods: This case-control study included 305 patients with a diagnosed second malignancy after almost 6 months after the diagnosis of primary breast cancer and 1,525 controls (ratio 1:5 of cases to controls) from a population-based cohort of 6,325 women. The control patients were randomly selected from the cohort and matched to the cases according to age at diagnosis, calendar period of diagnosis, disease stage, and time of follow-up. Results: BRCA1 or BRCA2 mutation, human epidermal growth factor receptor 2 (HER2)+ status, chemotherapy, and radiotherapy were related to increased risk of developing a second cancer, whereas hormonotherapy showed a protective effect. Chemotherapy, radiotherapy, and estrogenic receptor level <10% increased the risk of controlateral breast cancer. HER2+ status increased the risk of digestive system and thyroid tumors, while BRCA1 or BRCA2 mutation increased the risk of cancer in the genital system. Conclusion: Breast cancer survivors are exposed to an excess of risk of developing a second primary cancer. The development of excess of malignancies may be related either to patient and tumor characteristics, such as BRCA1 or BRCA2 mutation and HER2+ status, or to treatments factors.
2015
- The combination of bortezomib with enzastaurin or lenalidomide enhances cytotoxicity in follicular and mantle cell lymphoma cell lines
[Articolo su rivista]
Cosenza, Maria; Civallero, Monica; Pozzi, Samantha; Marcheselli, Luigi; Bari, Alessia; Sacchi, Stefano
abstract
We analyzed the combination of a proteasome inhibitor (bortezomib) with enzastaurin (PKC/AKT-inhibitor) or lenalidomide (immunomodulatory agent) for the inhibition of proliferation and induction of apoptosis in B-cell lymphoma cell lines and primary malignant cells. The effects of bortezomib, enzastaurin or lenalidomide, alone or in combinations, on cell viability and apoptosis were evaluated using the Cell Proliferation Kit and flow cytometry analysis. The interaction between drugs was examined by the Chou-Talalay method. Cell cycle analysis was performed by flow cytometry. The PI3K/AKT, PKC and MAPK/ERK signaling pathways were analyzed using western blot. Bortezomib with either enzastaurin or lenalidomide synergistically induced anti-proliferative and pro-apoptotic effects in B-cell lymphoma cells, even in the presence of the bone marrow microenvironment. The direct cytotoxicity is mediated by signaling events involving the PI3K/AKT, PKC and MAPK/ERK pathways leading to cell death. The significant increase of apoptosis was mediated by an increased ratio of pro-apoptotic proteins (Bax, Bad and Bim) to anti-apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1), triggering the cleavage of caspases -3, -9, -8 and PARP. Further evaluation of the combination of bortezomib with enzastaurin or lenalidomide for the treatment of B-cell lymphoma is warranted, with the goal to improve the quality of life and survival of patients. Copyright © 2014 John Wiley & Sons, Ltd.
2014
- Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)
[Capitolo/Saggio]
Pozzi, Samantha; Anesi, Alexandre; Generali, Luigi; Bari, Alessia; Consolo, Ugo; Chiarini, Luigi
abstract
Osteonecrosis of the jaw (ONJ) is a rare condition that has been mainly related to the treatment with i.v. bisphosphonates in patients affected by cancer bone disease. The ethiopathology is still unknown and the frequency is between 0.8 and 12 %. It can appear in edentulous patients, but invasive procedures have been demonstrated to increase the risk of developing this complication. Few cases have been described in the endodontic literature. In the next chapter, we will describe ONJ, will analyze the data from literature, and will report expert opinions and guidelines about the best clinical practice in the endodontic fi eld. Finally, since data in this field are limited, we would like to underline that the best treatment plan for cancer patients receiving bisphosphonates and requiring dental procedures is a multidisciplinary, case-by-case approach.
2014
- Defining the best cut-off value for lymphopenia in diffuse large B cell lymphoma treated with immuno-chemotherapy
[Articolo su rivista]
Bari, Alessia; Tadmor, T.; Sacchi, Stefano; Marcheselli, Luigi; Cox, C.; Liardo, ELIANA VALENTINA; Pozzi, Samantha; Beniamini, N.; Avivi, I.; Ferrari, Angela; Baldini, L.; Falorio, S.; Gobbi, P.; Federico, Massimo; Polliack, A.
abstract
Abstract not available
2014
- Dialysis-dependent renal failure at diagnosis continues to be associated with very poor outcome in multiple myeloma - response to Murphy et al
[Articolo su rivista]
Pozzi, Samantha; Bari, Alessia; Sacchi, Stefano
abstract
The study by Murphy et al supports the observation made
by several groups regarding the benefit of the novel agents in
both young and elderly patients affected by multiple
myeloma (MM) (Kumar et al, 2008; Ludwig et al, 2008;
Turesson et al, 2010; Pozzi et al, 2013). Their single institution
data collected over 18 years in 262 patients shows an
improvement in overall survival (OS) starting from 1995
with an OS not yet reached in the period 2007–2012, after
the introduction of bortezomib in their clinical practice.
However the study clearly highlights renal insufficiency as a
very poor prognostic factor, with a median OS shorter than
1 year in patients requiring dialysis.
In the past few years many attempts have been made to
classify and stratify patients based on various refined biological
characteristics, however, as clearly stated here, the clinical
presentation, particularly organ damage, still represents a
negative prognostic factor that not even modern medicine
has been able to overcome. The introduction of the International
Staging System Criteria (ISS) (Greipp et al, 2005) only
indirectly takes renal function into account, while the Durie
and Salmon Criteria differentiates stage ‘A’ and ‘B’ MM
based on kidney damage (Durie & Salmon, 1975). However
Durie-Salmon ‘B’ stage is based on a creatinine cut-off point
of 177 lmol/l and it is unable to better differentiate between
moderate and severe impairment of renal damage requiring
dialysis. It is also unable to predict the response to the
treatment and reversibility of the organ damage, between
possibly transitory kidney impairment due to dehydration,
hyperuricaemia and hypercalacemia, and cast nephropathy.
In this subset of MM patients it would be beneficial to
introduce further parameters in the staging system (i.e. glomerular
filtrate; type of light chain) in order to better stratify
the risks and prevent treatment-related toxicity. For this reason,
ad hoc clinical trials for this group of patients are
strongly needed (Haynes et al, 2012).
Finally, the Murphy study highlights the selection of
patients enrolled in clinical trials and the necessity to evaluate
the survival in the population of every day clinical practice,
together with the need to develop high resolution analysis
from data collected by cancer registers.
Moreover, early diagnosis, compared with late or misdiagnosis,
especially for light chains MM, is mandatory to prevent
severe organ damage.
2014
- Monocyte count at diagnosis is a prognostic parameter in diffuse large B-cell lymphoma: a large multicenter study involving 1191 patients, in the pre and post rituximab era
[Articolo su rivista]
Tadmor, T.; Bari, Alessia; Sacchi, Stefano; Marcheselli, Luigi; Liardo, ELIANA VALENTINA; Avivi, I.; Benyamini, N.; Attias, D.; Pozzi, Samantha; Cox, M. C.; Baldini, L.; Brugiatelli, M.; Federico, Massimo; Polliack, A.
abstract
In this study we assessed the prognostic significance of absolute monocyte count and selected the best cut-off value at diagnosis in a large cohort of patients with diffuse large B-cell lymphoma. Data were retrieved for therapy-naïve patients with diffuse large B-cell lymphoma followed in Israel and Italy during 1993-2010. A final cohort of 1017 patients was analyzed with a median follow up of 48 months and a 5-year overall survival rate of 68%. The best absolute monocyte count cut-off level was 630/mm(3) and the 5-year overall survival for patients with counts below this cut-off was 71%, whereas it was 59% for those with a count >630 mm(3) (P=0.0002). Of the 1017 patients, 521 (51%) were treated with chemo-immunotherapy, and in this cohort, using multivariate analysis, elevated monocyte count retained a negative prognostic value even when adjusted for International Prognostic Index (HR1.54, P=0.009). This large study shows that a simple parameter such as absolute monocyte count (>630/mm(3)) can easily be used routinely in the evaluation of newly diagnosed diffuse large B-cell lymphoma to identify high-risk patients with a worse survival in the rituximab era.
2014
- The potential of pralatrexate as a treatment of peripheral T-cell lymphoma
[Articolo su rivista]
Dondi, Alessandra; Bari, Alessia; Pozzi, Samantha; Ferri, Paola; Sacchi, Stefano
abstract
INTRODUCTION:
Peripheral T-cell lymphomas (PTCLs) are a group of rare malignancies originating from clonal proliferation of mature, post-thymic T cells that represent 10 - 15% of all non-Hodgkin's lymphomas with poor prognosis and median survival of 1 - 3 years. The standard treatment for PTCL has not yet been identified. Many patients with PTCL are refractory to first-line therapy. The complete response rate ranges from 36 to 66% according to different PTCL subtypes. Furthermore, those who reached a complete or partial response often have a shorter progression-free survival.
AREAS COVERED:
This paper discusses the potential of pralatrexate , a methotrexate analogue, as a treatment of PTCL. The authors report on the efficacy and safety data of controlled studies and describe the end points of ongoing trials. Pralatrexate was the first drug to obtain FDA approval for the treatment of patients with relapsed or refractory PTCL. However, the European Medicines Agency has refused marketing authorization.
EXPERT OPINION:
None of the treatments commonly used today have given satisfactory results. Pralatrexate seems to be one of the most promising agents in the treatment of patients with PTCL. Future efforts should be focused on better understanding the molecular pathogenesis of PTCL and on specific trials for different PTCL subtypes using rational drug combinations that include pralatrexate.
2014
- The undergraduate nursing student evaluation of clinical learning environment: an Italian survey [La valutazione dell'ambiente di apprendimento clinico da parte degli studenti del Corso di Laurea in Infermieristica: una indagine italiana]
[Articolo su rivista]
Magnani, Daniela; DI LORENZO, Rosaria; Bari, Alessia; Pozzi, Samantha; DEL GIOVANE, Cinzia; Ferri, Paola
abstract
BACKGROUND: Nursing students have to deal with many different clinical and practical aspects of knowledge to become skilled professionals. Student perception may be considered an indicator of teaching quality, since positive perception of students is strictly related to their effective professional learning. The Clinical Learning Environment and Supervision plus Nurse Teacher (CLES+T) scale is considered the gold standard psychometric instrument to evaluate both the quality and the climate of clinical learning environment.
AIMS: To evaluate the quality of nurse teaching by means of CLES+T scale and to highlight significant correlations between CLES+T scale and selected characteristics of both students and clinical environments.
METHODS: On 4 March 2013, a cross-sectional survey was conducted at University of Modena: CLES+T scale was administered during a plenary convocation to 242 nursing students who attended the second and third years of Nursing Degree. All 34 items of the scale were statistically analysed using the median test.
RESULTS: The median values were uniformly represented by "4" level (on the Likert scale). The final marks of clinical learning experience were the only variable statistically significantly related to the scale scores. The paediatrics and emergency areas obtained the highest scale scores.
CONCLUSIONS: The nursing student evaluations were uniformly positive and related to their positive final marks. A positive ward atmosphere was identified as especially important in this study. These data indicate that a non-hostile and hospitable environment can favour the best clinical learning. We conclude that CLES+T scale can be a useful instrument to explore the clinical climate in all hospital areas and to highlight critical clinical situations.
2013
- In vivo and in vitro effects of a novel anti-Dkk1 neutralizing antibody in multiple myeloma
[Articolo su rivista]
Pozzi, Samantha; Fulciniti, Mariateresa; Yan, Hua; Vallet, Sonia; Eda, Homare; Patel, Kishan; Santo, Loredana; Cirstea, Diana; Hideshima, Teru; Schirtzinge, Linda; Kuhstoss, Stuart; Anderson, Kenneth C.; Munshi, Nikhil; Scadden, David; Kronenberg, Henry M.; Raje, Noopur
abstract
Over-expression of the protein Dickkopf-1 (Dkk1) has been associated with multiple myeloma bone disease. Previous reports with the use of anti-Dkk1 neutralizing Ab directed strategies have demonstrated a pro-anabolic effect with associated anti-myeloma activity in 2 in vivo mouse models. However new insights on the role of the wnt pathway in osteoclasts (OC) are emerging and the potential effect of a neutralizing Ab to Dkk1 in osteoclastogenesis remains to be elucidated. In order to better define the effect of an anti-Dkk1 neutralizing Ab on osteoclastogenesis and myeloma , we studeied a novel anti-Dkk1 monoclonal Ab in our preclinical models. In vivo data confirmed the pro-anabolic and anti-MM effect. In vitro data in part confirmed the in vivo observation, suggesting an indirect anti-MM effect secondary to inhibition of osteoclastogenesis and thus the interaction between MM and bone microenvironment. However, when stuidies on osteoclastogenesis were extended to samples derived from MM patients, we observed a variable response to anti-Dkk1 treatment without correlation to expression of surface receptors for Dkk1 in OCs suggesting potential heterogeneity in the efficacy of such a strategy. In conclusion, Dkk1 is a promising target for the treatment of both MM and bone disease, and ongoing clinical studies will help elucidate its efficacy.
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
- 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.
2012
- Clinical trials of bisphosphonates in multiple myeloma
[Articolo su rivista]
Mahindra, Anuj; Pozzi, Samantha; Raje, Noopur
abstract
More than 80% of patients with multiple myeloma (MM) have osteolytic bone disease, which increases the risk of skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, and the need for radiotherapy or surgery. Bone disease is primarily due to increased osteoclastic activity and impaired osteoblast activity. Bisphosphonates are pyrophosphate analogues with high bone affinity that can inhibit osteoclastic activity. Pamidronate and zoledronic acid are the most commonly used bisphosphonates in multiple myeloma. Other agents include ibandronate and clodronate. Bisphosphonates are associated with several adverse events, such as renal toxicity and osteonecrosis of the jaw. The optimal duration of bisphosphonate therapy has yet to be determined. Clinical trials are investigating tailored approaches to management based on treatment-related changes in levels of bone resorption markers.
2012
- NVP-BEZ235 alone and in combination in mantle cell lymphoma: an effective therapeutic strategy
[Articolo su rivista]
Civallero, Monica; Cosenza, Maria; Marcheselli, Luigi; Pozzi, Samantha; Sacchi, Stefano
abstract
Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma; the complete response rate for standard therapies in use today is 85 - 90%. NVP-BEZ235 inhibits the PI3K/Akt/mTOR signaling axis at the level of both PI3K and mTOR. In this study, we analyzed the inhibitory effects of NVP-BEZ235 on mantle cell lines and its effects in combination with enzastaurin, everolimus and perifosine.
2011
- A novel role for CCL3 (MIP-1α) in myeloma-induced bone disease via osteocalcin downregulation and inhibition of osteoblast function.
[Articolo su rivista]
S., Vallet; Pozzi, Samantha; K., Patel; N., Vaghela; M. T., Fulciniti; P., Veiby; T., Hideshima; L., Santo; D., Cirstea; D. T., Scadden; K. C., Anderson; N., Raje
abstract
Upregulation of cytokines and chemokines is a frequent finding in multiple myeloma (MM). CCL3 (also known as MIP-1α) is a pro-inflammatory chemokine, levels of which in the MM microenvironment correlate with osteolytic lesions and tumor burden. CCL3 and its receptors, CCR1 and CCR5, contribute to the development of bone disease in MM by supporting tumor growth and regulating osteoclast (OC) differentiation. In this study, we identify inhibition of osteoblast (OB) function as an additional pathogenic mechanism in CCL3-induced bone disease. MM-derived and exogenous CCL3 represses mineralization and osteocalcin production by primary human bone marrow stromal cells and HS27A cells. Our results suggest that CCL3 effects on OBs are mediated by ERK activation and subsequent downregulation of the osteogenic transcription factor osterix. CCR1 inhibition reduced ERK phosphorylation and restored both osterix and osteocalcin expression in the presence of CCL3. Finally, treating SCID-hu mice with a small molecule CCR1 inhibitor suggests an upregulation of osteocalcin expression along with OC downregulation. Our results show that CCL3, in addition to its known catabolic activity, reduces bone formation by inhibiting OB function, and therefore contributes to OB/OC uncoupling in MM
2011
- Antimyeloma activity of a multitargeted kinase inhibitor, AT9283, via potent Aurora kinase and STAT3 inhibition either alone or in combination with lenalidomide.
[Articolo su rivista]
L., Santo; T., Hideshima; D., Cirstea; M., Bandi; E. A., Nelson; G., Gorgun; S., Rodig; S., Vallet; Pozzi, Samantha; K., Patel; C., Unitt; M., Squires; Y., Hu; D., Chauhan; A., Mahindra; N. C., Munshi; K. C., Anderson; N., Raje
abstract
AbstractPURPOSE: Aurora kinases, whose expression is linked to genetic instability and cellular proliferation, are being investigated as novel therapeutic targets in multiple myeloma (MM). In this study, we investigated the preclinical activity of a small-molecule multitargeted kinase inhibitor, AT9283, with potent activity against Aurora kinase A, Aurora kinase B, and Janus kinase 2/3.EXPERIMENTAL DESIGN: We evaluated the in vitro antimyeloma activity of AT9283 alone and in combination with lenalidomide and the in vivo efficacy by using a xenograft mouse model of human MM.RESULTS: Our data showed that AT9283 induced cell-growth inhibition and apoptosis in MM. Studying the apoptosis mechanism of AT9283 in MM, we observed features consistent with both Aurora kinase A and Aurora kinase B inhibition, such as increase of cells with polyploid DNA content, decrease in phospho-histone H3, and decrease in phospho-Aurora A. Importantly, AT9283 also inhibited STAT3 tyrosine phosphorylation in MM cells. Genetic depletion of STAT3, Aurora kinase A, or Aurora kinase B showed growth inhibition of MM cells, suggesting a role of AT9283-induced inhibition of these molecules in the underlying mechanism of MM cell death. In vivo studies showed decreased MM cell growth and prolonged survival in AT9283-treated mice compared with controls. Importantly, combination studies of AT9283 with lenalidomide showed significant synergistic cytotoxicity in MM cells, even in the presence of bone marrow stromal cells. Enhanced cytotoxicity was associated with increased inhibition of phosphorylated STAT3 and phosphorylated extracellular signal-regulated kinase.CONCLUSIONS: Demonstration of in vitro and in vivo anti-MM activity of AT9283 provides the rationale for the clinical evaluation of AT9283 as monotherapy and in combination therapy for treating patients with MM.
2011
- Targeting Bruton's Tyrosine Kinase As a Novel Approach to Inhibit Osteoclast Function in Multiple Myeloma
[Abstract in Atti di Convegno]
Eda, H; Santo, L; Cirstea, Dd; Pozzi, S; Canavese, M; Scullen, Ta; Vallet, S; Evans, E; Singh, J; Raje, Ns
abstract
ND
2011
- The role of bisphosphonates in multiple myeloma: Mechanisms, side effects, and the future
[Articolo su rivista]
Pozzi, Samantha; Raje, Noopur
abstract
Zoledronic acid and pamidronate are two potent anticatabolic nitrogen-containing bisphosphonates (BPs) used extensively in diseases with high bone turnover such as multiple myeloma (MM). In this review we focus on their biology and their current and future use in MM, and highlight some of the most common and emerging side effects. Although the primary target cells for BPs are osteoclasts, new insights suggest other cell types of the bone microenvironment as possible targets, including osteoblasts, endothelial cells, immune cells, and cancer cells. Here, we focus on the current guidelines for the use of BPs in MM and address side effects such as renal toxicity, osteonecrosis of the jaw, and lowenergy fractures. Finally, we approach the future of BP use inMMin the context of other bone-targeted agents, evaluating ongoing clinical trials addressing alternate dosing and schedules of BP administration in MM patients. © AlphaMed Press.
2011
- Therapy-related myeloid neoplasm in non-hodgkin lymphoma survivors.
[Articolo su rivista]
Bari, Alessia; Marcheselli, Luigi; Marcheselli, Raffaella; Liardo, Ev; Pozzi, Samantha; Ferri, Paola; Sacchi, Stefano
abstract
Relatively little data on secondary cancers is available regarding patients treated for non-Hodgkin lymphoma (NHL), compared with those treated for Hodgkin lymphoma. Evolving treatment regimens have improved survival outcomes for NHL patients. As a result of this improvement, secondary malignancies are becoming an important issue in NHL survivors. This review aims to report data on this topic previously published by our group, adding unpublished results from the Modena Cancer Registry (MCR). We recently performed four studies about secondary neoplasms in NHL survivors: two studies analysing the risk of secondary neoplasms in patients treated for indolent and aggressive NHL; a meta-analysis of 23 studies investigating the risk of secondary malignant neoplasm (SMN) after NHL treatment; and a still-unpublished study evaluating the incidence of therapy-related myeloid neoplasm (t-MN) in patients treated for NHL (from the MCR database). The first two studies analysed 563 patients with indolent NHL and 1280 patients with diffuse large B-cell lymphoma (DLBCL) enrolled in the Gruppo Italiano Studio Linfomi (GISL) trials. Results showed that the cumulative incidence of secondary tumours was 10.5% at 12 years for indolent NHL and 8.2% at 15 years for DLBCL. Results of the meta-analysis indicated that NHL patients experienced a 1.88-fold increased risk for SMN compared with the general population; the standardized incidence risk (SIR) for secondary acute myeloid leukaemia (AML) was 11.07. Based on data from the MCR from 2000 through 2008, we found that the SIR was 1.63 for developing a secondary malignancy after NHL, and 1.99 for developing secondary haematological malignancies. Regarding myelodysplastic syndrome and/or AML incidence, nine NHL patients developed t-MN with a higher risk than expected (SIR 8.8, 95% CI: 4.0-16.6). In conclusion, patients treated for NHL are at increased risk of developing SMN. Regarding t-MN, data from the meta-analysis and the MCR demonstrate an excessive risk of developing AML (SIR 11.07 and 5.7, respectively) compared with solid SMN after treatment for NHL. Thus long-term monitoring should be considered for NHL survivors.
2010
- AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3Β activation and RNA polymerase II inhibition
[Articolo su rivista]
Santo, L.; Vallet, S.; Hideshima, T.; Cirstea, D.; Ikeda, H.; Pozzi, S.; Patel, K.; Okawa, Y.; Gorgun, G.; Perrone, G.; Calabrese, E.; Yule, M.; Squires, M.; Ladetto, M.; Boccadoro, M.; Richardson, P. G.; Munshi, N. C.; Anderson, K. C.; Raje, N.
abstract
Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Overexpression of individual complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a novel small-molecule multi-CDK inhibitor, AT7519, in MM. We show the anti-MM activity of AT7519 displaying potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by [3 H] Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3Β (GSK-3Β) phosphorylation; conversely pretreatment with a selective GSK-3 inhibitor and shRNA GSK-3Β knockdown restored MM survival, suggesting the involvement of GSK-3Β in AT7519-induced apoptosis. GSK-3Β activation was independent of RNA pol II dephosphorylation confirmed by α-amanitin, a specific RNA pol II inihibitor, showing potent inhibition of RNA pol II phosphorylation without corresponding effects on GSK-3Β phosphorylation. These results offer new insights into the crucial, yet controversial role of GSK-3Β in MM and show significant anti-MM activity of AT7519, providing the rationale for its clinical evaluation in MM. © 2010 Macmillan Publishers Limited All rights reserved.
2010
- Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease
[Articolo su rivista]
S., Vallet; S., Mukherjee; N., Vaghela; T., Hideshima; M., Fulciniti; Pozzi, Samantha; L., Santo; D., Cirstea; K., Patel; A. R., Sohani; A., Guimaraes; W., Xie; D., Chauhan; J. A., Schoonmaker; E., Attar; M., Churchill; E., Weller; N., Munshi; J. S., Seehra; R., Weissleder; K. C., Anderson; D. T., Scadden; N., Raje
abstract
AbstractUnderstanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-beta family member, as a therapeutically amenable target exploited by multiple myeloma (MM) to alter its microenvironmental niche favoring osteolysis. Increased bone marrow plasma activin A levels were found in MM patients with osteolytic disease. MM cell engagement of marrow stromal cells enhanced activin A secretion via adhesion-mediated JNK activation. Activin A, in turn, inhibited osteoblast differentiation via SMAD2-dependent distal-less homeobox-5 down-regulation. Targeting activin A by a soluble decoy receptor reversed osteoblast inhibition, ameliorated MM bone disease, and inhibited tumor growth in an in vivo humanized MM model, setting the stage for testing in human clinical trials.
2010
- Bisphosphonates and Atypical Femoral Fractures
[Articolo su rivista]
Pozzi, S; Raje, N.
abstract
Comment on Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. [N Engl J Med. 2010]
2010
- Dual inhibition of akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma.
[Articolo su rivista]
D., Cirstea; T., Hideshima; S., Rodig; L., Santo; Pozzi, Samantha; S., Vallet; H., Ikeda; G., Perrone; G., Gorgun; K., Patel; N., Desai; P., Sportelli; S., Kapoor; S., Vali; S., Mukherjee; N. C., Munshi; K. C., Anderson; N., Raje
abstract
AbstractThe phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway mediates multiple myeloma (MM) cell proliferation, survival, and development of drug resistance, underscoring the role of mTOR inhibitors, such as rapamycin, with potential anti-MM activity. However, recent data show a positive feedback loop from mTOR/S6K1 to Akt, whereby Akt activation confers resistance to mTOR inhibitors. We confirmed that suppression of mTOR signaling in MM cells by rapamycin was associated with upregulation of Akt phosphorylation. We hypothesized that inhibiting this positive feedback by a potent Akt inhibitor perifosine would augment rapamycin-induced cytotoxicity in MM cells. Perifosine inhibited rapamycin-induced phosphorylated Akt, resulting in enhanced cytotoxicity in MM.1S cells even in the presence of interleukin-6, insulin-like growth factor-I, or bone marrow stromal cells. Moreover, rapamycin-induced autophagy in MM.1S MM cells, as evidenced by electron microscopy and immunocytochemistry, was augmented by perifosine. Combination therapy increased apoptosis detected by Annexin V/propidium iodide analysis and caspase/poly(ADP-ribose) polymerase cleavage. Importantly, in vivo antitumor activity and prolongation of survival in a MM mouse xenograft model after treatment was enhanced with combination of nanoparticle albumin-bound-rapamycin and perifosine. Utilizing the in silico predictive analysis, we confirmed our experimental findings of this drug combination on PI3K, Akt, mTOR kinases, and the caspases. Our data suggest that mutual suppression of the PI3K/Akt/mTOR pathway by rapamycin and perifosine combination induces synergistic MM cell cytotoxicity, providing the rationale for clinical trials in patients with relapsed/refractory MM
2009
- A RANDOMIZED PHASE II STUDY (GISL - MM03 TRIAL) WITH ORAL MELPHALAN+ PREDNISONE (MP) VERSUS MELPHALAN, + PREDNISONE + THALIDOMIDE (MPT) FOR NEWLY DIAGNOSED ELDERLY PATIENTS WITH MULTIPLE MYELOMA
[Abstract in Rivista]
Sacchi, Stefano; Marcheselli, Raffaella; Pozzi, Samantha; Bari, Alessia; O., Ciarcia; L., Masini; A., Lazzaro; F., Morabito; A., Fragasso; N., Di Renzo; G., Quarta; G., Buda; P., Musto; M. L., Vigliotti; A., Pastorini; M., Brugiatelli
abstract
Background. Several papers showed that MPT compared with MP improved response and survival outcomes. However, side effects increase and toxicity, as neutropenia, neuropathy, deep-vein thrombosis, depression and constipation reduce patients compliance. Thus, several patients have to discontinue or reduce the dose of Thalidomide. Aims. Aim of our research is to verify these results in a group of 128 patients not eligible for high dose treatment with stem cells support. Patients and Methods. The MM03 trial was approved by Ethical Committee of Modena and registered at Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali at the end 2004. A total of 128 patients were enrolled between January 2005 to October 2008: 53% entered MPT arm. Median age of patients were 75 years (range: 63-88 yrs), 50% were female, 55% had Durie and Salmon stage II and 45% had stage III. Distribution of M spike were: 67%, 22% and 11% for IgG, IgA and urine light chains. Univariate analysis of variables at baseline did not show any difference between the two arms. In arm A Melphalan was given at a dose of 0.25 mg/kg and Prednisone 60 mg/m2 for 4 days every 28 days; in arm B Thalidomide was added at a dose of 100 mg every day; a maximum of ten cycles was planned. At the end of induction therapy, 26 patients who had obtained Complete Response, Partial Response, Minimal Response or Stable disease were randomized for maintenance with Dexamethasone 20 mg, day 1-4 every 28 days or Dexamethasone at the same dose plus Thalidomide 100 mg/day every day. Only 14 patients follow this indication and assumed maintenance treatment for 6-12 months; no differences were observed between the 2 arm of maintenance. The use of growth factors, was at treating physicians discretion. Starting from May 2005 enoxiparin was recommended during the first 4 cycles of MPT arm. Results. Of 128 patients, 91 patients are evaluable for response while 20 are still on treatment. The response, including MR among all patients who entered protocol were 76%, while 9% had SD and 15% presented PD. Considering separately the two arm, we observed in arm A 12% CR, 43% PR, 9% MR, 3% SD and 23% PD and in arm B 18% CR, 57% PR, 11% MR, 5% SD and 9% PD. A comparison between 55% of CR plus PR in arm A with 75% in arm B shows a p=0.049, showing an advantage for MPT arm. After a median follow up of 14 months, median Overall Survival at 24 months are not still reached. During treatment or progression 24 patients died. Grade III/IV adverse events were: 6 deep-vein thrombosis, all in MPT arm, 1 during enoxaparin prophylaxis, 1 pneumonitis, 6 neutropenia, 3 neurotoxicities, 3 constipation. Conclusions. Our results show that the addition of Thalidomide to MP improve number and quality of response. We are still collecting data for a better definition of OS, FFS and toxicity in arm A in comparison with arm B, and they will be presented during the meeting
2009
- A high-affinity fully human anti-IL-6 mAb (OP-R003-1, 1339) for the
treatment of Multiple Myeloma
[Articolo su rivista]
M. T., Fulciniti; T., Hideshima; C., Vermot Desroches; Pozzi, Samantha; P., Nanjappa; Z., Shen; N., Patel; E. S., Smith; R., Prabhala; Y., Tai; P., Tassone; K. C., Anderson; N. C., Munshi
abstract
Purpose—We investigated the in vitro and in vivo anti-MM activity of mAb 1339, a high-affinity
fully humanized anti-IL-6 mAb (IgG1), alone and in combination with conventional and novel anti-
MM agents, as well as its effect on bone turnover.
Experimental Design—We examined the growth inhibitory effect of 1339 against MM cell lines
in the absence and in the presence of bone marrow stromal cells (BMSC) alone or in combination
with dexamethasone, bortezomib, perifosine and revlimid. Using the SCID-hu murine model of MM,
we also examined the effect of 1339 on MM cell growth and MM bone disease.
Results—mAb 1339 significantly inhibited growth of MM cell in the presence of BMSC in vitro,
associated with inhibition of phosphorylation of STAT3, ERK1/2 and Akt. In addition, mAb 1339
enhanced cytotoxicity induced by dexamethasone as well as bortezomib, lenalidomide, and
perifosine in a synergistic fashion. Importantly mAb 1339 significantly enhanced growth inhibitory
effects of dexamethasone in vivo in SCID-hu mouse model of MM. mAb 1339 treatment also resulted
in inhibition of osteoclastogenesis in vitro and bone remodeling in SCID-hu model.
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
- High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties.
[Articolo su rivista]
Pozzi, Samantha; S., Vallet; S., Mukherjee; D., Cirstea; N., Vaghela; L., Santo; E., Rosen; H., Ikeda; Y., Okawa; T., Kiziltepe; J., Schoonmaker; W., Xie; T., Hideshima; E., Weller; M. L., Bouxsein; N. C., Munshi; K. C., Anderson; N., Raje
abstract
AbstractPURPOSE: The increasing incidence of osteonecrosis of the jaw and its possible association with high cumulative doses of bisphosphonate led us to study the effects of high doses of zoledronic acid (ZA) on bone remodeling.EXPERIMENTAL DESIGN: Five-week-old C57BL6 mice were treated with saline or ZA weekly for 3 weeks at increasing doses (0.05-1 mg/Kg). Effects of ZA on bone remodeling were studied using standard assays.RESULTS: We observed an increase in bone mineral density and content in treated animals at doses of 0.05 mg/Kg, which was not further enhanced at higher doses of ZA. Trabecular bone volume at the proximal tibia and the distal femur assessed by histomorphometry and microCT, respectively, increased significantly in ZA-treated groups. There was however no difference between 0.5 and 1 mg/kg, suggesting a ceiling effect for ZA. ZA led to decreased numbers of osteoclasts and osteoblasts per bone perimeter that paralleled a significant reduction of serum levels of TRAC5b and osteocalcin in vivo. Effects on osteoblasts were confirmed in in vitro assays. Mechanical testing of the femur showed increased brittleness in ZA-treated mice.CONCLUSIONS: High doses of ZA inhibit both osteoclast and osteoblasts function and bone remodeling in vivo interfering with bone mechanical properties. No dose response was noted beyond 0.5 mg/kg suggesting that lower doses of ZA may be adequate in inhibiting bone resorption. Our data may help inform future studies of ZA use with respect to alternate and lower doses in the treatment of patients with cancer bone disease.
2009
- Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma.
[Articolo su rivista]
N., Raje; T., Hideshima; S., Mukherjee; M., Raab; S., Vallet; S., Chhetri; D., Cirstea; Pozzi, Samantha; C., Mitsiades; M., Rooney; T., Kiziltepe; K., Podar; Y., Okawa; H., Ikeda; R., Carrasco; P. G., Richardson; D., Chauhan; N. C., Munshi; S., Sharma; H., Parikh; B., Chabner; D., Scadden; K. C., Anderson
abstract
Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in >50% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclin-dependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspase-dependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.
2009
- Prognostic models for diffuse large B-cell lymphoma in the rituximab era: a never-ending story.
[Articolo su rivista]
Bari, Alessia; Marcheselli, Luigi; Sacchi, Stefano; Marcheselli, Raffaella; Pozzi, Samantha; Ferri, Paola; Balleari, E; Musto, P; Neri, S; Aloe Spiriti, Ma; Cox, M. C.
abstract
BACKGROUND: Improved treatment have modified survival outcome in patients with diffuse large B-cell lymphoma (DLBCL) and altered the importance of previously recognized prognostic markers.DESIGN AND METHODS: To evaluate International Prognostic Index (IPI) score before and after rituximab introduction and to validate the absolute lymphocyte count (ALC)/revised International Prognostic Index (R-IPI) model, we carried out a retrospective analysis on a total of 831 patients with DLBCL.RESULTS: Our results show that IPI lost its discriminating power with the introduction of rituximab. The analysis of our second set allowed us to validate the ALC/R-IPI model. The R-IPI and ALC/R-IPI could still be used for designing clinical trials, but both have difficulty recognizing a high percentage of poor prognosis patients, though it remains an important goal of a good prognostic model considering the modest impact of salvage treatments on survival.CONCLUSIONS: A new model on the basis of significant variables in the rituximab era and built on a large database of patients treated with rituximab is urgently needed. As prognostic models are changing with the efficacy and mechanisms of action of treatment utilized, looking for a new prognostic score is a never-ending story in which researchers are trying to hit a continuously moving target.
2009
- The Monoclonal Antibody nBT062 Conjugated to Cytotoxic
Maytansinoids Has Selective Cytotoxicity Against CD138-Positive
Multiple Myeloma Cells In vitro and In vivo
[Articolo su rivista]
H., Ikeda; T., Hideshima; M. T., Fulciniti; R. J., Lutz; H., Yasui; Y., Okawa; T., Kiziltepe; S., Vallet; Pozzi, Samantha; L., Santo; G., Perrone; Y., Tai; D., Cirstea; N. S., Raje; C., Uherek; B., Dälken; S., Aigner; F., Osterroth; N., Munshi; P., Richardson; K. C., Anderson
abstract
Purpose: We investigated the antitumor effect of murine/human chimeric CD138-
specific monoclonal antibody nBT062 conjugated with highly cytotoxic maytansinoid
derivatives against multiple myeloma (MM) cells in vitro and in vivo.
Experimental Design: We examined the growth inhibitory effect of BT062-SPDB-DM4,
BT062-SMCC-DM1, and BT062-SPP-DM1 against MM cell lines and primary tumor cells
from MM patients. We also examined in vivo activity of these agents in murine MM cell
xenograft model of human and severe combined immunodeficient (SCID) mice bearing
implant bone chips injected with human MM cells (SCID-hu model).
Results: Anti-CD138 immunoconjugates significantly inhibited growth of MM cell lines
and primary tumor cells from MM patients without cytotoxicity against peripheral
blood mononuclear cells from healthy volunteers. In MM cells, they induced G2-M cell
cycle arrest, followed by apoptosis associated with cleavage of caspase-3, caspase-8,
caspase-9, and poly(ADP-ribose) polymerase. Nonconjugated nBT062 completely
blocked cytotoxicity induced by nBT062-maytansinoid conjugate, confirming that specific
binding is required for inducing cytotoxicity. Moreover, nBT062-maytansinoid conjugates
blocked adhesion of MM cells to bone marrow stromal cells. The coculture of
MM cells with bone marrow stromal cells protects against dexamethasone-induced
death but had no effect on the cytotoxicity of immunoconjugates. Importantly,
nBT062-SPDB-DM4 and nBT062-SPP-DM1 significantly inhibited MM tumor growth in vivo and prolonged host survival in both the xenograft mouse models of human MM and SCID-hu mouse model.
Conclusion: These results provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM.
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
- AT7519, a Novel Small Molecule Multi-Cyclin Dependent Kinase Inhibitor, Induces Apoptosis in Multiple Myeloma VIA GSK3 beta
[Abstract in Rivista]
Santo, L; Vallet, S; Hideshima, T; Cirstea, D; Pozzi, S; Vaghela, N; Ikeda, H; Okawa, Y; Gorgun, G; Perrone, G; Calabrese, E; Squires, Ms; Ladetto, M; Munshi, Nc; Boccadoro, M; Anderson, Kc; Raje, N.
abstract
Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Overexpression of individual complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a novel small-molecule multi-CDK inhibitor, AT7519, in MM. We show the anti-MM activity of AT7519 displaying potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by [(3)H] Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3beta (GSK-3beta) phosphorylation; conversely pretreatment with a selective GSK-3 inhibitor and shRNA GSK-3beta knockdown restored MM survival, suggesting the involvement of GSK-3beta in AT7519-induced apoptosis. GSK-3beta activation was independent of RNA pol II dephosphorylation confirmed by alpha-amanitin, a specific RNA pol II inihibitor, showing potent inhibition of RNA pol II phosphorylation without corresponding effects on GSK-3beta phosphorylation. These results offer new insights into the crucial, yet controversial role of GSK-3beta in MM and show significant anti-MM activity of AT7519, providing the rationale for its clinical evaluation in MM.
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
- Fatty acid synthase is a novel therapeutic target in multiple myeloma.
[Articolo su rivista]
Y., Okawa; T., Hideshima; H., Ikeda; N., Raje; S., Vallet; T., Kiziltepe; H., Yasui; S., Enatsu; Pozzi, Samantha; I., Breitkreutz; D., Cirstea; L., Santo; P., Richardson; K. C., Anderson
abstract
AbstractThis study investigated the biological significance of the inhibition of fatty acid synthase (FAS) in multiple myeloma (MM) using the small molecule inhibitor Cerulenin. Cerulenin triggered growth inhibition in both MM cell lines and MM patient cells, and overcame the survival and growth advantages conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. It induced apoptosis in MM cell lines with only modest activation of caspase -8, -9, -3 and PARP; moreover, the pan-caspase inhibitor Z-VAD-FMK did not inhibit Cerulenin-induced apoptosis and cell death. In addition, treatment of MM cells with Cerulenin primarily up-regulated apoptosis-inducing factor/endonuclease G, mediators of caspase-independent apoptosis. Importantly, Cerulenin induced endoplasmic reticulum stress response via up-regulation of the Grp78/IRE1alpha/JNK pathway. Although the C-Jun-NH(2)-terminal kinase (JNK) inhibitor SP600215 blocked Cerulenin-induced cytotoxicity, it did not inhibit apoptosis and caspase cleavage. Furthermore, Cerulenin showed synergistic cytotoxic effects with various agents including Bortezomib, Melphalan and Doxorubicin. Our results therefore indicate that inhibition of FAS by Cerulenin primarily triggered caspase-independent apoptosis and JNK-dependent cytotoxicity in MM cells. This report demonstrated that inhibition of FAS has anti-tumour activity against MM cells, suggesting that it represents a novel therapeutic target in MM.
2008
- Pharmacologic targeting of a stem/progenitor
population in vivo is associated with
enhanced bone regeneration in mice
[Articolo su rivista]
S., Mukherjee; N., Raje; J. A., Schoonmaker; J. C., Liu; T., Hideshima; M. N., Wein; D. C., Jones; S., Vallet; M. L., Bouxsein; Pozzi, Samantha; S., Chhetri; Y. D., Seo; J. P., Aronson; C., Patel; M. T., Fulciniti; L. E., Purton; L. H., Glimcher; J. B., Lian; G., Stein; K. C., Anderson; D. T., Scadden
abstract
Drug targeting of adult stem cells has been proposed as a strategy for regenerative medicine, but very few drugs
are known to target stem cell populations in vivo. Mesenchymal stem/progenitor cells (MSCs) are a multipotent
population of cells that can differentiate into muscle, bone, fat, and other cell types in context-specific
manners. Bortezomib (Bzb) is a clinically available proteasome inhibitor used in the treatment of multiple
myeloma. Here, we show that Bzb induces MSCs to preferentially undergo osteoblastic differentiation, in part
by modulation of the bone-specifying transcription factor runt-related transcription factor 2 (Runx-2) in mice.
Mice implanted with MSCs showed increased ectopic ossicle and bone formation when recipients received low
doses of Bzb. Furthermore, this treatment increased bone formation and rescued bone loss in a mouse model
of osteoporosis. Thus, we show that a tissue-resident adult stem cell population in vivo can be pharmacologically
modified to promote a regenerative function in adult animals.
2008
- Role of thalidomide in previously untreated patients with multiple myeloma
[Articolo su rivista]
Musto, P; D'Auria, F; Pietrantuono, G; Bringhen, S; Morabito, F; Di Raimondo, F; Pozzi, Samantha; Sacchi, Stefano; Boccadoro, M; Palumbo, A.
abstract
Thalidomide represents one of the most relevant therapeutic advances for patients with multiple myeloma over the last 10 years. Despite some toxicities, it has demonstrated significant efficacy in elderly patients, as well as in the setting of younger subjects receiving autologous stem cell transplantation. Here, we report and discuss the clinical results achieved with thalidomide alone or in combination with dexamethasone or other drugs, such as melphalan, cyclophosphamide, doxorubicin and bortezomib, in previously untreated myeloma patients.
2008
- Second malignancies after treatment of diffuse large B-cell non-Hodgkin's lymphoma: a GISL cohort study
[Articolo su rivista]
Sacchi, Stefano; Marcheselli, Luigi; Bari, Alessia; Marcheselli, Raffaella; Pozzi, Samantha; Gobbi, Pg; Angrilli, F; Brugiatelli, M; Musto, P; Federico, Massimo
abstract
BACKGROUND: Improved treatment has increased the life expectancy of patients with non-Hodgkin's lymphoma, but few studies have addressed the issue of second cancer in patients treated for diffuse large B-cell lymphoma. The aims of this study were to determine the incidence and time free of second cancers in this subset of patients. DESIGN AND METHODS: We evaluated a cohort of 1280 patients with diffuse large B-cell lymphoma who were first treated between 1988 and 2003. We utilized the central database of the Gruppo Italiano Studio Linfomi, which includes data on demographics, clinical characteristics, laboratory parameters, treatment and follow-up of all patients with non-Hodgkin's lymphoma enrolled in clinical trials. RESULTS: After a median follow-up of 51 months, 48 patients had developed a second cancer: 13 hematologic malignancies and 35 solid tumors. The overall standardized incidence ratio in our cohort (with a median age of 58 years) matched that of the general Italian population. The incidence ratio of second tumors was age related, and the age groups 20-39 and 40-59 years showed an increased risk. Overall, the cumulative incidence of second cancer was 8.2% at 15 years. A multivariate analysis showed that older age at the time of diagnosis of lymphoma had a negative influence on the time free of second tumors. CONCLUSIONS: In our cohort, only young patients showed an increased incidence ratio of second malignancies, while the incidence ratio in patients aged over 59 years matched the incidence in the Italian general population. Demographics, baseline characteristics, laboratory parameters and treatment modalities did not have any significant impact on the incidence ratio of a second cancer.
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
- 5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells.
[Articolo su rivista]
T., Kiziltepe; T., Hideshima; L., Catley; N., Raje; H., Yasui; N., Shiraishi; Y., Okawa; H., Ikeda; S., Vallet; Pozzi, Samantha; K., Ishitsuka; E. M., Ocio; D., Chauhan; K. C., Anderson
abstract
AbstractIn this study, we investigated the cytotoxicity of 5-azacytidine, a DNA methyltransferase inhibitor, against multiple myeloma (MM) cells, and characterized DNA damage-related mechanisms of cell death. 5-Azacytidine showed significant cytotoxicity against both conventional therapy-sensitive and therapy-resistant MM cell lines, as well as multidrug-resistant patient-derived MM cells, with IC(50) of approximately 0.8-3 micromol/L. Conversely, 5-azacytidine was not cytotoxic to peripheral blood mononuclear cells or patient-derived bone marrow stromal cells (BMSC) at these doses. Importantly, 5-azacytidine overcame the survival and growth advantages conferred by exogenous interleukin-6 (IL-6), insulin-like growth factor-I (IGF-I), or by adherence of MM cells to BMSCs. 5-Azacytidine treatment induced DNA double-strand break (DSB) responses, as evidenced by H2AX, Chk2, and p53 phosphorylations, and apoptosis of MM cells. 5-Azacytidine-induced apoptosis was both caspase dependent and independent, with caspase 8 and caspase 9 cleavage; Mcl-1 cleavage; Bax, Puma, and Noxa up-regulation; as well as release of AIF and EndoG from the mitochondria. Finally, we show that 5-azacytidine-induced DNA DSB responses were mediated predominantly by ATR, and that doxorubicin, as well as bortezomib, synergistically enhanced 5-azacytidine-induced MM cell death. Taken together, these data provide the preclinical rationale for the clinical evaluation of 5-azacytidine, alone and in combination with doxorubicin and bortezomib, to improve patient outcome in MM.
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
- 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
- MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts
[Articolo su rivista]
S., Vallet; N., Raje; K., Ishitsuka; T., Hideshima; K., Podar; S., Chhetri; Pozzi, Samantha; I., Breitkreutz; T., Kiziltepe; H., Yasui; E. M., Ocio; N., Shiraishi; J., Jin; Y., Okawa; H., Ikeda; S., Mukherjee; N., Vaghela; D., Cirstea; M., Ladetto; M., Boccadoro; K. C., Anderson
abstract
The interaction between osteoclasts (OCs)
and multiple myeloma (MM) cells plays a
key role in the pathogenesis of MMrelated
osteolytic bone disease (OBD).
MM cells promote OC formation and, in
turn, OCs enhance MM cell proliferation.
Chemokines are mediators of MM effects
on bone and vice versa; in particular,
CCL3 enhances OC formation and promotes
MM cell migration and survival.
Here, we characterize the effects of
MLN3897, a novel specific antagonist of
the chemokine receptor CCR1, on both
OC formation and OC-MM cell interactions.
MLN3897 demonstrates significant
impairment of OC formation (by 40%) and
function (by 70%), associated with decreased
precursor cell multinucleation
and down-regulation of c-fos signaling.
OCs secrete high levels of CCL3, which
triggers MM cell migration; conversely,
MLN3897 abrogates its effects by inhibiting
Akt signaling. Moreover, MM cellto-
OC adhesion was abrogated by
MLN3897, thereby inhibiting MM cell survival
and proliferation. Our results therefore
show novel biologic sequelae of
CCL3 and its inhibition in both osteoclastogenesis
and MM cell growth, providing
the preclinical rationale for clinical trials
of MLN3897 to treat OBD in MM.
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
- Rituximab in combination with fludarabine and cyclophosphamide in the treatment of patients with recurrent follicular lymphoma
[Articolo su rivista]
Sacchi, Stefano; Pozzi, Samantha; Marcheselli, Raffaella; Federico, Massimo; Tucci, A; Merli, F; Orsucci, L; Liberati, M; Vallisa, D; Brugiatelli, M.
abstract
The current study was conducted to asses the safety profile and clinical activity of rituximab in combination with fludarabine and cyclophosphamide in patients with recurrent follicular lymphoma (FL). METHODS: This study was a noncomparative, multicenter, phase II study. Between March 2000 and December 2002, 54 patients with recurrent FL were enrolled in the FC+R trial. Patients received fludarabine at a dose of 25 mg/m(2) and cyclophosphamide at a dose of 300 mg/m(2) daily for 3 consecutive days, every 3 weeks for 4 cycles. Rituximab was administered at a dose of 375 mg/m(2) beginning 2 weeks after the first course of fludarabine and cyclophosphamide and then on Day 1 of each cycle thereafter. The planned treatment duration was 10 weeks. RESULTS: Overall, 92% of patients completed the planned therapy in 10 to 14 weeks and 74% achieved a complete response (CR). Among patients with BCL2-positive bone marrow, 86% obtained a molecular disease remission (MR). The median survival from treatment (SFT), the duration of disease remission (DR), and time to disease progression (TTP) had not been reached after a median follow-up of 45 months. Of the baseline characteristics, >2 previous treatments, BCL2-positive bone marrow, and low Follicular Lymphoma International Prognostic Index (FLIPI) score were found to be associated with better DR and/or TTP. Hematologic toxicity was transient and reversible, with the exception of 3 patients with severe and prolonged neutropenia. Three patients presented with infections, 1 of whom died of bronchopneumonia. CONCLUSIONS: The FC+R scheme, a nonanthracycline-containing regimen lasting up to 10 weeks, was found to be relatively well-tolerated and demonstrated significant antilymphoma activity with excellent clinical CR and molecular response rates.
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.
2007
- Secondary malignancies after treatment of aggressive non-Hodgkin lymphoma: A GISL cohort study on 1259 patients
[Abstract in Rivista]
Sacchi, Stefano; Luigi, Marcheselli; Bari, Alessia; Marcheselli, Raffaella; Pozzi, Samantha; Giovanni, Quarta; Nicola Di, Renzo; Alberto, Fragasso; Francesco, Angrilli; Federico, Massimo
abstract
BACKGROUND Secondary malignancies have been associated with Non Hodgkin Lymphoma (NHL) treatment. Nevertheless few analyses have addressed this issue focusing on aggressive lymphoma. Aims of this study were to determine the incidence and the risk factors for developing secondary cancer during long term follow up of patients treated for aggressive lymphoma. METHODS For the purpose of this study we identified in the GISL database, 1259 naïve patients with histologically confirmed diagnosis of aggressive NHL. Observed cancer were classified by site. The incidence numbers of second neoplasia was compared to the incidence of malignancies in the Italian population. The standardized incidence ratio was calculated from the ratio between observed and expected number of cancers. Absolute excess risk was calculated by subtracting the expected from the observed cases and dividing by the person-years at risk. The Time Free 2nd Tumour (TF2T) was measured from the end of the first treatment to last follow-up or date of diagnosis. Cumulative incidences were estimated either with a Kaplan-Meier estimate or by Gooley’s method. Effects of potential risk factors on second cancer rates were examined in a Cox proportional-hazard model. RESULTS The cohort consisted of 1259 patients enrolled in GISL trials in the period 1988–2003, accounting for 6180 person-year at risk of second tumor. Median age at diagnosis was 58 years. All patients were treated with chemotherapy either alone or in combination with radiotherapy. During follow up, 44 patients (3.5%) developed a second cancer. Twelve out of 44 patients developed hematological malignancies and 32 solid tumors, including 7 lung cancer, 6 colorectal cancer, 4 prostate cancer and 15 other type of cancers. The median time for developing second tumors was 42 months. The risk of secondary malignancy overall was not increased. The analysis of risk by cohort of age at diagnosis of second cancer showed an excess of risk for the cohort age 20–39 and 40–59 years. Cumulative incidence of second malignancy, estimated by Kaplan Meier and by Gooley’s method at 5, 10 and 15 years was 3.2%, 6.9% and 13.8%, and 2.7%, 5.2% and 9.6%, respectively. By univariate analysis we observed a significant negative impact on TF2T for age at first treatment and only marginally significant for elevated LDH level. Further, we performed a Cox regression analysis with gender, age at 1st treatment and LDH >UNL that showed the prognostic ability of these variables in predicting the risk of second tumour. We divided the log(HR) predicted from multivariate analysis, at the 33° and the 66° percentiles to obtain a score system. We observed three groups with significant difference (p< .0001) in the risk of developing second cancers. CONCLUSIONS Our results showed that the risk of second malignancy overall was not increased in patients treated for aggressive lymphoma. Cancer risk was age-related, as demonstrated by the excess of risk observed in the cohort age 20–39 and 40–59 years. Further, utilizing age, male gender and LDH in a Cox regression analysis, we demonstrated the prognostic value of these variables and we produced a score system able to identify groups with different risk of developing
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
- Bortezomib and plasma cell leukemia
[Abstract in Rivista]
Pellegrino, Musto; Marialucia, Barone; Roberto, Guariglia; Giuseppe, Pietrantuono; Francesca, Gay; Fausto, Rossini; Tommasina, Guglielmelli; Vincenzo, Pitini; Felicetto, Ferrara; Monica, Galli; Antonietta, Falcone; Pozzi, Samantha; Fiorella, D’Auria; Sacchi, Stefano; Mario, Boccadoro; Antonio, Palumbo
abstract
Bortezomib (Velcade) is currently approved in USA and EU for the treatment of resistant/relapsed multiple mieloma (MM). Some reports have suggested that bortezomib is particularly effective for the treatment of extramedullary MM. However, there are very few data about the efficacy of this drug in plasma cell leukemia (PCL), a MM variant usually characterized by very poor prognosis. We retrospectively evaluated 9 patients with PCL diagnosed between October, 2002, and May, 2006, who had received bortezomib for the treatment of their disease (6 males, 3 females; median age 63 years, range 55–74). Six patients had primary and 3 secondary PCL. Eight patients had previously received 1 to 4 lines of chemotherapy, including autologous transplantation (5) and thalidomide (4). One patient was treated at diagnosis. Circulating plasma cells ranged from 2 to 71 x 10e9/L. Median WBC count was 23 x 10e9/L (range 8.1–113). Two patients had a moderate degree of renal failure, 3 had extramedullary disease (jaw, liver, soft tissues). Del 13 was observed in 4 out of 5 patients with available karyotype. Bortezomib was given using the standard schedule of 1.3 mg/sqm days 1, 4, 8, 11, with an interval of 10 days between cycles. Two patients received dexamethasone and thalidomide, 1 thalidomide alone and 3 doxorubicin and dexamethasone in combination with bortezomib. A median of 4 cycles was administered (range 2–6). Grade 3–4 hematological toxicity occurred in 7 patients, while neurological grade 3 toxicity was observed in a single patient. Infections (grade 3) occurred in 4 patients. Other toxicities (diarrhoea, nausea, skin rash) never reached grade 3. Three patients required red cell and/or platelet support. In 3 subjects a reduction of bortezomib dose was required due to hematological or neurological toxicity. Four partial remissions (reduction of M-component > 50%), 3 near-complete remissions (disappearance of M-component at electrophoresis, but positive immunofixation) and 2 complete remissions (negative immunofixation) were achieved (100% overall response), whose duration ranged from 2 to 14 months. In 4 patients autologous transplant procedures were started after response induced by bortezomib. Eight patients are currently alive 7–45 months after diagnosis of PCL. One patient, who had interrupted the treatment after 2 cycles due to herpes zoster, died of progressive disease 7 months later. Our data indicate that bortezomib is very effective in inducing significant responses in patients with primary or secondary PCL and that this drug should be considered for the initial treatment of this disease. Curiously, during the review work, we recorded 3 cases of PCL developed in MM patients under salvage therapies including bortezomib. This intriguing finding, which strongly contrasts with the very good results obtained in patients with previously established PCL, would warrant to be further investigated with "ad hoc" studies.
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
- 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
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
- Biological effects of Atra and Arsenic Trioxide on short term cultures of non-M3 leukemic blasts
[Articolo su rivista]
Cosenza, Maria; Civallero, Monica; Sacchi, Stefano; Marcheselli, Raffaella; Pozzi, Samantha
abstract
The efficacy of All-Trans Retinoic Acid (Atra) and Arsenic Trioxide (As2O3) in the treatment of Acute Promyelocytic Leukemia (APL) is well known. Further, these drugs inhibit cell growth and induce apoptosis in several cell lines, but few data are reported on leukemic blasts. The aim of this study was to evaluate the biological effects on non-M3 Acute Myeloid Leukemia (AML) cells. Blasts of six patients, after exposition to Atra and As2O3 were tested for growth inhibition, induction of apoptosis and change in cell cycle distribution, evaluating cell viability, percentage of apoptotic cells and of blasts positive for Ki-67 and BrdU. In the present study we demonstrated that either Atra or As2O3 inhibit leukemic cells proliferation by induction of apoptosis. The effects are time and dose dependent. We did not observe additive or synergistic effects with the combination of the drugs. Further, our results showed that Atra and As2O3 have effects on cell cycle distribution reducing S-phase and proliferating cells. These results should be taken in to account preparing future laboratory and clinical experimental protocols that associate these drugs with antineoplastic agents with different cell cycle specificity.
2004
- AUTOLOGOUS STEM CELL TRANSPLANTATION FOR NEWLY DIAGNOSED FOLLICULAR LYMPHOMAS: LOW TOXICITY AND EXTENDED PROGRESSION FREE SURVIVAL. R1235 Barcelona, Spain. Bone Marrow Transplantation March 2004, Volume 33, Supplement 1
[Abstract in Rivista]
Narni, Franco; A., Donelli; A., Cuoghi; P., Bresciani; Pozzi, Samantha; Marasca, Roberto; G., Leonardi; M., Morselli; Luppi, Mario; G., Longo; Torelli, Giuseppe
abstract
In spite of an indolent course, advanced stage follicularlymphomas (FL) are incurable with conventional chemotherapy.High dose therapy could be investigated in selected patients,provided toxicity were acceptable. Improvements in supporttherapy and the widespread use of peripheral blood stem cells(SC) have made autologous transplantation a relatively safeprocedure. This prompted us to start a pilot study and, since1995, 23 patients have been enrolled at our center. Median agewas 49 (26 - 65). Most patients (80%) had stage IV disease andbone marrow involvement. For patients who achieved a completeresponse or a good partial response after CHOP, SC weremobilized with cyclophosphamide or DHAP plus G-CSF, andhigh dose therapy consisted of BEAM. High risk patients or poorresponders (residual high tumor burden or bone marrowinfiltration >50%) switched to a program of high dose sequentialtherapy. Nine patients received not-manipulated hematopoieticSC, 7 received ''ex vivo'' purged SC (6 by CD34+ positiveselection; 1 by positive+negative selection), and 8 patientsunderwent ''in vivo'' purging with anti-CD20 monoclonal antibody(rituximab). Residual disease was monitored at different steps bynested PCR. Treatment was well tolerated, with a median time toengrafment of 9 days (7-12), and a median stay in hospital of 22days (15-35). RBC and platelet transfusions were necessary,respectively, in 52% and 100% of the patients. The meannumber of RBC and platelet units given to transfused patientswas, respectively, 2.2 (1-5) and 3.7 (1-7). Fever occurred in 52%of the patients (mean 2,8 days in febrile patients) and mucositisin 85%. We did not observe, so far, any case of myelodysplasiaor secondary cancer. With a median FU of 58 (8-95) monthsfrom transplant, all patients are alive, 5 have relapsed, and 5-years estimated PFS is 70%. CD34+ selection had no impact onrelapse. In one patient, molecular response could be restoredand maintained by rituximab alone. Only a few data have beenpublished regarding autologous transplantation in FL patients atdiagnosis. Although the FU is relatively short and the number ofpatients still small, the present data suggest that autologoustransplant is a safe and effective therapy for selected, not heavilypretreated young patients with advanced stage disease.Especially since ''in vivo'' purging strategies can easily be carriedout, autologous SC transplantation should be investigated inrandomized trials.
2004
- Autologous stem cell transplantation for newly diagnosed follicular lymphomas: low toxicity and extended progression free survival
[Articolo su rivista]
Narni, Franco; Donelli, A; Cuoghi, A; Bresciani, P; Pozzi, S; Marasca, Roberto; Leonardi, G; Morselli, M; Luppi, Mario; Longo, G; Torelli, Giuseppe
abstract
2003
- A simple and safe nomogram for the management of oral anticoagulation prior to minor surgery
[Articolo su rivista]
Marietta, M.; Bertesi, M.; Simoni, L.; Pozzi, S.; Castelli, I.; Cappi, C.; Torelli, G.
abstract
In 80 consecutive, anticoagulated patients scheduled for minor surgery, we reduced warfarin daily dosage by 50% on days 4, 3 and 2 before the surgery, restoring the original dose the day immediately before surgery. The evening after surgery, patients took a double warfarin dose, and then the usual maintenance dose was reintroduced. The mean International Normalized Ratio (INR) value assessed 1 week before surgery was 2.63 (range 1.88-3.87); it decreased at the moment of performing surgery to 1.68 (range 1.42-2.20; P < 0.05 with respect to the preoperative value), and returned to 2.43 7 days after (range 1.96-3.51, P = ns with respect to the preoperative value). No significant difference was found comparing prothrombin fragment 1.2 (F1.2) levels 1 week before surgery and on the morning of surgery (0.49 ng/ml vs 0.67 ng/ml, P = ns), suggesting that no activation of blood coagulation had taken place following the reduction of anticoagulant therapy. Patients developed neither major nor minor bleeding, nor thromboembolism during the procedures or up to I month after surgery. In our experience, this method for the management of anticoagulation before minor surgery has been shown to be safe and useful, avoiding the cumbersome shift to either intravenous or subcutaneous heparin.
2003
- Acquired haemophilia in HIV negative, HHV-8 positive multicentric Castleman's disease: a case report
[Articolo su rivista]
M., Marietta; Pozzi, Samantha; Luppi, Mario; M., Bertesi; C., Cappi; M., Morselli; Torelli, Giuseppe
abstract
Multicentric Castleman's Disease (MCD) is an atypical lymphoproliferative disorder, related to human herpesvirus 8 (HHV-8) infection and often associated with autoimmune diseases such as haemolytic anaemia and thrombocytopenia. Acquired haemophilia (AH) is a rare, life-threatening disease, which can occur in association with lymphoproliferative disorders, although only one case of AH in MCD has been described so far. We report the case of a human immuno deficiency virus negative 71-yr-old woman referred to our hospital for prolonged bleeding on surgical site following a lymph node biopsy. Lymph node histology revealed MCD, while the screening for the bleeding disorder showed prolonged activated partial thromboplastin time (APTT) (ratio: 1.89, normal value <1.24), low factor VIII (FVIII:C) levels (6%) with anti-factor VIII antibodies (2.3 Bethesda units), leading to a diagnosis of AH. Virological studies on plasma, lymphocyte and bronchoalveolar wash showed positivity for HHV-8 infection. Treatment with steroids (metilprednisolone 1-1.5 mg/kg/d) and cyclophosphamide (100 mg/d orally) was unsuccessful, and then antiviral therapy with cidofovir (5 mg/kg/wk) was started. A transient normalisation of APTT was seen after two administrations of cidofovir, but then coagulation parameters worsened and a large haematoma of the arm appeared. Bleeding was successfully stopped with two boluses of recombinant activated factor VII (Novoseven 90 microg/kg). Therapy with anti-CD 20 monoclonal antibody rituximab (Mabthera 375 mg/m2 once a week for 4 wk) was started, and following two administrations APTT normalised once again. Cardiological and neurological complications arose before the third dose of rituximab and the patient died shortly afterwards.
2002
- Low-molecular-weight heparin for vertebral artery dissection
[Articolo su rivista]
Marietta, M; Bertesi, M; Rozzi, N; Cano, Mc; Vallone, S; Cappi, C; Pozzi, S; Torelli, Giuseppe; Giuseppe,
abstract
A case of vertebral artery dissection and consequent basilar artery thrombosis in a 6-year-old patient is reported. The patient was treated with subcutaneous low-molecular-weight heparin at therapeutic doses (enoxaparin, 100 IU/kg twice daily) for 3 weeks, then reduced to 2,000 IU/day for 3 more weeks. After this time a magnetic resonance angiogram was obtained that showed complete recanalization of the left basilar artery. Enoxaparin proved to be a safe and useful therapy for thrombosis accompanying vertebral artery dissection.
1999
- Primary cardiac lymphoma: A case report and review
[Articolo su rivista]
Pozzi, Samantha
abstract
Primary cardiac lymphoma is classically defined as an extranodal non-Hodgkin's lymphoma exclusively located in the heart and/or pericardium. However, over the last few years, this definition has been extended to include other localizations on condition that these are clearly less important then a cardiac site, that must remain the first,during the illness course,and the most important for its entity. PCL is extremely rare in immunocompetent patients, accounting for 1.3% of all cardiac tumours and 0.5% of all extranodal lymphomas, but it has been encountered with increasing frequency in patients with AIDS or other severe immunodepressive syndromes. PCL is difficult to diagnose, especially during the early stage of the disease, because of its non-specific clinical manifestations, the limited possibility of using non-invasive diagnostic techniques, and difficulties or delays in applying invasive methods. The malignancy of its histotypes and its delicate location are responsible for its rapid and frequently unfavourable evolution. Successful treatment, which is mainly based on anthracycline-containing polychemotherapies, is heavily dependent on an early diagnosis. After a general review of the literature, the authors describe the clinical case of a patient with a PCL that had a secondary central nervous system location, treated with polychemotherapy and autologous peripheral blood stem cell transplantation. Emphasis is placed on the fact that it is more difficult to eradicate the disease from the central nervous system than from the heart.