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Leonardo POTENZA

Professore Associato
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto

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Pubblicazioni

- "Metodo per la diagnosi e/o il monitoraggio della mucormicosi" - "Method for the diagnosis of and/or monitoring mucormycosis" [Brevetto]
Luppi, Mario; Potenza, Leonardo; Barozzi, Patrizia; Vallerini, Daniela; Forghieri, Fabio
abstract

A method is described for the diagnosis and/or monitoring of active or previous infection by Mucor which consists in the identification of Mucorales-specific T cells in samples from biological fluids taken from the patient and put into contact with a Mucor antigen. These specific immune responses can be detected by the execution of immunoenzymatic assays (ELISPOT, Quantiferon) or of immunocytofluorimetric assays [Cytokine Secretion Assay (CSA), Intracellular Cytokine Staining (ICS)] in vitro. In greater detail, the method in question provides for checking for the presence of specific IFN-γ producing T cells, of specific IL-10 producing T cells and/or specific IL- 4 producing T cells.

- Metodo per la diagnosi e/o il monitoraggio dell’ aspergillosi invasiva [Brevetto]
Torelli, Giuseppe; Luppi, Mario; Barozzi, Patrizia; Potenza, Leonardo
abstract

La presente invenzione si riferisce ad un metodo per la diagnosi e/o ilmonitoraggio dell’infezione attiva o pregressa da Aspergillus fumigatus checomprende l’esecuzione di un saggio immunoenzimatico in vitro (ELISPOT) incui il campione da fluidi biologici prelevato dal paziente è messo in contatto conun antigene di Aspergillus fumigatus.

2023 - COVID-19 omicron variant outbreak in a hematopoietic stem cell transplant unit [Articolo su rivista]
Gilioli, A.; Bresciani, P.; Franceschini, E.; Messerotti, A.; Pioli, V.; Colasante, C.; Bettelli, F.; Giusti, D.; Forghieri, F.; Morselli, M.; Colaci, E.; Potenza, L.; Gennari, W.; Pecorari, M.; Marasca, R.; Candoni, A.; Mussini, C.; Trenti, T.; Comoli, P.; Luppi, M.; Cuoghi, A.
abstract

Recommendations and guidelines for management of SARS-COV-2 infection in hematologic patients were developed in the very difficult context of dealing with novel viral variants from one pandemic wave to another, with different susceptibility to available drugs and vaccines. Moreover, the largest SARS-COV-2 case series in patients treated for hematologic malignancies, including stem cell transplant recipients, was published before the Omicron surge, and refers mainly to Alpha and Delta viral variants. These infections had very high mortality, in a period when antivirals and monoclonal antibodies were mostly unavailable. Here, we report for the first time a SARS-COV-2 Omicron variant outbreak inside a Bone Marrow Transplant (BMT) Unit, describing the characteristics, clinical course, and infection outcomes shortly before and shortly after myeloablative transplantation. We detail how infections were treated off-label and managed inside the BMT ward, to guarantee the best possible outcomes while avoiding risks for non-infected inpatients. The positive outcomes observed suggest that it may not be absolutely necessary to obtain SARS-CoV-2 PCR negativity before BMT in hematologic patients after treated infection, in cases with long-term PCR positivity and high-risk hematologic disease.

2023 - Characteristics and clinical behavior of acute myeloid leukemia harboring rare non-A/B/D nucleophosmin (NPM1) gene mutation subtypes: a single-center experience and review of the literature [Articolo su rivista]
Mutti, M.; Cordella, S.; Parisotto, A.; Bettelli, F.; Morselli, M.; Cuoghi, A.; Bresciani, P.; Messerotti, A.; Gilioli, A.; Pioli, V.; Giusti, D.; Colaci, E.; Cassanelli, L.; Paolini, A.; Martinelli, S.; Maffei, R.; Riva, G.; Nasillo, V.; Sarti, M.; Trenti, T.; Comoli, P.; Tagliafico, E.; Manfredini, R.; Eccher, A.; Lagreca, I.; Barozzi, P.; Potenza, L.; Marasca, R.; Candoni, A.; Luppi, M.; Forghieri, F.
abstract

2023 - Chromosome 9p Duplication Promotes T-Cell Exhaustion and Enhances Stem Cell Clonogenic Potential in JAK2-Mutant Myeloproliferative Neoplasms [Abstract in Rivista]
Norfo, Ruggiero; Carretta, Chiara; Parenti, Sandra; Badii, Filippo; Bertesi, Matteo; Rontauroli, Sebastiano; Tavernari, Lara; Genovese, Elena; Sperduti, Samantha; Enzo, Elena; Mirabile, Margherita; Pedrazzi, Francesca; Pessina, Chiara; Colugnat, Ilaria; Mora, Barbara; Maccaferri, Monica; Tenedini, Elena; Martinelli, Silvia; Bianchi, Elisa; Casarini, Livio; Potenza, Leonardo; Luppi, Mario; Tagliafico, Enrico; Guglielmelli, Paola; Simoni, Manuela; Passamonti, Francesco; Vannucchi, Alessandro Maria; Manfredini, Rossella
abstract

2023 - Early palliative care for solid and blood cancer patients and caregivers: Quantitative and qualitative results of a long-term experience as a case of value-based medicine [Articolo su rivista]
Bigi, Sarah; Borelli, Eleonora; Potenza, Leonardo; Gilioli, Fabio; Artioli, Fabrizio; Porzio, Giampiero; Luppi, Mario; Bandieri, Elena
abstract

Introduction: Cancer patients and their caregivers have substantial unmet needs, that negatively impact the clinical outcome and quality of life. However, interventions aimed to address such needs are still suboptimal, failing to answer the recent healthcare call for the adoption of value-based models of care. In the case of incurable oncologic and hematologic cancers, a value-based model of care should plan advanced care on patients' needs and include the quality of death as an outcome. The integration of early palliative care into standard oncologic care for patients with advanced cancers represents a recent innovative model of assistance whose benefits for patients and caregivers are now widely recognized. The key elements underlying the reasons behind these benefits are the multidisciplinary collaboration (teamwork), an honest and empathetic communication between the early palliative care team, the patient, and the caregiver (rapport building), and the ability to detect changes in the physical/psychosocial wellbeing of the patient, along the whole disease trajectory (constant monitoring). Methods: This community case study documents the quantitative and qualitative results of a long term clinical and research experience in delivering early palliative care service to address both solid and blood cancer patients' and their primary caregivers' needs. Results: Data showed decreased use of chemotherapy, blood transfusions and referral to intensive care units near the end of life; increased life expectancy; improved symptom burden and mood; increased frequency of goals-of-care and advanced care planning conversations. Hope perception among bereaved caregivers was associated with resilience and realistic expectations raising from honest communication with the early palliative care team and appreciation toward the model. Patients and caregivers perceived the possibility of a good death as realistic and not as an unlikely event as it was for patients and caregivers on standard oncologic care only. Gratitude expressions toward the model and the team were frequently identified in their reports and positively associated with communication and spirituality. Conclusions: These findings are discussed in the context of an updated literature review regarding value-based care and suggest that early palliative care integrated into standard oncology care may be considered as an effective model of value-based care.

2023 - Early palliative care versus usual haematological care in multiple myeloma: retrospective cohort study [Articolo su rivista]
Giusti, D.; Colaci, E.; Pioli, V.; Banchelli, F.; Maccaferri, M.; Leonardi, G.; Marasca, R.; Morselli, M.; Forghieri, F.; Bettelli, F.; Cuoghi, A.; Bresciani, P.; Messerotti, A.; Gilioli, A.; Candoni, A.; Cassanelli, L.; Sbadili, E.; Bassoli, I.; Longo, G.; Gilioli, F.; Borelli, E.; Bigi, S.; D'Amico, R.; Porro, C. A.; Odejide, O.; Zimmermann, C.; Efficace, F.; Bruera, E.; Luppi, M.; Bandieri, E.; Potenza, L.
abstract

Objectives Although early palliative care (EPC) is beneficial in acute myeloid leukaemia, little is known about EPC value in multiple myeloma (MM). We compared quality indicators for palliative and end of life (EOL) care in patients with MM receiving EPC with those of patients who received usual haematological care (UHC).Methods This observational, retrospective study was based on 290 consecutive patients with MM. The following indicators were abstracted: providing psychological support, assessing/managing pain, discussing goals of care, promoting advance care plan, accessing home care services; no anti MM treatment within 14 and 30 days and hospice length of stay >7 days before death; no cardiopulmonary resuscitation, no intubation, <2 hospitalisations and emergency department visits within 30 days before death. Comparisons were performed using unadjusted and confounder adjusted regression models.Results 55 patients received EPC and 231 UHC. Compared with UHC patients, EPC patients had a significantly higher number of quality indicators of care (mean 2.62 +/- 1.25 vs 1.12 +/- 0.95; p<0.0001)); a significant reduction of pain intensity over time (p<0.01) and a trend towards reduced aggressiveness at EOL, with the same survival (5.3 vs 5.46 years; p=0.74)).Conclusions Our data support the value of integrating EPC into MM routine practice and lay the groundwork for future prospective comparative studies.

2023 - Effects of the BTN162b2 mRNA COVID-19 vaccine in humoral and cellular immunity in patients with chronic lymphocytic leukemia [Articolo su rivista]
Fiorcari, S.; Atene, C. G.; Maffei, R.; Mesini, N.; Debbia, G.; Colasante, C.; Pozzi, S.; Barbieri, E.; Maccaferri, M.; Leonardi, G.; Potenza, L.; Luppi, M.; Marasca, R.
abstract

Chronic lymphocytic leukemia (CLL), the most common leukemia in the western countries, is characterized by immunosuppression due to disease itself and cytotoxic treatments. Since the beginning of COVID-19 pandemic, patients with CLL appear to be a vulnerable population. In addition, phase III mRNA vaccine trials did not provide information about the efficacy in immunocomprised population. In CLL, the antibody-mediated response to SARS-CoV-2 vaccine is impaired. The goal of this study was to evaluate the effects of SARS-CoV-2 vaccination on humoral immune response and on cellular immunity in CLL patients. Humoral immune response to BNT162b2 messenger RNA COVID-19 vaccine was evaluated in 44 CLL patients comprising 20 treatment-naïve, 14 under treatment with ibrutinib and 10 in follow-up after completion of therapy. A positive serological response to SARS-CoV-2 vaccination with IgG titers higher than 13 UA/ml was detected in 54.6% of CLL patients with a higher response in patients who obtained remission after treatment. Reduced antibody response was detected in patients under ibrutinib treatment. T-cell response to overlapping pool of peptides representing the spike region was assessed in paired CLL samples collected before and after 1 month from the second dose of COVID-19 vaccine in treatment-naïve and ibrutinib-treated CLL patients using cytokine secretion assay. Both CD3+ CD4+ and CD3+ CD8+ T cells are able to mount a cellular response to spike peptides with secretion of IFNγ and TNFα before and after vaccination in both treatment naïve and ibrutinib-treated patients and this cellular immune response is independent by COVID-19 vaccination. Collectively, T cell response to spike peptides appeared more blunted in CLL patients under treatment with ibrutinib compared to untreated ones. Our study supports the need for optimization of vaccination strategy to achieve an adequate immune response keeping strict preventive measures by CLL patients against COVID-19.

2023 - Inhibition of ERK1/2 signaling prevents bone marrow fibrosis by reducing osteopontin plasma levels in a myelofibrosis mouse model [Articolo su rivista]
Bianchi, Elisa; Rontauroli, Sebastiano; Tavernari, Lara; Mirabile, Margherita; Pedrazzi, Francesca; Genovese, Elena; Sartini, Stefano; Dall'Ora, Massimiliano; Grisendi, Giulia; Fabbiani, Luca; Maccaferri, Monica; Carretta, Chiara; Parenti, Sandra; Fantini, Sebastian; Bartalucci, Niccolò; Calabresi, Laura; Balliu, Manjola; Guglielmelli, Paola; Potenza, Leonardo; Tagliafico, Enrico; Losi, Lorena; Dominici, Massimo; Luppi, Mario; Vannucchi, Alessandro Maria; Manfredini, Rossella
abstract

Clonal myeloproliferation and development of bone marrow (BM) fibrosis are the major pathogenetic events in myelofibrosis (MF). The identification of novel antifibrotic strategies is of utmost importance since the effectiveness of current therapies in reverting BM fibrosis is debated. We previously demonstrated that osteopontin (OPN) has a profibrotic role in MF by promoting mesenchymal stromal cells proliferation and collagen production. Moreover, increased plasma OPN correlated with higher BM fibrosis grade and inferior overall survival in MF patients. To understand whether OPN is a druggable target in MF, we assessed putative inhibitors of OPN expression in vitro and identified ERK1/2 as a major regulator of OPN production. Increased OPN plasma levels were associated with BM fibrosis development in the Romiplostim-induced MF mouse model. Moreover, ERK1/2 inhibition led to a remarkable reduction of OPN production and BM fibrosis in Romiplostim-treated mice. Strikingly, the antifibrotic effect of ERK1/2 inhibition can be mainly ascribed to the reduced OPN production since it could be recapitulated through the administration of anti-OPN neutralizing antibody. Our results demonstrate that OPN is a novel druggable target in MF and pave the way to antifibrotic therapies based on the inhibition of ERK1/2-driven OPN production or the neutralization of OPN activity.

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.

2023 - Perceptions of Death Among Patients with Advanced Cancer Receiving Early Palliative Care and Their Caregivers: Results from a Mixed-Method Analysis [Articolo su rivista]
Bigi, S.; Ganfi, V.; Borelli, E.; Potenza, L.; Artioli, F.; Eliardo, S.; Mucciarini, C.; Cottafavi, L.; Ferrari, U.; Lombardo, L.; Cagossi, K.; Pietramaggiori, A.; Fantuzzi, V.; Bernardini, I.; Cruciani, M.; Cacciari, C.; Odejide, O.; Adolfo Porro, C.; Zimmermann, C.; Efficace, F.; Bruera, E.; Luppi, M.; Bandieri, E.
abstract

BACKGROUND: Oncologists are often concerned that talking about death with patients may hinder their relationship. However, the views of death held by patients have not been thoroughly investigated. This study aimed to describe the perception of death among patients with advanced cancer receiving early palliative care (EPC) and their caregivers. MATERIAL AND METHODS: Qualitative and quantitative analyses were performed on 2 databases: (a) transcripts of open-ended questionnaires administered to 130 cancer patients receiving EPC with a mean age of 68.4 years and to 115 primary caregivers of patients on EPC with a mean age of 56.8; (b) texts collected from an Italian forum, containing instances of web-mediated interactions between patients and their caregivers. RESULTS: Quantitative analysis shows that: (a) patients and caregivers are not afraid of speaking about death; (b) patients and caregivers on EPC use the word "death" significantly more than patients on standard oncology care (SOC) and their caregivers (P < .0001). For both participants on EPC and SOC, the adjectives and verbs associated with the word "death" have positive connotations; however, these associations are significantly more frequent for participants on EPC (verbs, Ps < .0001; adjectives, Ps < .003). Qualitative analysis reveals that these positive connotations refer to an actual, positive experience of the end of life in the EPC group and a wish or a negated event in the SOC group. CONCLUSIONS: EPC interventions, along with proper physician-patient communication, may be associated with an increased acceptance of death in patients with advanced cancer and their caregivers.

2023 - Prognostic Relevance of Multi-Antigenic Myeloma-Specific T-Cell Assay in Patients with Monoclonal Gammopathies [Articolo su rivista]
Lagreca, Ivana; Nasillo, Vincenzo; Barozzi, Patrizia; Castelli, Ilaria; Basso, Sabrina; Castellano, Sara; Paolini, Ambra; Maccaferri, Monica; Colaci, Elisabetta; Vallerini, Daniela; Natali, Patrizia; Debbia, Daria; Pirotti, Tommaso; Ottomano, Anna Maria; Maffei, Rossana; Bettelli, Francesca; Giusti, Davide; Messerotti, Andrea; Gilioli, Andrea; Pioli, Valeria; Leonardi, Giovanna; Forghieri, Fabio; Bresciani, Paola; Cuoghi, Angela; Morselli, Monica; Manfredini, Rossella; Longo, Giuseppe; Candoni, Anna; Marasca, Roberto; Potenza, Leonardo; Tagliafico, Enrico; Trenti, Tommaso; Comoli, Patrizia; Luppi, Mario; Riva, Giovanni
abstract

: Multiple Myeloma (MM) typically originates from underlying precursor conditions, known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). Validated risk factors, related to the main features of the clonal plasma cells, are employed in the current prognostic models to assess long-term probabilities of progression to MM. In addition, new prognostic immunologic parameters, measuring protective MM-specific T-cell responses, could help to identify patients with shorter time-to-progression. In this report, we described a novel Multi-antigenic Myeloma-specific (MaMs) T-cell assay, based on ELISpot technology, providing simultaneous evaluation of T-cell responses towards ten different MM-associated antigens. When performed during long-term follow-up (mean 28 months) of 33 patients with either MGUS or SMM, such deca-antigenic myeloma-specific immunoassay allowed to significantly distinguish between stable vs. progressive disease (p < 0.001), independently from the Mayo Clinic risk category. Here, we report the first clinical experience showing that a wide (multi-antigen), standardized (irrespective to patients' HLA), MM-specific T-cell assay may routinely be applied, as a promising prognostic tool, during the follow-up of MGUS/SMM patients. Larger studies are needed to improve the antigenic panel and further explore the prognostic value of MaMs test in the risk assessment of patients with monoclonal gammopathies.

2023 - Role of Notch2 pathway in mature B cell malignancies [Articolo su rivista]
Mesini, N.; Fiorcari, S.; Atene, C. G.; Maffei, R.; Potenza, L.; Luppi, M.; Marasca, R.
abstract

In recent decades, the Notch pathway has been characterized as a key regulatory signaling of cell-fate decisions evolutionarily conserved in many organisms and different tissues during lifespan. At the same time, many studies suggest a link between alterations of this signaling and tumor genesis or progression. In lymphopoiesis, the Notch pathway plays a fundamental role in the correct differentiation of T and B cells, but its deregulated activity leads to leukemic onset and evolution. Notch and its ligands Delta/Jagged exhibit a pivotal role in the crosstalk between leukemic cells and their environment. This review is focused in particular on Notch2 receptor activity. Members of Notch2 pathway have been reported to be mutated in Chronic Lymphocytic Leukemia (CLL), Splenic Marginal Zone Lymphoma (SMZL) and Nodal Marginal Zone Lymphoma (NMZL). CLL is a B cell malignancy in which leukemic clones establish supportive crosstalk with non-malignant cells of the tumor microenvironment to grow, survive, and resist even the new generation of drugs. SMZL and NMZL are indolent B cell neoplasms distinguished by a distinct pattern of dissemination. In SMZL leukemic cells affect mainly the spleen, bone marrow, and peripheral blood, while NMZL has a leading nodal distribution. Since Notch2 is involved in the commitment of leukemic cells to the marginal zone as a major regulator of B cell physiological differentiation, it is predominantly affected by the molecular lesions found in both SMZL and NMZL. In light of these findings, a better understanding of the Notch receptor family pathogenic role, in particular Notch2, is desirable because it is still incomplete, not only in the physiological development of B lymphocytes but also in leukemia progression and resistance. Several therapeutic strategies capable of interfering with Notch signaling, such as monoclonal antibodies, enzyme or complex inhibitors, are being analyzed. To avoid the unwanted multiple “on target” toxicity encountered during the systemic inhibition of Notch signaling, the study of an appropriate pharmaceutical formulation is a pressing need. This is why, to date, there are still no Notch-targeted therapies approved. An accurate analysis of the Notch pathway could be useful to drive the discovery of new therapeutic targets and the development of more effective therapies.

2023 - Stigma of Palliative Care among Patients with Advanced Cancer and Their Caregivers on Early Palliative Care [Articolo su rivista]
Bandieri, Elena; Borelli, Eleonora; Gilioli, Fabio; Bigi, Sarah; Mucciarini, Claudia; Ferrari, Umberto; Eliardo, Sonia; Pinto, Lidia; Porro, Carlo Adolfo; Efficace, Fabio; Luppi, Mario; Potenza, Leonardo
abstract

: The early referral to palliative care (PC) represents a successful value-based model with proven benefits regarding the quality of life and clinical outcomes for advanced cancer patients and their caregivers. Yet, its provision remains typically confined to the last weeks of life as per the historical, late PC model. The stigma according to which PC represents end-of-life care has been identified as the root of the problem. To explore the presence and effects of the stigma in a clinical context, we surveyed 78 patients and 110 caregivers (mean age: 71.7 and 60.7, respectively) on early PC to study what their perception of PC was before their direct experience. The responses were analyzed through a qualitative descriptive approach. The participants explicitly mentioned a lack of knowledge about PC (53% of the sample), which they identified also among physicians and the population (13%); an identification of PC with the late PC model (53%); and a detrimental reaction to the proposal of an early PC referral (83%). However, the participants explicitly mentioned that a direct experience of early PC allowed for an acquired awareness of early PC meaning and benefits (52%), as well as a comprehension of its differences with late PC (34%); the regret for the delayed referral (8%); the perception of the word "palliative" as a barrier (21%); and the belief that early PC should be part of the cancer routine practice (25%). A comprehensive multi-level intervention is necessary for a widespread understanding of the essence of anticipated PC.

2022 - Adverse outcome associated with daratumumab-based treatments in relapsed/refractory multiple myeloma patients with amplification of chromosome arm 1q21: a single-center retrospective experience [Articolo su rivista]
Barbieri, Emiliano; Maccaferri, Monica; Leonardi, Giovanna; Giacobbi, Francesca; Corradini, Giorgia; Lagreca, Ivana; Barozzi, Patrizia; Potenza, Leonardo; Marasca, Roberto; Luppi, Mario
abstract

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 - BTK Inhibitors Impair Platelet-Mediated Antifungal Activity [Articolo su rivista]
Nasillo, V.; Lagreca, I.; Vallerini, D.; Barozzi, P.; Riva, G.; Maccaferri, M.; Paolini, A.; Forghieri, F.; Fiorcari, S.; Maffei, R.; Martinelli, S.; Atene, C. G.; Castelli, I.; Marasca, R.; Potenza, L.; Comoli, P.; Manfredini, R.; Tagliafico, E.; Trenti, T.; Luppi, M.
abstract

In recent years, the introduction of new drugs targeting Bruton’s tyrosine kinase (BTK) has allowed dramatic improvement in the prognosis of patients with chronic lymphocytic leukemia (CLL) and other B-cell neoplasms. Although these small molecules were initially considered less immunosuppressive than chemoimmunotherapy, an increasing number of reports have described the occurrence of unexpected opportunistic fungal infections, in particular invasive aspergillosis (IA). BTK represents a crucial molecule in several signaling pathways depending on different immune receptors. Based on a variety of specific off-target effects on innate immunity, namely on neutrophils, monocytes, pulmonary macrophages, and nurse-like cells, ibrutinib has been proposed as a new host factor for the definition of probable invasive pulmonary mold disease. The role of platelets in the control of fungal growth, through granule-dependent mechanisms, was described in vitro almost two decades ago and is, so far, neglected by experts in the field of clinical management of IA. In the present study, we confirm the antifungal role of platelets, and we show, for the first time, that the exposure to BTK inhibitors impairs several immune functions of platelets in response to Aspergillus fumigatus, i.e., the ability to adhere to conidia, activation (as indicated by reduced expression of P-selectin), and direct killing activity. In conclusion, our experimental data suggest that antiplatelet effects of BTK inhibitors may contribute to an increased risk for IA in CLL patients.

2022 - Early Palliative Care in Acute Myeloid Leukemia [Articolo su rivista]
Potenza, L.; Borelli, E.; Bigi, S.; Giusti, D.; Longo, G.; Odejide, O.; Porro, C. A.; Zimmermann, C.; Efficace, F.; Bruera, E.; Luppi, M.; Bandieri, E.
abstract

Background: Several novel targeted therapies seem to improve the outcome of acute myeloid leukemia (AML) patients. Nonetheless, the 5-year survival rate remains below 40%, and the trajectory of the disease remains physically and emotionally challenging, with little time to make relevant decisions. For patients with advanced solid tumors, the integration of early palliative care (EPC) with standard oncologic care a few weeks after diagnosis has demonstrated several benefits. However, this model is underutilized in patients with hematologic malignancies. Methods: In this article, we analyze the palliative care (PC) needs of AML patients, examine the operational aspects of an integrated model, and review the evidence in favor of EPC integration in the AML course. Results: AML patients have a high burden of physical and psychological symptoms and high use of avoidant coping strategies. Emerging studies, including a phase III randomized controlled trial, have reported that EPC is feasible for inpatients and outpatients, improves quality of life (QoL), promotes adaptive coping, reduces psychological symptoms, and enhances the quality of end-of-life care. Conclusions: EPC should become the new standard of care for AML patients. However, this raises issues about the urgent development of adequate programs of education to increase timely access to PC.

2022 - Edmonton symptom assessment system Global Distress Score and overall survival in acute leukaemia [Articolo su rivista]
Morselli, M.; Banchelli, F.; Borelli, E.; Cordella, S.; Forghieri, F.; Bettelli, F.; Bigi, S.; Longo, G.; D'Amico, R.; Porro, C. A.; Efficace, F.; Bruera, E.; Luppi, M.; Bandieri, E.; Potenza, L.
abstract

2022 - Edmonton symptom assessment system global distress score and overall survival among patients with advanced cancer receiving early palliative care [Articolo su rivista]
Bandieri, E.; Banchelli, F.; Borelli, E.; D'Amico, R.; Efficace, F.; Bruera, E.; Luppi, M.; Potenza, L.
abstract

2022 - Gratitude among advanced cancer patients and their caregivers: The role of early palliative care [Articolo su rivista]
Borelli, E.; Bigi, S.; Potenza, L.; Gilioli, F.; Artioli, F.; Porzio, G.; Porro, C. A.; Efficace, F.; Bruera, E.; Luppi, M.; Bandieri, E.
abstract

Objective: A cancer diagnosis represents a unique trauma, given its life-threatening, multidimensional, and uncertain nature. Gratitude is a construct representing the emotional state that arises when individuals recognize that a benefit has been received as a result of someone else’s action or a spiritual entity’s intervention. Based on the positive psychological wellbeing, gratitude has been associated with improved health outcomes even in the disease setting. Thus, the models of care that foster gratitude should be adopted in the clinical context. This study aims to explore whether and how gratitude may originate in patients with advanced cancer and their caregivers undergoing early palliative care (EPC). Methods: We analyzed 251 reports from 133 patients and 118 caregivers describing their clinical experience in two EPC units. The sources of gratitude were identified and ranked based on their frequencies. Words expressing gratitude and words referring to communication and spirituality were collected by means of the Linguistic Inquiry and Word Count software and correlated. Results: In total, 123 (92.5%) of 133 patients’ and 97 (82.2%) of 118 caregivers’ reports, respectively, included explicit or implicit expressions of gratitude. Gratitude was associated specifically with successful physical symptom management, emotional support, improved attitude toward death, better information, humanity, and the familiar environment. The use of words of gratitude in patients’ reports was positively correlated with the use of words referring to communication (r =.215, p =.026) and spirituality (r =.612, p <.001). Conclusion: Our results suggest that interventions within the EPC model based on doctor–patient–caregiver communication may allow patients and caregivers to experience a feeling of gratitude, and this may represent a resource to be exploited to improve their physical and psychosocial wellbeing.

2022 - Indoleamine 2, 3-Dioxygenase 1 Mediates Survival Signals in Chronic Lymphocytic Leukemia via Kynurenine/Aryl Hydrocarbon Receptor-Mediated MCL1 Modulation [Articolo su rivista]
Atene, C. G.; Fiorcari, S.; Mesini, N.; Alboni, S.; Martinelli, S.; Maccaferri, M.; Leonardi, G.; Potenza, L.; Luppi, M.; Maffei, R.; Marasca, R.
abstract

The indoleamine 2,3-dioxygenase 1 (IDO1) metabolic circuitry, comprising the first tryptophan (Trp) catabolite L-kynurenine (Kyn) and the aryl hydrocarbon receptor (AHR), has emerged as a mechanism of cancer immune evasion. Here, we investigated the functional role of the IDO1/Kyn/AHR axis in chronic lymphocytic leukemia (CLL). Our data show that CLL cells expressed an active form of the IDO1 enzyme and microenvironmental stimuli can positively modulate its expression. Interferon (IFN)-γ induces IDO1 expression through the Jak/STAT1 pathway and mediates Kyn production concomitantly with Trp consumption in CLL-conditioned media, while INCB018424 (ruxolitinib), a JAK1/2 inhibitor, impaired both effects. To characterize the involvement of IDO1 in leukemic cell maintenance, we overexpressed IDO1 by vector transfection measuring enhanced resistance to spontaneous apoptosis. IDO1 pro-survival influence was confirmed by treating CLL cells with Kyn, which mediated the increase of induced myeloid leukemia cell differentiation protein (MCL1). Conversely, AHR silencing or its blockade via CH-223191 improved the apoptosis of leukemic clones and mitigated MCL1 expression. Moreover, Kyn-treated CLL cells are less affected by the pro-apoptotic effect of ABT-199 (venetoclax), while CH-223191 showed synergistic/additive cytotoxicity with this drug. Lastly, targeting directly MCL1 in CLL cells with AMG-176, we abrogate the pro-survival effect of Kyn. In conclusion, our data identify IDO1/Kyn/AHR signaling as a new therapeutic target for CLL, describing for the first time its role in CLL pathobiology.

2022 - Invasive aspergillosis in relapsed/refractory acute myeloid leukaemia patients: Results from SEIFEM 2016-B survey [Articolo su rivista]
Del Principe, M. I.; Dragonetti, G.; Conti, A.; Verga, L.; Ballanti, S.; Fanci, R.; Candoni, A.; Marchesi, F.; Cattaneo, C.; Lessi, F.; Fracchiolla, N.; Spolzino, A.; Prezioso, L.; Delia, M.; Potenza, L.; Decembrino, N.; Castagnola, C.; Nadali, G.; Picardi, M.; Zama, D.; Orciulo, E.; Veggia, B.; Garzia, M.; Dargenio, M.; Melillo, L.; Manetta, S.; Russo, D.; Mancini, V.; Piedimonte, M.; Tisi, M. C.; Toschi, N.; Busca, A.; Pagano, L.
abstract

Background: In patients with relapsed/refractory acute myeloid leukaemia (R/R AML) who received salvage chemotherapy, limited and not updated studies explored the incidence of invasive aspergillosis (IA) and the role of antifungal prophylaxis (AP). The aims of this multicentre retrospective ‘SEIFEM 2016-B’ study were as follows: (1) to evaluate the current rate and the outcome of proven/probable IA and (2) to assess the efficacy of AP, in a large ‘real life’ series of patient with R/R AML submitted to salvage chemotherapy. Results: Of 2250 R/R AML patients, a total of 74 cases of IA (5.1%) were recorded as follows: 10 (0.7%) proven and 64 (4.3%) probable. Information about AP were available in 73/74 (99%) patients. Fifty-eight (79%) breakthrough infections occurred, mainly during AP with posaconazole [25 (43%)]. The patients who received AP during salvage chemotherapy showed a benefit from antifungal therapy (AT) than patients who did not received AP [43 (86%) vs 7 (14%); p <.033]. In a multivariate analysis, AP and absence of severe mucositis had a significant favourable effect on overall response rate. Conclusion: Our data demonstrated that the incidence of IA during the salvage chemotherapy is similar to the past. Nevertheless, the attributable mortality rate (AMR) appears to be lower than that previously reported in R/R AML. Further prospective studies should be performed to confirm our preliminary observation and understand and the why a decreased AMR is reported in this setting of high-risk patients.

2022 - Need for integrating early palliative care with standard hematology care long before the allogeneic hemopoietic stem cells transplantation [Articolo su rivista]
Potenza, L.; Borelli, E.; Bigi, S.; Ganfi, V.; Luppi, M.; Bandieri, E.
abstract

2022 - Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1 [Articolo su rivista]
Fiorcari, S.; Maffei, R.; Atene, C. G.; Mesini, N.; Maccaferri, M.; Leonardi, G.; Martinelli, S.; Paolini, A.; Nasillo, V.; Debbia, G.; Potenza, L.; Luppi, M.; Marasca, R.
abstract

Chronic lymphocytic leukemia (CLL) has experienced a clinical revolution—thanks to the discovery of crucial pathogenic mechanisms. CLL is still an incurable disease due to intrinsic or acquired resistance of the leukemic clone. Venetoclax is a Bcl-2 inhibitor with a marked activity in CLL, but emerging patterns of resistance are being described. We hypothesize that intrinsic features of CLL cells may contribute to drive mechanisms of resistance to venetoclax. We analyzed the expression of Interferon Regulatory Factor 4 (IRF4), Notch2, and Mcl-1 in a cohort of CLL patients. We evaluated CLL cell viability after genetic and pharmaceutical modulation of Notch2 expression in patients harboring trisomy 12. We tested venetoclax in trisomy 12 CLL cells either silenced or not for Notch2 expression or in combination with an inhibitor of Mcl-1, AMG-176. Trisomy 12 CLL cells were characterized by low expression of IRF4 associated with high levels of Notch2 and Mcl-1. Notch2 and Mcl-1 expression determined protection of CLL cells from spontaneous and drug-induced apoptosis. Considering the involvement of Mcl-1 in venetoclax resistance, our data demonstrated a contribution of high levels of Notch2 and Mcl-1 in a reduced response to venetoclax in CLL cells carrying trisomy 12. Furthermore, reduction of Mcl-1 expression by silencing Notch2 or by treatment with AMG-176 was able to restore the response of CLL cells to venetoclax. The expression of Notch2 identifies a subset of CLL patients, mainly harboring trisomy 12, characterized by high levels of Mcl-1. This biological mechanism may compromise an effective response to venetoclax.

2022 - Perceptions of Hope Among Bereaved Caregivers of Cancer Patients Who Received Early Palliative Care: A Content and Lexicographic Analysis [Articolo su rivista]
Bigi, Sarah; Ganfi, Vittorio; Borelli, Eleonora; Potenza, Leonardo; Artioli, Fabrizio; Eliardo, Sonia; Mucciarini, Claudia; Cottafavi, Luca; Cruciani, Massimiliano; Cacciari, Cristina; Odejide, Oreofe; Porro, Carlo Adolfo; Zimmermann, Camilla; Efficace, Fabio; Bruera, Eduardo; Luppi, Mario; Bandieri, Elena
abstract

2022 - Physicians’ Perceptions of Clinical Utility of a Digital Health Tool for Electronic Patient-Reported Outcome Monitoring in Real-Life Hematology Practice. Evidence From the GIMEMA-ALLIANCE Platform [Articolo su rivista]
Efficace, F.; Patriarca, A.; Luppi, M.; Potenza, L.; Caocci, G.; Tafuri, A.; Fazio, F.; Cartoni, C.; Petrucci, M. T.; Carmosino, I.; Moia, R.; Margiotta Casaluci, G.; Boggione, P.; Colaci, E.; Giusti, D.; Pioli, V.; Sparano, F.; Cottone, F.; De Fabritiis, P.; Ardu, N. R.; Niscola, P.; Capodanno, I.; Leporace, A. P.; Pelliccia, S.; Lugli, E.; La Sala, E.; Rigacci, L.; Santopietro, M.; Fozza, C.; Siragusa, S.; Breccia, M.; Fazi, P.; Vignetti, M.
abstract

Digital health tools are increasingly being used in cancer care and may include electronic patient-reported outcome (ePRO) monitoring systems. We examined physicians’ perceptions of usability and clinical utility of a digital health tool (GIMEMA-ALLIANCE platform) for ePRO monitoring in the real-life practice of patients with hematologic malignancies. This tool allows for the collection and assessment of ePROs with real-time graphical presentation of results to medical staff. Based on a predefined algorithm, automated alerts are sent to medical staff. Participating hematologists completed an online survey on their experience with the platform. Of the 201 patients invited to participate between December 2020 and June 2021 (cut-off date for current analysis), 180 (90%) agreed to enter the platform and had a median age of 57 years. Twenty-three hematologists with a median age of 42 years and an average of 17 years of experience in clinical practice were surveyed. All hematologists agreed or strongly agreed that the platform was easy to use, and 87%, agreed or strongly agreed that ePROs data were useful to enhance communication with their patients. The majority of physicians (78%) accessed the platform at least once per month to consult the symptom and health status profile of their patients. The frequency of access was independent of physician sex (p=0.393) and years of experience in clinical practice (p=0.404). In conclusion, our preliminary results support the clinical utility, from the perspective of the treating hematologist, of integrating ePROs into the routine cancer care of patients with hematologic malignancies.

2022 - Survey on the effectiveness of telephone-based communication with relatives of hospitalized cancer patients in COVID-19 era in Italy [Articolo su rivista]
Ricco, B.; Fiorani, C.; Ferrara, L.; Potenza, L.; Saviola, A.; Malavasi, N.; Acquaviva, G.; Carboni, C.; Scarabelli, L.; Dominici, M.; Luppi, M.; Longo, G.
abstract

Objective: No-visitor policies adopted to prevent coronavirus disease-19 (COVID-19) spread in hospital wards have deeply impacted communication with patients and their relatives. Whereas in pre-COVID-19 era family-clinician meetings were held in person, during the pandemic interactions often took place over the phone, frequently causing feelings of uncertainty and distress to the close ones at home. The goal of this study was to assess and improve the effectiveness of structured telephone-based communication with hospitalized onco-hematological patients’ relatives in COVID-19 era. Methods: After no-visitor policy was adopted in the Onco-Hematological Unit of Modena, inpatients’ relatives were contacted daily for clinical updates. After discharge, a telephone satisfaction survey was administered to all contact people of patients consecutive admitted between December 2020 and January 2021 (n = 97). Mean score of response and potential statistically significative differences depending on respondents’ characteristics were assessed. Results: Most relatives were satisfied with the communication received with a mean total score of 4.69 on a 5-point Likert scale (standard deviation: 0.60). Results showed high satisfaction rate with both the informative (mean ± SD: 4.66 ± 0.64) and emotional (mean ± SD: 4.66 ± 0.58) content, with no significant difference depending on respondents’ demographic characteristics (p > 0.05). Conclusion: A structured telephone-based communication may be a reasonable substitute for face-to-face meetings; especially if regular in time, conducted by the same doctor and integrated with video calls. Our findings might assist health workers in implementing measures to minimize the psychological effects of no-visitor policies during hospitalization. Clinical updates delivery through structured phone calls and video calls could become an opportunity also in post-COVID era.

2022 - The Response to Oxidative Damage Correlates with Driver Mutations and Clinical Outcome in Patients with Myelofibrosis [Articolo su rivista]
Genovese, E.; Mirabile, M.; Rontauroli, S.; Sartini, S.; Fantini, S.; Tavernari, L.; Maccaferri, M.; Guglielmelli, P.; Bianchi, E.; Parenti, S.; Carretta, C.; Mallia, S.; Castellano, S.; Colasante, C.; Balliu, M.; Bartalucci, N.; Palmieri, R.; Ottone, T.; Mora, B.; Potenza, L.; Passamonti, F.; Voso, M. T.; Luppi, M.; Vannucchi, A. M.; Tagliafico, E.; Manfredini, R.
abstract

Myelofibrosis (MF) is the Philadelphia-negative myeloproliferative neoplasm characterized by the worst prognosis and no response to conventional therapy. Driver mutations in JAK2 and CALR impact on JAK-STAT pathway activation but also on the production of reactive oxygen species (ROS). ROS play a pivotal role in inflammation-induced oxidative damage to cellular components including DNA, therefore leading to greater genomic instability and promoting cell transformation. In order to unveil the role of driver mutations in oxidative stress, we assessed ROS levels in CD34+ hematopoietic stem/progenitor cells of MF patients. Our results demonstrated that ROS production in CD34+ cells from CALR-mutated MF patients is far greater compared with patients harboring JAK2 mutation, and this leads to increased oxidative DNA damage. Moreover, CALR-mutant cells show less superoxide dismutase (SOD) antioxidant activity than JAK2-mutated ones. Here, we show that high plasma levels of total antioxidant capacity (TAC) correlate with detrimental clinical features, such as high levels of lactate dehydrogenase (LDH) and circulating CD34+ cells. Moreover, in JAK2-mutated patients, high plasma level of TAC is also associated with a poor overall survival (OS), and multivariate analysis demonstrated that high TAC classification is an independent prognostic factor allowing the identification of patients with inferior OS in both DIPSS lowest and highest categories. Altogether, our data suggest that a different capability to respond to oxidative stress can be one of the mechanisms underlying disease progression of myelofibrosis.

2022 - The Role of T Cell Immunity in Monoclonal Gammopathy and Multiple Myeloma: From Immunopathogenesis to Novel Therapeutic Approaches [Articolo su rivista]
Lagreca, I.; Riva, G.; Nasillo, V.; Barozzi, P.; Castelli, I.; Basso, S.; Bettelli, F.; Giusti, D.; Cuoghi, A.; Bresciani, P.; Messerotti, A.; Gilioli, A.; Pioli, V.; Colasante, C.; Vallerini, D.; Paolini, A.; Maccaferri, M.; Donatelli, F.; Forghieri, F.; Morselli, M.; Colaci, E.; Leonardi, G.; Marasca, R.; Potenza, L.; Manfredini, R.; Tagliafico, E.; Trenti, T.; Comoli, P.; Luppi, M.
abstract

Multiple Myeloma (MM) is a malignant growth of clonal plasma cells, typically arising from asymptomatic precursor conditions, namely monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Profound immunological dysfunctions and cyto-kine deregulation are known to characterize the evolution of the disease, allowing immune escape and proliferation of neoplastic plasma cells. In the past decades, several studies have shown that the immune system can recognize MGUS and MM clonal cells, suggesting that anti-myeloma T cell immunity could be harnessed for therapeutic purposes. In line with this notion, chimeric antigen receptor T cell (CAR-T) therapy is emerging as a novel treatment in MM, especially in the re-lapsed/refractory disease setting. In this review, we focus on the pivotal contribution of T cell im-pairment in the immunopathogenesis of plasma cell dyscrasias and, in particular, in the disease progression from MGUS to SMM and MM, highlighting the potentials of T cell-based immunother-apeutic approaches in these settings.

2021 - A single-tube multiplex method for monitoring mutations in cysteine 481 of Bruton Tyrosine Kinase (BTK) gene in chronic lymphocytic leukemia patients treated with ibrutinib [Articolo su rivista]
Maffei, R.; Fiorcari, S.; Atene, C. G.; Martinelli, S.; Scarfo, L.; Bonfiglio, S.; Maccaferri, M.; Ljungstrom, V.; Zucchini, P.; Forghieri, F.; Potenza, L.; Ghia, P.; Marasca, R.; Trenti, T.; Tagliafico, E.; Luppi, M.
abstract

2021 - Changes in Cancer Patients' and Caregivers' Disease Perceptions While Receiving Early Palliative Care: A Qualitative and Quantitative Analysis [Articolo su rivista]
Borelli, Eleonora; Bigi, Sarah; Potenza, Leonardo; Eliardo, Sonia; Artioli, Fabrizio; Mucciarini, Claudia; Cottafavi, Luca; Cagossi, Katia; Razzini, Giorgia; Cruciani, Massimiliano; Pietramaggiori, Alessandra; Fantuzzi, Valeria; Lombardo, Laura; Ferrari, Umberto; Ganfi, Vittorio; Lui, Fausta; Odejide, Oreofe; Cacciari, Cristina; Porro, Carlo Adolfo; Zimmermann, Camilla; Efficace, Fabio; Bruera, Eduardo; Luppi, Mario; Bandieri, Elena
abstract

2021 - Cytomegalovirus reactivation after hematopoietic stem cell transplant with CMV-IG prophylaxis: A monocentric retrospective analysis [Articolo su rivista]
Gilioli, A.; Messerotti, A.; Bresciani, P.; Cuoghi, A.; Pioli, V.; Colasante, C.; Bettelli, F.; Giusti, D.; Forghieri, F.; Potenza, L.; Donatelli, F.; Giubbolini, R.; Galassi, L.; Marasca, R.; Banchelli, F.; D'Amico, R.; Pecorari, M.; Gennari, W.; Trenti, T.; Comoli, P.; Luppi, M.; Narni, F.
abstract

Human cytomegalovirus (CMV) represents the most common viral infection after hematopoietic stem cell transplant (HSCT), mainly occurring as reactivation from latency in seropositive patients, with a different prevalence based on the extent and timing of seroconversion in a specific population. Here, we retrospectively analyzed a cohort of patients who underwent HSCT at our Institution between 2013 and 2018, all of whom were prophylactically treated with CMV-IG (Megalotect Biotest®), to define the incidence and clinical outcomes of CMV reactivation and clinically significant infection. CMV infection occurred in 69% of our patient series, mainly resulting from reactivation, and CMV clinically significant infection (CS-CMVi) occurred in 48% of prophylactically treated patients. CMV infection and CS-CMVi impacted neither on relapse incidence nor on overall survival nor on relapse-free survival. Moreover, a very low incidence of CMV end-organ disease was documented. CMV-IG used alone as prophylactic therapy after HSCT does not effectively prevent CMV reactivation.

2021 - Different semantic and affective meaning of the words associated to physical and social pain in cancer patients on early palliative/supportive care and in healthy, pain-free individuals [Articolo su rivista]
Borelli, Eleonora; Bigi, Sarah; Potenza, Leonardo; Artioli, Fabrizio; Eliardo, Sonia; Mucciarini, Claudia; Cagossi, Katia; Razzini, Giorgia; Pasqualini, Antonella; Lui, Fausta; Ferlazzo, Fabio; Cruciani, Massimiliano; Bruera, Eduardo; Efficace, Fabio; Luppi, Mario; Cacciari, Cristina; Porro, Carlo Adolfo; Bandieri, Elena
abstract

2021 - Early palliative/supportive care in acute myeloid leukaemia allows low aggression end-of-life interventions: Observational outpatient study [Articolo su rivista]
Potenza, L.; Scaravaglio, M.; Fortuna, D.; Giusti, D.; Colaci, E.; Pioli, V.; Morselli, M.; Forghieri, F.; Bettelli, F.; Messerotti, A.; Catellani, H.; Gilioli, A.; Marasca, R.; Borelli, E.; Bigi, S.; Longo, G.; Banchelli, F.; D'Amico, R.; L Back, A.; Efficace, F.; Bruera, E.; Luppi, M.; Bandieri, E.
abstract

Objectives: Early palliative supportive care has been associated with many advantages in patients with advanced cancer. However, this model is underutilised in patients with haematological malignancies. We investigated the presence and described the frequency of quality indicators for palliative care and end-of-life care in a cohort of patients with acute myeloid leukaemia receiving early palliative supportive care. Methods: This is an observational, retrospective study based on 215 patients consecutively enrolled at a haematology early palliative supportive care clinic in Modena, Italy. Comprehensive hospital chart reviews were performed to abstract the presence of well-established quality indicators for palliative care and for aggressiveness of care near the end of life. Results: 131 patients received a full early palliative supportive care intervention. All patients had at least one and 67 (51%) patients had four or more quality indicators for palliative care. Only 2.7% of them received chemotherapy in the last 14 days of life. None underwent intubation or cardiopulmonary resuscitation and was admitted to intensive care unit during the last month of life. Only 4% had either multiple hospitalisations or two or more emergency department access. Approximately half of them died at home or in a hospice. More than 40% did not receive transfusions within 7 days of death. The remaining 84 patients, considered late referrals to palliative care, demonstrated sensibly lower frequencies of the same indicators. Conclusions: Patients with acute myeloid leukaemia receiving early palliative supportive care demonstrated high frequency of quality indicators for palliative care and low rates of treatment aggressiveness at the end of life.

2021 - Education of early palliative care specialists among hematologists and oncologists to address patients’ rather than physicians’ rights [Articolo su rivista]
Potenza, L.; Luppi, M.; Borelli, E.; Bigi, S.; Bandieri, E.
abstract

2021 - How to improve prognostication in acute myeloid leukemia with cbfb‐myh11 fusion transcript: Focus on the role of molecular measurable residual disease (mrd) monitoring [Articolo su rivista]
Talami, A.; Bettelli, F.; Pioli, V.; Giusti, D.; Gilioli, A.; Colasante, C.; Galassi, L.; Giubbolini, R.; Catellani, H.; Donatelli, F.; Maffei, R.; Martinelli, S.; Barozzi, P.; Potenza, L.; Marasca, R.; Trenti, T.; Tagliafico, E.; Comoli, P.; Luppi, M.; Forghieri, F.
abstract

Acute myeloid leukemia (AML) carrying inv(16)/t(16;16), resulting in fusion transcript CBFB‐MYH11, belongs to the favorable‐risk category. However, even if most patients obtain morphological complete remission after induction, approximately 30% of cases eventually relapse. While well‐established clinical features and concomitant cytogenetic/molecular lesions have been recognized to be relevant to predict prognosis at disease onset, the independent prognostic impact of measurable residual disease (MRD) monitoring by quantitative real‐time reverse transcriptase polymerase chain reaction (qRT‐PCR), mainly in predicting relapse, actually supersedes other prognostic factors. Although the ELN Working Party recently indicated that patients affected with CBFB‐MYH11 AML should have MRD assessment at informative clinical timepoints, at least after two cycles of intensive chemotherapy and after the end of treatment, several controversies could be raised, especially on the frequency of subsequent serial monitoring, the most significant MRD thresholds (most commonly 0.1%) and on the best source to be analyzed, namely, bone marrow or peripheral blood samples. Moreover, persisting low‐level MRD positivity at the end of treatment is relatively common and not predictive of relapse, provided that transcript levels remain stably below specific thresholds. Rising MRD levels suggestive of molecular relapse/progression should thus be confirmed in subsequent samples. Further prospective studies would be required to optimize postremission monitoring and to define effective MRD‐based therapeutic strategies.

2021 - IRF4 L116R mutation promotes proliferation of chronic lymphocytic leukemia B cells inducing MYC [Articolo su rivista]
Benatti, S.; Atene, C. G.; Fiorcari, S.; Mesini, N.; Martinelli, S.; Zucchini, P.; Bacchelli, F.; Maccaferri, M.; Debbia, G.; Potenza, L.; Rossi, D.; Vallisa, D.; Trentin, L.; Gaidano, G.; Luppi, M.; Marasca, R.; Maffei, R.
abstract

2021 - IRF4 modulates the response to BCR activation in chronic lymphocytic leukemia regulating IKAROS and SYK [Articolo su rivista]
Maffei, R.; Fiorcari, S.; Benatti, S.; Atene, C. G.; Martinelli, S.; Zucchini, P.; Potenza, L.; Luppi, M.; Marasca, R.
abstract

Interferon regulatory factor 4 (IRF4) is a transcriptional regulator of immune system development and function. Here, we investigated the role of IRF4 in controlling responsiveness to B-cell receptor (BCR) stimulation in chronic lymphocytic leukemia (CLL). We modulated IRF4 levels by transfecting CLL cells with an IRF4 vector or by silencing using small-interfering RNAs. Higher IRF4 levels attenuated BCR signaling by reducing AKT and ERK phosphorylation and calcium release. Conversely, IRF4 reduction improved the strength of the intracellular cascade activated by BCR engagement. Our results also indicated that IRF4 negatively regulates the expression of the spleen tyrosine kinase SYK, a crucial protein for propagation of BCR signaling, and the zinc finger DNA-binding protein IKAROS. We modulated IKAROS protein levels both by genetic manipulation and pharmacologically by treating CLL cells with lenalidomide and avadomide (IMIDs). IKAROS promoted BCR signaling by reducing the expression of inositol 5-phosphatase SHIP1. Lastly, IMIDs induced IRF4 expression, while down-regulating IKAROS and interfered with survival advantage mediated by BCR triggering, also in combination with ibrutinib. Overall, our findings elucidate the mechanism by which IRF4 tunes BCR signaling in CLL cells. Low IRF4 levels allow an efficient transmission of BCR signal throughout the accumulation of SYK and IKAROS.

2021 - Ibrutinib interferes with innate immunity in chronic lymphocytic leukemia patients during COVID-19 infection [Articolo su rivista]
Fiorcari, S.; Atene, C. G.; Maffei, R.; Debbia, G.; Potenza, L.; Luppi, M.; Marasca, R.
abstract

2021 - Increased Plasma Levels of lncRNAs LINC01268, GAS5 and MALAT1 Correlate with Negative Prognostic Factors in Myelofibrosis [Articolo su rivista]
Fantini, Sebastian; Rontauroli, Sebastiano; Sartini, Stefano; Mirabile, Margherita; Bianchi, Elisa; Badii, Filippo; Maccaferri, Monica; Guglielmelli, Paola; Ottone, Tiziana; Palmieri, Raffaele; Genovese, Elena; Carretta, Chiara; Parenti, Sandra; Mallia, Selene; Tavernari, Lara; Salvadori, Costanza; Gesullo, Francesca; Maccari, Chiara; Zizza, Michela; Grande, Alexis; Salmoiraghi, Silvia; Mora, Barbara; Potenza, Leonardo; Rosti, Vittorio; Passamonti, Francesco; Rambaldi, Alessandro; Voso, Maria Teresa; Mecucci, Cristina; Tagliafico, Enrico; Luppi, Mario; Vannucchi, Alessandro Maria; Manfredini, Rossella
abstract

: Long non-coding RNAs (lncRNAs) have been recently described as key mediators in the development of hematological malignancies. In the last years, circulating lncRNAs have been proposed as a new class of non-invasive biomarkers for cancer diagnosis and prognosis and to predict treatment response. The present study is aimed to investigate the potential of circulating lncRNAs as non-invasive prognostic biomarkers in myelofibrosis (MF), the most severe among Philadelphia-negative myeloproliferative neoplasms. We detected increased levels of seven circulating lncRNAs in plasma samples of MF patients (n = 143), compared to healthy controls (n = 65). Among these, high levels of LINC01268, MALAT1 or GAS5 correlate with detrimental clinical variables, such as high count of leukocytes and CD34+ cells, severe grade of bone marrow fibrosis and presence of splenomegaly. Strikingly, high plasma levels of LINC01268 (p = 0.0018), GAS5 (p = 0.0008) or MALAT1 (p = 0.0348) are also associated with a poor overall-survival while high levels of LINC01268 correlate with a shorter leukemia-free-survival. Finally, multivariate analysis demonstrated that the plasma level of LINC01268 is an independent prognostic variable, suggesting that, if confirmed in future in an independent patients' cohort, it could be used for further studies to design an updated classification model for MF patients.

2021 - Inflammatory microenvironment and specific t cells in myeloproliferative neoplasms: Immunopathogenesis and novel immunotherapies [Articolo su rivista]
Nasillo, V.; Riva, G.; Paolini, A.; Forghieri, F.; Roncati, L.; Lusenti, B.; Maccaferri, M.; Messerotti, A.; Pioli, V.; Gilioli, A.; Bettelli, F.; Giusti, D.; Barozzi, P.; Lagreca, I.; Maffei, R.; Marasca, R.; Potenza, L.; Comoli, P.; Manfredini, R.; Maiorana, A.; Tagliafico, E.; Luppi, M.; Trenti, T.
abstract

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hemato-logical malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as in-triguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.

2021 - Multiparametric flow cytometry for MRD monitoring in hematologic malignancies: Clinical applications and new challenges [Articolo su rivista]
Riva, G.; Nasillo, V.; Ottomano, A. M.; Bergonzini, G.; Paolini, A.; Forghieri, F.; Lusenti, B.; Barozzi, P.; Lagreca, I.; Fiorcari, S.; Martinelli, S.; Maffei, R.; Marasca, R.; Potenza, L.; Comoli, P.; Manfredini, R.; Tagliafico, E.; Trenti, T.; Luppi, M.
abstract

In hematologic cancers, Minimal Residual Disease (MRD) monitoring, using either molecular (PCR) or immunophenotypic (MFC) diagnostics, allows the identification of rare cancer cells, readily detectable either in the bone marrow or in the peripheral blood at very low levels, far below the limit of classic microscopy. In this paper, we outlined the state-of-the-art of MFC-based MRD detection in different hematologic settings, highlighting main recommendations and new challenges for using such a method in patients with acute leukemias or chronic hematologic neoplasms. The combination of new molecular technologies with advanced flow cytometry is progressively allowing clinicians to design a personalized therapeutic path, proportionate to the biological aggressiveness of the disease, in particular by using novel immunotherapies, in view of a modern decision-making process, based on precision medicine. Along with the evolution of immunophenotypic and molecular diagnostics, the assessment of Minimal Residual Disease (MRD) has progressively become a keystone in the clinical management of hematologic malignancies, enabling valuable post-therapy risk stratifications and guiding risk-adapted therapeutic approaches. However, specific prognostic values of MRD in different hematological settings, as well as its appropriate clinical uses (basically, when to measure it and how to deal with different MRD levels), still need further investigations, aiming to improve standardization and harmonization of MRD monitoring protocols and MRD-driven therapeutic strategies. Currently, MRD measurement in hematological neoplasms with bone marrow involvement is based on advanced highly sensitive methods, able to detect either specific genetic abnormalities (by PCRbased techniques and next-generation sequencing) or tumor-associated immunophenotypic profiles (by multiparametric flow cytometry, MFC). In this review, we focus on the growing clinical role for MFC-MRD diagnostics in hematological malignancies-from acute myeloid and lymphoblastic leukemias (AML, B-ALL and T-ALL), to chronic lymphocytic leukemia (CLL) and multiple myeloma (MM)-providing a comparative overview on technical aspects, clinical implications, advantages and pitfalls of MFC-MRD monitoring in different clinical settings.

2021 - Neoantigen-specific T-cell immune responses: The paradigm of NPM1-mutated acute myeloid leukemia [Articolo su rivista]
Forghieri, F.; Riva, G.; Lagreca, I.; Barozzi, P.; Bettelli, F.; Paolini, A.; Nasillo, V.; Lusenti, B.; Pioli, V.; Giusti, D.; Gilioli, A.; Colasante, C.; Galassi, L.; Catellani, H.; Donatelli, F.; Talami, A.; Maffei, R.; Martinelli, S.; Potenza, L.; Marasca, R.; Tagliafico, E.; Manfredini, R.; Trenti, T.; Comoli, P.; Luppi, M.
abstract

The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicat-ing persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients.

2021 - Nurse-Like Cells and Chronic Lymphocytic Leukemia B Cells: A Mutualistic Crosstalk inside Tissue Microenvironments [Articolo su rivista]
Fiorcari, S.; Maffei, R.; Atene, C. G.; Potenza, L.; Luppi, M.; Marasca, R.
abstract

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and is an example of hematological disease where cooperation between genetic defects and tumor microenvironmental interaction is involved in pathogenesis. CLL is a disease that is considered as "addicted to the host"; indeed, the crosstalk between leukemic cells and the tumor microenvironment is essential for leukemic clone maintenance supporting CLL cells' survival, proliferation, and protection from drug-induced apoptosis. CLL cells are not innocent bystanders but actively model and manipulate the surrounding microenvironment to their own advantage. Besides the different players involved in this crosstalk, nurse-like cells (NLC) resemble features related to leukemia-associated macrophages with an important function in preserving CLL cell survival and supporting an immunosuppressive microenvironment. This review provides a comprehensive overview of the role played by NLC in creating a nurturing and permissive milieu for CLL cells, illustrating the therapeutic possibilities in order to specifically target and re-educate them.

2021 - Polymorphisms within the TNFSF4 and mapkapk2 loci influence the risk of developing invasive aspergillosis: A two-stage case control study in the context of the aspbiomics consortium [Articolo su rivista]
Sanchez-Maldonado, J. M.; Moniz-Diez, A.; Ter Horst, R.; Campa, D.; Cabrera-Serrano, A. J.; Martinez-Bueno, M.; Garrido-Collado, M. P.; Hernandez-Mohedo, F.; Fernandez-Puerta, L.; Lopez-Nevot, M. A.; Cunha, C.; Gonzalez-Sierra, P. A.; Springer, J.; Lackner, M.; Alcazar-Fuoli, L.; Fianchi, L.; Aguado, J. M.; Pagano, L.; Lopez-Fernandez, E.; Clavero, E.; Potenza, L.; Luppi, M.; Moratalla, L.; Solano, C.; Sampedro, A.; Cuenca-Estrella, M.; Lass-Florl, C.; Canzian, F.; Loeffler, J.; Li, Y.; Einsele, H.; Netea, M. G.; Vazquez, L.; Carvalho, A.; Jurado, M.; Sainz, J.
abstract

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD-plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD-B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16-cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.

2021 - Pre-existing cytopenia heralding de novo acute myeloid leukemia: Uncommon presentation of NPM1-mutated AML in a single-center study [Articolo su rivista]
Galassi, L.; Colasante, C.; Bettelli, F.; Gilioli, A.; Pioli, V.; Giusti, D.; Morselli, M.; Paolini, A.; Nasillo, V.; Lusenti, B.; Colaci, E.; Donatelli, F.; Catellani, H.; Pozzi, S.; Barbieri, E.; del Rosso, M. N.; Barozzi, P.; Lagreca, I.; Martinelli, S.; Maffei, R.; Riva, G.; Tenedini, E.; Roncati, L.; Marasca, R.; Potenza, L.; Comoli, P.; Trenti, T.; Manfredini, R.; Tagliafico, E.; Luppi, M.; Forghieri, F.
abstract

2020 - Acute myeloid leukemia in patients living with HIV infection: Several questions, fewer answers [Articolo su rivista]
Forghieri, F.; Nasillo, V.; Bettelli, F.; Pioli, V.; Giusti, D.; Gilioli, A.; Mussini, C.; Tagliafico, E.; Trenti, T.; Cossarizza, A.; Maffei, R.; Barozzi, P.; Potenza, L.; Marasca, R.; Narni, F.; Luppi, M.
abstract

Both human immunodeficiency virus (HIV) infection and acute myeloid leukemia (AML) may be considered relatively uncommon disorders in the general population, but the precise incidence of AML in people living with HIV infection (PLWH) is uncertain. However, life expectancy of newly infected HIV-positive patients receiving anti-retroviral therapy (ART) is gradually increasing, rivaling that of age-matched HIV-negative individuals, so that the occurrence of AML is also expected to progressively increase. Even if HIV is not reported to be directly mutagenic, several indirect leukemogenic mechanisms, mainly based on bone marrow microenvironment disruption, have been proposed. Despite a well-controlled HIV infection under ART should no longer be considered per se a contraindication to intensive chemotherapeutic approaches, including allogeneic hematopoietic stem cell transplantation, in selected fit patients with AML, survival outcomes are still generally unsatisfactory. We discussed several controversial issues about pathogenesis and clinical management of AML in PLWH, but few evidence-based answers may currently be provided, due to the limited number of cases reported in the literature, mainly as case reports or small retrospective case series. Prospective multicenter clinical trials are warranted to more precisely investigate epidemiology and cytogenetic/molecular features of AML in PLWH, but also to standardize and further improve its therapeutic management.

2020 - BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia [Articolo su rivista]
Fiorcari, S.; Maffei, R.; Vallerini, D.; Scarfo, L.; Barozzi, P.; Maccaferri, M.; Potenza, L.; Ghia, P.; Luppi, M.; Marasca, R.
abstract

Infections represent a cause of morbidity and mortality in patients affected by chronic lymphocytic leukemia (CLL). Introduction of new drugs in CLL clinical practice has showed impressive efficacy, in particular those targeting BTK. Among the consistent clinical data, an increasing number of reports describing the occurrence of unexpected opportunistic fungal infections has been reported during treatment with ibrutinib in the first 6 months of treatment. The reason underlying manifestations of invasive fungal infections in patients treated with ibrutinib is still under investigation. Our study aimed to understand the impact of BTK inhibition on immune response to fungal infection mediated by macrophages and CD14+ monocytic population obtained from CLL patients. Exposure to ibrutinib and acalabrutinib reduced signaling pathways activated by Aspergillus fumigatus determining an exacerbation of an immunosuppressive signature, a reduction of phagocytosis and a significant deficit in the secretion of inflammatory cytokines either in macrophages and monocytes isolated from CLL patients and healthy donors. These effects lead to a failure in completely counteracting conidia germination. In addition we investigated the biological effects of ibrutinib on monocyte counterpart in patients who were undergoing therapy. A significant impairment in cytokine secretion and a deficit of phagocytosis in circulating monocytes were detected after 3 months of treatment. Thus, our results uncover modifications in the innate response in CLL patients induced by ibrutinib that may impair the immunological response to fungal infection. BTK inhibition affects a productive immune response of CLL-associated macrophages (NLC) during Aspergillus fumigatus infection. Reduction of TNF-α secretion and phagocytosis are detected in monocytes isolated from CLL patients during ibrutinib therapy.

2020 - COVID-19 Pandemic and Cancer: The Importance of Early Palliative Care [Articolo su rivista]
Potenza, L.; Luppi, M.; Efficace, F.; Bruera, E.; Bandieri, E.
abstract

In terms of clinical and ethical situations, this narrative compares the COVID-19 pandemic to the cancer endemic and shares information that may be helpful to improve the management of both future pandemics and cancer care.

2020 - Early Palliative Care: A Necessary Intervention for Patients Ineligibile to Approved Potentially Life-saving CAR T-cell Therapy [Articolo su rivista]
Potenza, L.; Luppi, M.; Efficace, F.; Bruera, E.; Bandieri, E.
abstract

2020 - Early versus delayed palliative/supportive care in advanced cancer: An observational study [Articolo su rivista]
Bandieri, E.; Banchelli, F.; Artioli, F.; Mucciarini, C.; Razzini, G.; Cruciani, M.; Potenza, L.; D'Amico, R.; Efficace, F.; Bruera, E.; Luppi, M.
abstract

Objective: The positive impact of early palliative care interventions in advanced cancer patients has so far been largely evaluated in randomised controlled trials. This study aimed at providing information on the value of early palliative/supportive care, integrated with standard oncologic care, in a real-life setting. Methods: This was a retrospective observational study of 292 advanced cancer patients consecutively admitted at Carpi Hospital in Modena, Italy, between 2014 and 2017. For the purpose of this analysis, patients were classified into two groups (early and delayed palliative/supportive care patients), and analysed for different clinical indicators. Early and delayed palliative/supportive care were classified according to the time elapsed from advanced cancer diagnosis until palliative/supportive care start. Results: A total of 200 patients (68%), with at least three visits, were included in the analyses. The frequency of chemotherapy use in the last 60 days of life was 3.4% and 24.6% in the early and delayed groups, respectively (adjusted OR=0.1; 95% CI 0.0 to 0.4; p=0.002). The estimated survival probability at 1 year was 74.5% (95% CI 65.0% to 85.4%) and 45.5% (95% CI 37.6% to 55.0%), in the early and delayed groups, respectively. Performance status, pain and all the Edmonton Symptom Assessment Scale items, assessed at baseline and at 1 to 12 weeks after the intervention, showed significant improvement over time. However, no between-group differences were found with regard to symptom outcomes. Conclusions: An earlier palliative/supportive care intervention was associated with reduced aggressiveness of therapy, in patients receiving community oncology care. Symptom burden was improved by early palliative/supportive care, independently of the timing of patient referral.

2020 - Epidemiology and clinical outcomes of latent tuberculosis infection in adults affected with acute leukemia or aplastic anemia: a retrospective single-center study [Articolo su rivista]
Bettelli, F.; Giusti, D.; Morselli, M.; Colaci, E.; Nasillo, V.; Pioli, V.; Gilioli, A.; Iotti, S.; Galassi, L.; Giubbolini, R.; Colasante, C.; Catellani, H.; Barozzi, P.; Lagreca, I.; Vallerini, D.; Maffei, R.; Franceschini, E.; Mussini, C.; Banchelli, F.; D'Amico, R.; Marasca, R.; Narni, F.; Potenza, L.; Comoli, P.; Luppi, M.; Forghieri, F.
abstract

2020 - Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium [Articolo su rivista]
Sanchez-Maldonado, J. M.; Campa, D.; Springer, J.; Badiola, J.; Niazi, Y.; Moniz-Diez, A.; Hernandez-Mohedo, F.; Gonzalez-Sierra, P.; Ter Horst, R.; Macauda, A.; Brezina, S.; Cunha, C.; Lackner, M.; Lopez-Nevot, M. A.; Fianchi, L.; Pagano, L.; Lopez-Fernandez, E.; Potenza, L.; Luppi, M.; Moratalla, L.; Rodriguez-Sevilla, J. J.; Fonseca, J. E.; Tormo, M.; Solano, C.; Clavero, E.; Romero, A.; Li, Y.; Lass-Florl, C.; Einsele, H.; Vazquez, L.; Loeffler, J.; Hemminki, K.; Carvalho, A.; Netea, M. G.; Gsur, A.; Dumontet, C.; Canzian, F.; Forsti, A.; Jurado, M.; Sainz, J.
abstract

The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

2020 - Ibrutinib Is a Newly Recognized Host Factor for the Definition of Probable Invasive Pulmonary Mold Disease, Based on Off-target Effects, Unrelated to Its B-cell Immunosuppressant Activity [Articolo su rivista]
Luppi, Mario; Forghieri, Fabio; Potenza, Leonardo
abstract

2020 - Immunomodulatory effect of ibrutinib: Reducing the barrier against fungal infections [Articolo su rivista]
Maffei, R.; Maccaferri, M.; Arletti, L.; Fiorcari, S.; Benatti, S.; Potenza, L.; Luppi, M.; Marasca, Roberto
abstract

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is increasingly used in the treatment of chronic lymphocytic leukemia (CLL). Moreover, very promising results have been reported in other B-cell malignancies, including primary central nervous system lymphoma (PCNSL). Although well-tolerated in the majority of patients, ibrutinib demonstrates in some cases troublesome toxicities, including invasive fungal infections (IFIs). In the present review, we summarize clinical manifestations of IFIs in patients treated with ibrutinib, generally characterized by an early onset, mild clinical manifestations, asymptomatic/low symptomatic pulmonary localization and high incidence of central nervous system (CNS) involvement. IFI risk appears particularly increased in patients receiving ibrutinib associated with other immune modulator agents, especially with steroids or immune-chemotherapy. Moreover, the immunomodulatory effect of ibrutinib is described, pointing the attention on the involvement of specific molecules targeted by ibrutinib in innate and adaptive response to fungal infection. Overall, the findings indicate the ibrutinib may rapidly impair innate immune cell functions, while concomitantly restoring an effective protective potential of adaptive immune compartment. A correct awareness, especially when other predisposing factors are present, is warranted about the potential risk of IFIs in ibrutinib-treated patients.

2020 - Independent research on cancer pain management in the setting of early palliative care: A flywheel to counteract general opioid misuse and abuse [Articolo su rivista]
Bandieri, E.; Potenza, L.; Efficace, F.; Bruera, E.; Luppi, M.
abstract

The increased recognition of the high prevalence and important burden of cancer pain and the documentation of a large proportion of patients receiving inadequate analgesic treatment should have reinforced the need for evidence-based recommendations. The World health Organization (WHO) guidelines on cancer pain management—or palliative care—are traditionally based on a sequential, three-step, analgesic ladder according to pain intensity: nonopioids (paracetamol or nonsteroidal anti-inflammatory drugs) to mild pain in step I; weak opioids (eg, codeine or tramadol) to mild-moderate pain in step II; and strong opioids to moderate-severe pain in step. III. Despite the widespread use of this ladder, unrelieved pain continues to be a substantial concern in one third of patients with either solid or hematologic malignancies. The sequential WHO analgesic ladder, and in particular, the usefulness of step II opioids have been questioned but there are no universally used guidelines for the treatment of pain in patients with advanced cancer and not all guideline recommendations are evidence-based. The American Society of Clinical Oncology and the European Society of Medical Oncology have recommended the implementation of early palliative care (EPC), which is a novel model of care, consisting of delivering dedicated palliative service concurrent with active treatment as early as possible in the cancer disease trajectory. Improvement in cancer pain management is one of the several important positive effects following EPC interventions. Independent well-designed research studies on pharmacological interventions on cancer pain, especially in the EPC setting are warranted and may contribute to spur research initiatives to investigate the poorly addressed issues of pain management in non cancer patients.

2020 - Investigating the association between physicians self-efficacy regarding communication skills and risk of “burnout” [Articolo su rivista]
Messerotti, Andrea; Banchelli, Federico; Ferrari, Silvia; Barbieri, Emiliano; Bettelli, Francesca; Bandieri, Elena; Giusti, Davide; Catellani, Hillary; Borelli, Eleonora; Colaci, Elisabetta; Pioli, Valeria; Morselli, Monica; Forghieri, Fabio; Galeazzi, Gian Maria; Marasca, Roberto; Bigi, Sarah; D’Amico, Roberto; Martin, Peter; Efficace, Fabio; Luppi, Mario; Potenza, Leonardo
abstract

2020 - Npm1‐mutated myeloid neoplasms with <20% blasts: A really distinct clinico‐pathologic entity? [Articolo su rivista]
Forghieri, F.; Nasillo, V.; Paolini, A.; Bettelli, F.; Pioli, V.; Giusti, D.; Gilioli, A.; Colasante, C.; Acquaviva, G.; Riva, G.; Barozzi, P.; Maffei, R.; Potenza, L.; Marasca, R.; Fozza, C.; Tagliafico, E.; Trenti, T.; Comoli, P.; Longo, G.; Luppi, M.
abstract

Nucleophosmin (NPM1) gene mutations rarely occur in non‐acute myeloid neoplasms (MNs) with &lt;20% blasts. Among nearly 10,000 patients investigated so far, molecular analyses documented NPM1 mutations in around 2% of myelodysplastic syndrome (MDS) cases, mainly belonging to MDS with excess of blasts, and 3% of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) cases, prevalently classified as chronic myelomonocytic leukemia. These uncommon malignancies are associated with an aggressive clinical course, relatively rapid progression to overt acute myeloid leukemia (AML) and poor survival outcomes, raising controversies on their classification as distinct clinico‐pathologic entities. Furthermore, fit patients with NPM1‐mutated MNs with &lt;20% blasts could benefit most from upfront intensive chemotherapy for AML rather than from moderate intensity MDS‐directed therapies, although no firm conclusion can currently be drawn on best therapeutic approaches, due to the limited available data, obtained from small and mainly retrospective series. Caution is also suggested in definitely diagnosing NPM1‐mutated MNs with blast count &lt;20%, since NPM1‐mutated AML cases frequently present dysplastic features and multilineage bone marrow cells showing abnormal cytoplasmic NPM1 protein delocalization by immunohistochemical staining, therefore belonging to NPM1‐mutated clone regardless of blast morphology. Further prospective studies are warranted to definitely assess whether NPM1 mutations may become sufficient to diagnose AML, irrespective of blast percentage.

2020 - Polymorphisms within the ARNT2 and CX3CR1 Genes Are Associated with the Risk of Developing Invasive Aspergillosis [Articolo su rivista]
Lupianez, C. B.; Martinez-Bueno, M.; Sanchez-Maldonado, J. M.; Badiola, J.; Cunha, C.; Springer, J.; Lackner, M.; Segura-Catena, J.; Canet, L. M.; Alcazar-Fuoli, L.; Lopez-Nevot, M. A.; Fianchi, L.; Aguado, J. M.; Pagano, L.; Lopez-Fernandez, E.; Alarcon-Riquelme, M.; Potenza, L.; Goncalves, S. M.; Luppi, M.; Moratalla, L.; Solano, C.; Sampedro, A.; Gonzalez-Sierra, P.; Cuenca-Estrella, M.; Lagrou, K.; Maertens, J. A.; Lass-Florl, C.; Einsele, H.; Vazquez, L.; Loeffler, J.; Rios-Tamayo, R.; Carvalho, A.; Jurado, M.; Sainz, J.
abstract

Invasive aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplantation, and recent studies have shown that genetic factors contribute to disease susceptibility. In this two-stage, population-based, case-control study, we evaluated whether 7 potentially functional single nucleotide polymorphisms (SNPs) within the ARNT2 and CX3CR1 genes influence the risk of IA in high-risk hematological patients. We genotyped selected SNPs in a cohort of 500 hematological patients (103 of those had been diagnosed with proven or probable IA), and we evaluated their association with the risk of developing IA. The association of the most interesting markers of IA risk was then validated in a replication population, including 474 subjects (94 IA and 380 non-IA patients). Functional experiments were also performed to confirm the biological relevance of the most interesting markers. The meta-analysis of both populations showed that carriers of the ARNT2rs1374213G, CX3CR1rs7631529A, and CX3CR1rs9823718G alleles (where the RefSeq identifier appears as a subscript) had a significantly increased risk of developing IA according to a log-additive model (P value from the meta-analysis [PMeta] = 9.8 · 10-5, PMeta = 1.5 · 10-4, and PMeta =7.9 · 10-5, respectively). Haplotype analysis also confirmed the association of the CX3CR1 haplotype with AG CGG with an increased risk of IA (P = 4.0 · 10-4). Mechanistically, we observed that monocyte-derived macrophages (MDM) from subjects carrying the ARNTR2rs1374213G allele or the GG genotype showed a significantly impaired fungicidal activity but that MDM from carriers of the ARNT2rs1374213G and CX3CR1rs9823718G or CX3CR1rs7631529A alleles had deregulated immune responses to Aspergillus conidia. These results, together with those from expression quantitative trait locus (eQTL) data browsers showing a strong correlation of the CX3CR1rs9823718G allele with lower levels of CX3CR1 mRNA in whole peripheral blood (P = 2.46 · 10-7) and primary monocytes (P = 4.31 · 10-7), highlight the role of the ARNT2 and CX3CR1 loci in modulating and predicting IA risk and provide new insights into the host immune mechanisms involved in IA development.

2020 - Selective inhibition of PI3Kγ affects survival and proliferation of chronic lymphocytic leukemia B cells [Articolo su rivista]
Maffei, R.; Benatti, S.; Atene, C. G.; Debbia, G.; Zucchini, P.; Potenza, L.; Luppi, M.; Fiorcari, S.; Marasca, R.
abstract

the catalytic p110gamma of PI3K is implicated in the survival and proliferation of CLL cells. Our findings support the idea that CLL cells are peculiar in the attitude to sense microenvironmental signals throughout the engagement of multiple PI3Ks. PI3Kgamma inhibition by IPI-549 may directly promote CLL apoptosis, but may also interfere with signals derived from several accessory cells of stromal and immune system. Together with the reported ability of PI3Kgamma inhibition in prevention of CLL migration and adhesion, our data provide knowledge to justify further clinical development of PI3Kc inhibition in CLL cells.

2019 - 'Real-life' analysis of the role of antifungal prophylaxis in preventing invasive aspergillosis in AML patients undergoing consolidation therapy: Sorveglianza Epidemiologica Infezioni nelle Emopatie (SEIFEM) 2016 study [Articolo su rivista]
Del Principe, Maria Ilaria; Dragonetti, Giulia; Verga, Luisa; Candoni, Anna; Marchesi, Francesco; Cattaneo, Chiara; Delia, Mario; Potenza, Leonardo; Farina, Francesca; Ballanti, Stelvio; Decembrino, Nunzia; Castagnola, Carlo; Nadali, Gianpaolo; Fanci, Rosa; Orciulo, Enrico; Veggia, Barbara; Offidani, Massimo; Melillo, Lorella; Manetta, Sara; Tumbarello, Mario; Venditti, Adriano; Busca, Alessandro; Aversa, Franco; Pagano, Livio
abstract

We evaluated the incidence of proven/probable invasive aspergillosis (IA) and the role of antifungal prophylaxis (AP) in a 'real-life' setting of patients with AML receiving intensive consolidation therapy.

2019 - Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia [Articolo su rivista]
Forghieri, Fabio; Riva, Giovanni; Lagreca, Ivana; Barozzi, Patrizia; Vallerini, Daniela; Morselli, Monica; Paolini, Ambra; Bresciani, Paola; Colaci, Elisabetta; Maccaferri, Monica; Gilioli, Andrea; Nasillo, Vincenzo; Messerotti, Andrea; Pioli, Valeria; Arletti, Laura; Giusti, Davide; Bettelli, Francesca; Celli, Melania; Donatelli, Francesca; Corradini, Giorgia; Basso, Sabrina; Gurrado, Antonella; Cellini, Monica; Trenti, Tommaso; Marasca, Roberto; Narni, Franco; Martelli, Maria Paola; Falini, Brunangelo; Potenza, Leonardo; Luppi, Mario; Comoli, Patrizia
abstract

Nucleophosmin(NPM1)-mutated protein, a leukemia-specific antigen, represents an ideal target for AML immunotherapy. We investigated the dynamics of NPM1-mutated-specific T cells on PB and BM samples, collected from 31 adult NPM1-mutated AML patients throughout the disease course, and stimulated with mixtures of 18 short and long peptides (9-18mers), deriving from the complete C-terminal of the NPM1-mutated protein. Two 9-mer peptides, namely LAVEEVSLR and AVEEVSLRK (13.9-14.9), were identified as the most immunogenic epitopes. IFNγ-producing NPM1-mutated-specific T cells were observed by ELISPOT assay after stimulation with peptides 13.9-14.9 in 43/85 (50.6%) PB and 34/80 (42.5%) BM samples. An inverse correlation between MRD kinetics and anti-leukemic specific T cells was observed. Cytokine Secretion Assays allowed to predominantly and respectively identify Effector Memory and Central Memory T cells among IFNγ-producing and IL2-producing T cells. Moreover, NPM1-mutated-specific CTLs against primary leukemic blasts or PHA-blasts pulsed with different peptide pools could be expanded ex vivo from NPM1-mutated AML patients or primed in healthy donors. We describe the spontaneous appearance and persistence of NPM1-mutated-specific T cells, which may contribute to the maintenance of long-lasting remissions. Future studies are warranted to investigate the potential role of both autologous and allogeneic adoptive immunotherapy in NPM1-mutated AML patients.

2019 - Clinical differences in sarcoidosis patients with and without lymphoma: a single-center retrospective cohort analysis. [Articolo su rivista]
Cerri, Stefania; Fontana, Matteo; Balduzzi, Sara; Potenza, Leonardo; Faverio, Paola; Luppi, Mario; Damico, Roberto; Spagnolo, Paolo; Clini, Enrico; Luppi, Fabrizio
abstract

We retrospectively reviewed the database&nbsp;of the “Center for Rare Lung Diseases” at the University Hospital of Modena to identify all subjects with a diagnosis of sarcoidosis between 1990 and 2013, with the aim to evaluate clinical, functional and serological differences related to the presence of lymphoma in sarcoidosis patients, as well as difference in survival. This study suggests the existence of clinical, radiological and serological differences in sarcoidosis with or without lymphoma syndrome. The knowledge of these differences seems important for a timely diagnosis and treatment. However, further prospective studies are required to confirm present observations.

2019 - Rhodotorula infection in haematological patient: risk factors and outcome [Articolo su rivista]
Potenza, Leonardo; Chitasombat, Maria N; Klimko, Nikolay; Bettelli, Francesca; Dragonetti, Giulia; Del Principe, Maria Ilaria; Nucci, Marcio; Busca, Alessandro; Fracchiolla, Nicola; Sciumè, Mariarita; Spolzino, Angelica; Delia, Mario; Mancini, Valentina; Nadali, Gian Paolo; Dargenio, Michela; Shadrivova, Olga; Bacchelli, Federico; Aversa, Franco; Sanguinetti, Maurizio; Luppi, Mario; Kontoyiannis, Dimitrios P; Pagano, Livio
abstract

Rhodotorula spp are uncommon yeasts able to cause infections with high mortality rates. Rhodotorula infections have been associated with the presence of central venous catheter (CVC), immunosuppression, exposure to antifungals and the presence of either solid or hematologic malignancies. However, in this latter setting, only a few cases have so far been reported.

2019 - T-cell large granular lymphocyte leukemia in solid organ transplant recipients: case series and review of the literature [Articolo su rivista]
Alfano, G.; Fontana, F.; Colaci, E.; Mori, G.; Cerami, C.; Messerotti, A.; Potenza, L.; Luppi, M.; Cappelli, G.
abstract

T-cell large granular lymphocyte (T-LGL) leukemia is a rare clonal proliferation of cytotoxic lymphocytes rarely described in solid organ transplant (SOT). We reviewed records from 656 kidney transplant recipients in follow-up at our Center from January 1998 to July 2017. In addition, we researched, through PubMed, further&nbsp;reports of T-LGL leukemia in SOT from March 1981 to December 2017. We identified six cases of T-LGL leukemia in our cohort of patients and 10 in the literature. This lymphoproliferative disorder was detected in one combined liver–kidney, one liver and 14–kidney transplant recipients. Median age at presentation was 46.5&nbsp;years (IQR 39.2–56.9). The disease developed after a median age of 10&nbsp;years (IQR 4.9–12) from transplantation. Anemia was the most common presentation (62.5%) followed by lymphocytosis (43.7%) and thrombocytopenia (31.2%). Splenomegaly was reported in 43.7% of the patients. Eight patients (50%) who experienced severe symptoms were treated with non-specific immunosuppressive agents. Six of them (75%) had a good outcome, whereas two (25%) remained red blood cell transfusion dependent. No cases progressed to aggressive T-LGL leukemia or died of cancer at the end of follow-up. These results suggest that T-LGL leukemia is a rare but potentially disruptive hematological disorder in the post-transplant period.

2018 - Angiopoietin-2 acts as a survival factor for chronic lymphocytic leukemia B cells throughout Tie-2 receptor engagement [Articolo su rivista]
Maffei, Rossana; Fiorcari, Stefania; Martinelli, Silvia; Guarnotta, Carla; Benatti, Stefania; Belmonte, Beatrice; Potenza, Leonardo; Luppi, Mario; Marasca, Roberto
abstract

we demonstrated that: (i) CLL cells expressed Tie-2 receptor both in peripheral blood and in lymph nodes; (ii) Ang2 may interact with Tie-2 in CLL mediating a survival signal throughout PI3K-AKT signalling, and (iii) the interruption of Ang2/Tie-2 signalling may be effective in CLL.

2018 - Breast Location for De Novo Extramedullary Myeloid Sarcoma [Articolo su rivista]
Tazzioli, Giovanni; Palma, Enza; Anna, Gambini; Messerotti, Andrea; Potenza, Leonardo; Luppi, Mario; Drago, Antonella; Grazia Amorico, Maria; Barbolini, Monica; Ficarra, Guido; Piacentini, Federico
abstract

Background: Myeloid Sarcoma (MS) is a rare hematologic cancer, which can occur as a breast mass to be distinguished from other non-hematopoietic tumors. Case Presentation: This report describe the unusual clinical history of a young woman diagnosed with MS. Radiotherapy/surgery alone may be inadequate, while chemotherapy and hematopoietic stem cell transplantation demonstrated to improve the prognosis for the isolated extramedullary localization. Conclusion: Performing a needle biopsy in order to exclude the diagnosis of a primitive breast disease is irreplaceable.

2018 - Effectiveness of originator (Neupogen) and biosimilar (Zarzio) filgrastim in autologous peripheral blood stem cell mobilization in adults with acute myeloid leukemia: a single-center retrospective study [Articolo su rivista]
Nasillo, Vincenzo; Paolini, Ambra; Riva, Giovanni; Morselli, Monica; Potenza, Leonardo; Coluccio, Valeria; Maccaferri, Monica; Colaci, Elisabetta; Fantuzzi, Valeria; Messerotti, Andrea; Arletti, Laura; Pioli, Valeria; Lugli, Elisabetta; Gilioli, Andrea; Quadrelli, Chiara; Zucchini, Patrizia; Vallerini, Daniela; Lagreca, Ivana; Barozzi, Patrizia; Cuoghi, Angela; Bresciani, Paola; Marasca, Roberto; Mariano, Maria Teresa; Ceccherelli, Giovanni; Comoli, Patrizia; Campioli, Daniele; Trenti, Tommaso; Narni, Franco; Luppi, Mario; Forghieri, Fabio
abstract

n.d.

2018 - Idelalisib impairs T-cell-mediated immunity in chronic lymphocytic leukemia [Articolo su rivista]
Martinelli, Silvia; Maffei, Rossana; Fiorcari, Stefania; Quadrelli, Chiara; Zucchini, Patrizia; Benatti, Stefania; Potenza, Leonardo; Luppi, Mario; Marasca, Roberto
abstract

n.d.

2018 - Immunophenotypic Profile and Clinical Outcome of Monoclonal B-cell Lymphocytosis in Kidney Transplantation [Articolo su rivista]
Alfano, G; Fontana, F; Colaci, E; Franceschini, E; Ligabue, G; Messerotti, A; Bettelli, Francesca; Grottola, A; Gennari, W; Potenza, L; Guaraldi, G; Mussini, C; Luppi, M; Cappelli, G
abstract

Monoclonal B-cell lymphocytosis (MBL) is a lymphoproliferative disorder characterized by clonal expansion of a B-cell population in peripheral blood of otherwise healthy subjects. MBL is divided into CLL (chronic lymphocytic leukemia)-like, atypical CLL-like and non-CLL MBL. The aim of this study was to evaluate immunophenotypic characteristics and clinical outcomes of MBL in kidney transplant (KT) recipients. We retrospectively evaluated 593 kidney transplant (KT) recipients in follow-up at our center. Among them, 157 patients underwent peripheral blood flow-cytometry for different clinical indications. A 6-color panel flow-cytometry was used to diagnose MBL. MBL was detected in 5 of 157 KT recipients. Immunophenotypic characterization of MBL showed four cases of non-CLL MBL and one case of CLL-like MBL. At presentation, median age was 65 years (range 61-73). After a median follow-up of 3.1 years (95%CI; 1.1-5) from diagnosis, patients did not progress either to CLL or lymphoma. The disorder did not increase the risk of malignancy, severe infections, graft loss and mortality among our KT recipients. Surprisingly, all cases were also affected by concomitant monoclonal gammopathy of undetermined significance, which did not progress to multiple myeloma during follow-up. In conclusion, our data suggest that MBL is an age-related disorder, with non-CLL MBL being the most common subtype among KT recipients. This article is protected by copyright. All rights reserved.

2018 - Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives [Articolo su rivista]
Forghieri, Fabio; Comoli, Patrizia; Marasca, Roberto; Potenza, Leonardo; Luppi, Mario
abstract

Acute myeloid leukemia (AML) with NPM1 gene mutations is currently recognized as a distinct entity, due to its unique biological and clinical features. We summarize here the results of published studies investigating the clinical application of minimal/measurable residual disease (MRD) in patients with NPM1-mutated AML, receiving either intensive chemotherapy or hematopoietic stem cell transplantation. Several clinical trials have so far demonstrated a significant independent prognostic impact of molecular MRD monitoring in NPM1-mutated AML and, accordingly, the Consensus Document from the European Leukemia Net MRD Working Party has recently recommended that NPM1-mutated AML patients have MRD assessment at informative clinical timepoints during treatment and follow-up. However, several controversies remain, mainly with regard to the most clinically significant timepoints and the MRD thresholds to be considered, but also with respect to the optimal source to be analyzed, namely bone marrow or peripheral blood samples, and the correlation of MRD with other known prognostic indicators. Moreover, we discuss potential advantages, as well as drawbacks, of newer molecular technologies such as digital droplet PCR and next-generation sequencing in comparison to conventional RQ-PCR to quantify NPM1-mutated MRD. In conclusion, further prospective clinical trials are warranted to standardize MRD monitoring strategies and to optimize MRD-guided therapeutic interventions in NPM1-mutated AML patients.

2017 - BCR-ABL-specific T-cell therapy in Ph+ ALL patients on tyrosine-kinase inhibitors [Articolo su rivista]
Comoli, Patrizia; Basso, Sabrina; Riva, Giovanni; Barozzi, Patrizia; Guido, Ilaria; Gurrado, Antonella; Quartuccio, Giuseppe; Rubert, Laura; Lagreca, Ivana; Vallerini, Daniela; Forghieri, Fabio; Morselli, Monica; Bresciani, Paola; Cuoghi, Angela; Paolini, Ambra; Colaci, Elisabetta; Marasca, Roberto; Cuneo, Antonio; Iughetti, Lorenzo; Trenti, Tommaso; Narni, Franco; Foà, Robin; Zecca, Marco; Luppi, Mario; Potenza, Leonardo
abstract

Although the emergence of bone marrow (BM)-resident (p190)BCR-ABL-specific T lymphocytes has been correlated with hematologic and cytogenetic remissions in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) undergoing maintenance tyrosine-kinase inhibitor treatment, little is known about the possibility of culturing these cells ex vivo and using them in T-cell therapy strategies. We investigated the feasibility of expanding/priming (p190)BCR-ABL-specific T cells in vitro by stimulation with dendritic cells pulsed with (p190)BCR-ABL peptides derived from the BCR-ABL junctional region and alternative splicing, and of adoptively administering them to patients with relapsed disease. We report on the feasibility of producing clinical-grade BCR-ABL-specific cytotoxic T lymphocytes (CTLs), endowed with antileukemia activity, from Ph(+) ALL patients and healthy donors. We treated 3 patients with Ph(+) ALL with autologous or allogeneic (p190)BCR-ABL-specific CTLs. No postinfusion toxicity was observed, except for a grade II skin graft-versus-host disease in the patient treated for hematologic relapse. All patients achieved a molecular or hematologic complete remission (CR) after T-cell therapy, upon emergence of (p190)BCR-ABL-specific T cells in the BM. Our results show that (p190)BCR-ABL-specific CTLs are capable of controlling treatment-refractory Ph(+) ALL in vivo, and support the development of adoptive immunotherapeutic approaches with BCR-ABL CTLs in Ph(+) ALL.

2017 - Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation [Articolo su rivista]
Franceschini, Erica; Plessi, Jessica; Zona, Stefano; Santoro, Antonella; Digaetano, Margherita; Fontana, Francesco; Alfano, Gaetano; Guaraldi, Giovanni; Comoli, Patrizia; Facchini, Francesca; Potenza, Leonardo; Gennari, William; Codeluppi, Mauro; Luppi, Mario; Cappelli, Gianni; Gyssens, Inge C.; Mussini, Cristina
abstract

Background. Posttransplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality in solid organ transplants. Epstein Barr virus (EBV) plays a major role in PTLD development. Guidelines recommend EBV viral load (VL) monitoring in high-risk populations in the first year. Methods. Retrospective observational study in all adult patients who had at least 1 EBV-VL performed in the postkidney transplant (KT) period from January 2005 to December 2014 at the Policlinico Modena Hospital. We compared patients with negative EBV-DNA to patients with positive EBV-DNA and we described PTLD developed in the study period. Results.One hundred ninety (36.3%) KT patients of 523 were screened for EBV-DNA with 796 samples. One hundred twenty-eight (67.4%) of 190 tested patients presented at least 1 positive sample for EBV. Older age, the use of sirolimus, everolimus, and steroids were associated with EBV-DNA positivity in the univariate analysis. Nine (1.7%) of 523 patients had PTLD. Incidence rate of PTLD in the KT cohort was 0.19/100 person year follow-up (95% confidence interval, 0.09-0.37). One of 9 patients developed early PTLD and was a high-risk patient. Only this PTLD case was positive for EBV. No PTLD case had an EBV-VL superior to 4000 copies/mL. Conclusions. Our results suggest that the keystone of PTLD diagnosis is the clinical suspicion. Our study suggests that, in line with guidelines, EBV-VL assays may be avoided in low-risk patients in the absence of a strong clinical PTLD suspicion without increasing patients' risk of developing PTLD. This represents a safe and cost-saving clinical strategy for our center

2017 - Detection of Fusarium-specific T cells in hematologic patients with invasive fusariosis [Articolo su rivista]
Vallerini, Daniela; Forghieri, Fabio; Lagreca, Ivana; Riva, Giovanni; Barozzi, Patrizia; Quadrelli, Chiara; Morselli, Monica; Bresciani, Paola; Cuoghi, Angela; Coluccio, Valeria; Maccaferri, Monica; Paolini, Ambra; Colaci, Elisabetta; Marasca, Roberto; Narni, Franco; Cellini, Monica; Beauvais, Anne; Latgè, Jean Paul; Romani, Luigina; Iughetti, Lorenzo; Comoli, Patrizia; Campioli, Daniele; Trenti, Tommaso; Luppi, Mario; Potenza, Leonardo
abstract

N.A.

2017 - Macitentan, a double antagonist of endothelin receptors, efficiently impairs migration and microenvironmental survival signals in chronic lymphocytic leukemia [Articolo su rivista]
Maffei, Rossana; Fiorcari, Stefania; Vaisitti, Tiziana; Martinelli, Silvia; Benatti, Stefania; Debbia, Giulia; Rossi, Davide; Zucchini, Patrizia; Potenza, Leonardo; Luppi, Mario; Gaidano, Gianluca; Deaglio, Silvia; Marasca, Roberto
abstract

The crosstalk between chronic lymphocytic leukemia (CLL) cells and tumor microenvironment is essential for leukemic clone maintenance, supporting CLL cells survival, proliferation and protection from drug-induced apoptosis. Over the past years, the role of several soluble factors involved in these processes has been studied. CLL cells express higher levels of endothelin 1 (ET-1) and ETA receptor as compared to normal B cells. Upon ET-1 stimulation, CLL cells improve their survival and proliferation and reduce their sensitivity to the phosphoinositide-3-kinase d inhibitor idelalisib and to fludarabine. Here, we demonstrate that CLL cells express not only ETA receptor but also ETB receptor. ET-1 acts as a homing factor supporting CLL cells migration and adhesion to microenvironmental cells. In addition, ET-1 stimulates a pro-angiogenic profile of CLL cells increasing VEGF expression through hypoxia-inducible factor-1 (HIF-1α) accumulation in CLL cells. Macitentan, a specific dual inhibitor of ETAand ETBreceptors, targets CLL cells affecting leukemic cells migration and adhesion and overcoming the pro-survival and proliferation signals mediated by microenvironment. Furthermore, macitentan cooperates with ibrutinib inhibiting the BCR pathway and with ABT-199 disrupting BCL2 pathway. Our data describe the biological effects of a new drug, macitentan, able to counteract essential processes in CLL pathobiology as survival, migration, trafficking and drug resistance. These findings envision the possibility to interfere with ET receptors activity using macitentan as a possible novel therapeutic strategy for CLL patients.

2017 - Mantle cell lymphoma of the thyroid: The helpful role of cell-blocks [Articolo su rivista]
Mengoli, M. C.; Nasillo, V.; Potenza, L.; Piana, S.
abstract

2017 - Monoclonal Gammopathy of Undetermined Significance After Kidney Transplantation: Single-Center Experience [Articolo su rivista]
Alfano, Gaetano; Fontana, Francesco; Colaci, Elisabetta; Messerotti, Andrea; Bettelli, Francesca; Potenza, Leonardo; Luppi, Mario; Cappelli, Gianni
abstract

Background: Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell disorder. Prevalence and clinical outcomes of MGUS in kidney transplant (KT) recipients have been previously reported in few studies with conflicting results. Methods: We conducted a retrospective study in a population of 548 KT recipients transplanted between 1998 and 2015. Results: Thirty-nine (8.1%) subjects developed MGUS after KT. At diagnosis of MGUS, the average age was 52 ± 9.2 years, and 23% of the patients were younger than 50 years. Occurrence of MGUS was not influenced by age and sex. After a mean follow-up of 7.8 years, only 1 (2.5%) patient progressed to multiple myeloma. We found no differences in the incidence of solid and hematological malignancies, serious infections, graft failure, and mortality between KT patients with MGUS and a matched cohort of KT recipients without MGUS. The MGUS group had a significantly higher prevalence of monoclonal B cell lymphocytosis, premalignant condition poorly described in KT recipients. Prior history of glomerulonephritis or interstitial nephritis, as cause of renal failure, represented the only predictive factor for MGUS development. Conclusions: MGUS is a premalignant disorder frequently encountered in KT recipients. We found no differences in clinical outcomes between MGUS patients and KT controls.

2017 - Multicenter Prospective Study for Laboratory Diagnosis of HHV8 Infection in Solid Organ Donors and Transplant Recipients and Evaluation of the Clinical Impact After Transplantation [Articolo su rivista]
Chiereghin, Angela; Barozzi, Patrizia; Petrisli, Evangelia; Piccirilli, Giulia; Gabrielli, Liliana; Riva, Giovanni; Potenza, Leonardo; Cappelli, Gianni; de Ruvo, Nicola; Libri, Irene; Maggiore, Umberto; Morelli, Maria Cristina; Potena, Luciano; Todeschini, Paola; Gibertoni, Dino; Labanti, Manuel; Sangiorgi, Gabriela; la Manna, Gaetano; Pinna, Antonio Daniele; Luppi, Mario; Lazzarotto, Tiziana
abstract

BACKGROUND: We performed serological and molecular pretransplant screening in solid organ transplant (SOT) donors and recipients in north-central Italy and a surveillance program for human herpes virus 8 (HHV8) infection after transplant, aiming to establish an optimal management of HHV8 infection in SOT recipients. METHODS: For pretransplant HHV8 screening in both donors and recipients, 6 serological (4 indirect immunofluorescent assays (IFA) and 2 enzyme-linked immunosorbent assays (ELISA) - both HHV8 lytic and latent antigen-based) and 2 molecular assays were used. A reference standard to identify HHV8-positive patients was defined by at least 2 positive assays. All transplant patients at risk to develop HHV8-related disease underwent virological posttransplant monitoring by quantitative real-time PCR assay. RESULTS: HHV8 seroprevalence was 4% (10/249) in donors and 18% (93/517) in organ recipients. The best performance was obtained by 2 lytic antigen-based IFAs that showed almost perfect agreement to the reference standard (0.943 and 0.931 Cohen’s kappa). HHV8-DNA was detected in 6.8% and 2.9% of HHV8-seropositive donor samples by in-house nested PCR and quantitative real-time PCR assays, respectively. After transplant, 3 out of 12 (25%) HHV8-mismatch patients (seropositive donor/seronegative recipient) developed a primary infection, 1 of whom developed a lethal nonmalignant illness. Two out of 93 HHV8-seropositive recipients (2.1%) had viral replication in posttransplant period, 1 of whom developed Kaposi’s sarcoma. CONCLUSIONS: Serological assays, specifically lytic IFAs, were the best methodological approach to identify HHV8-infected SOT donors and recipients. A very low incidence (1.9%) of posttransplant HHV8-related disease was observed.

2017 - Risk stratification for invasive fungal infections in patients with hematological malignancies: SEIFEM recommendations [Articolo su rivista]
Pagano, Livio; Busca, Alessandro; Candoni, Anna; Cattaneo, Chiara; Cesaro, Simone; Fanci, Rosa; Nadali, Gianpaolo; Potenza, Leonardo; Russo, Domenico; Tumbarello, Mario; Nosari, Annamaria; Aversa, Franco; Lessi, Federica; Criscuolo, Marianna; Farina, Francesca; Tisi, Maria Chiara; Turri, Gloria; Barone, Angelica; Spolzino, Angelica; Del Principe, Maria Ilaria; Quinto, Angela Maria; Di Blasi, Roberta; Maracci, Laura; Nabergoj, Mitja; Cambò, Benedetta; Pegoraro, Anna; Marchesi, Francesco; Pascale, Silvia; Passi, Angela; Carlisi, Melania; Polverelli, Nicola; Beggia, Barbara; Rambaldi, Benedetta; Prezioso, Lucia; Sanna, Marco
abstract

Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in immunocompromised patients. Patients with hematological malignancies undergoing conventional chemotherapy, autologous or allogeneic hematopoietic stem cell transplantation are considered at high risk, and Aspergillus spp. represents the most frequently isolated micro-organisms. In the last years, attention has also been focused on other rare molds (e.g., Zygomycetes, Fusarium spp.) responsible for devastating clinical manifestations. The extensive use of antifungal prophylaxis has reduced the infections from yeasts (e.g., candidemia) even though they are still associated with high mortality rates. This paper analyzes concurrent multiple predisposing factors that could favor the onset of fungal infections. Although neutropenia is common to almost all hematologic patients, other factors play a key role in specific patients, in particular in patients with AML or allogeneic HSCT recipients. Defining those patients at higher risk of IFIs may help to design the most appropriate diagnostic work-up and antifungal strategy.

2017 - SEIFEM 2010-E: economic evaluation of posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia receiving induction chemotherapy [Articolo su rivista]
Busca, Alessandro; Lessi, Federica; Verga, Luisa; Candoni, Anna; Cattaneo, Chiara; Cesaro, Simone; Dragonetti, Giulia; Delia, Mario; De Luca, Alessio; Guglielmi, Gaspare; Tumbarello, Mario; Martino, Giordana; Nadali, Gianpaolo; Fanci, Rosa; Picardi, Marco; Potenza, Leonardo; Nosari, Annamaria; Aversa, Franco; Pagano, Livio
abstract

Posaconazole demonstrated clinical superiority over fluconazole and itraconazole for prophylaxis of mold infections, although concerns exist regarding the high acquisition cost for posaconazole. In this respect, we sought to analyze the costs of antifungal prophylaxis in patients with acute myeloid leukemia (AML) who received prophylactic posaconazole (n = 510, 58%), itraconazole (n = 120, 14%) or fluconazole (n = 175, 20%) during induction chemotherapy. The estimated cost of antifungal prophylaxis as well as the costs of subsequent systemic antifungal therapy for treatening an invasive fungal infections (IFI) was higher in the posaconazole group compared to itraconazole and fluconazole groups. Based on the Monte Carlo simulations, the itraconazole group had the highest cost, followed by the posaconazole and fluconazole group, although the overall survival was higher in the posaconazole group as compared to the other groups. In conclusion, the cost of prophylaxis with posaconazole in AML patients compares favorably with conventional antifungal agents.

2017 - The expression of endothelin-1 in chronic lymphocytic leukemia is controlled by epigenetic mechanisms and extracellular stimuli. [Articolo su rivista]
Martinelli, Silvia; Maffei, Rossana; Fiorcari, Stefania; Quadrelli, Chiara; Zucchini, Patrizia; Benatti, Stefania; Potenza, Leonardo; Luppi, Mario; Marasca, Roberto
abstract

Endothelin-1 (ET-1) is a hormone peptide widely expressed and is involved in several biological processes, important not only for normal cell function but also for tumor development, including cell proliferation, invasion, metastasis, angiogenesis and osteogenesis. In accordance, ET-1 was already shown to contribute to the growth and progression of many different solid cancers. We recently demonstrated that ET-1 has a role in the pathogenesis of chronic lymphocytic leukemia (CLL) where it is abnormally expressed. In the context of this malignancy, ET-1 is able to mediate survival, drug-resistance and growth signals in leukemic cells. Previous studies, not conducted in CLL, have shown that ET-1 regulatory mechanisms are numerous and cell specific. Here, we valued the expression of ET-1 in CLL, in relation to DNA methylation but also in response to stimulation of some important pathways for the dialogue between CLL and microenvironment. We found that a high methylation of ET-1 first intron affects the basal expression of ET-1 in CLL. Moreover, we showed that the activation of CD40 or Toll-like receptor (TLR) by extracellular stimuli produces an augment of ET-1 level in CLL cells. Finally, we demonstrated the fundamental role of NF-kB signalling pathway in promoting and maintaining ET-1 expression in CLL cells, both in basal conditions and after CD40 activation.

2017 - The importance of cytogenetic and molecular analyses in eosinophilia-associated myeloproliferative neoplasms: an unusual case with normal karyotype and TNIP1- PDGFRB rearrangement and overview of PDGFRB partner genes [Articolo su rivista]
Maccaferri, Monica; Pierini, V.; Di Giacomo, D.; Zucchini, Patrizia; Forghieri, Fabio; Bonacorsi, G.; Paolini, Ambra; Quadrelli, Chiara; Giacobbi, F.; Fontana, Francesco; Cappelli, Gianni; Potenza, Leonardo; Marasca, Roberto; Luppi, Mario; Mecucci, C.
abstract

Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of eosinophilia-associated myeloproliferative neoplasms (Eo-MPN). Here, we would like to report a case of Eo-MPN with normal karyotype and rearrangement of TNIP1-PDGFRB, with unusual clinical presentation, which delayed the diagnosis and initiation of an appropriate therapy. We would also like to provide a review of the so far reported PDGFRB fusion partners in myeloid neoplasms, either myeloproliferative or myelodysplastic, summarizing clinical features and response to imatinib

2016 - All-trans retinoic acid (ATRA) in non-promyelocytic acute myeloid leukemia (AML): results of combination of ATRA with low-dose Ara-C in three elderly patients with NPM1-mutated AML unfit for intensive chemotherapy and review of the literature [Articolo su rivista]
Forghieri, Fabio; Bigliardi, Sara; Quadrelli, Chiara; Morselli, Monica; Potenza, Leonardo; Paolini, Ambra; Colaci, Elisabetta; Barozzi, Patrizia; Zucchini, Patrizia; Riva, Giovanni; Vallerini, Daniela; Lagreca, Ivana; Marasca, Roberto; Narni, Franco; Venditti, Adriano; Martelli, Maria Paola; Falini, Brunangelo; Lo Coco, Francesco; Amadori, Sergio; Luppi, Mario
abstract

Based upon the clinical behavior of three patients, we suggest that the combination of low-dose Ara-C and all-trans retinoic acid may potentially be effective in some elderly patients, unfit for intensive chemotherapy, affected with NPM1-mutated acute myeloid leukemia without FLT3 mutations, warranting perspective clinical studies in these selected patients.

2016 - Chronic and recurrent benign lymphadenopathy without constitutional symptoms associated with human herpesvirus-6B reactivation [Articolo su rivista]
Forghieri, Fabio; Luppi, Mario; Barozzi, Patrizia; Riva, Giovanni; Monica, Morselli; Bigliardi, Sara; Quadrelli, Chiara; Vallerini, Daniela; Maccaferri, Monica; Coluccio, Valeria; Paolini, Ambra; Colaci, Elisabetta; Goretta, Bonacorsi; Maiorana, Antonino; Sara, Tagliazucchi; Fabio, Rumpianesi; Mattioli, Francesco; Presutti, Livio; Gelmini, Roberta; Cermelli, Claudio; Giulio, Rossi; Patrizia, Comoli; Marasca, Roberto; Narni, Franco; Potenza, Leonardo
abstract

Chronic/recurrent behaviour may be encountered in some distinct atypical or malignant lymphoproliferations, while recurrences are not generally observed in reactive/benign lymphadenopathies. We retrospectively anal- ysed a consecutive series of 486 human immunodeficiency virus-negative adults, who underwent lymphadenectomy. Neoplastic and benign/reactive histopathological pictures were documented in 299 (61 5%) and 187 (38 5%) cases, respectively. Of note, seven of the 111 (6 3%) patients with benign lymphadenopathy without well-defined aetiology, showed chronic/ recurrent behaviour, without constitutional symptoms. Enlarged lymph nodes were round in shape and hypoechoic, mimicking lymphoma. Reac- tive follicular hyperplasia and paracortical expansion were observed. Human herpesvirus (HHV)-6B positive staining in follicular dendritic cells (FDCs) was documented in all seven patients. Serological, molecular and immunological examinations suggested HHV-6B reactivation. Among the remaining 104 cases with reactive lymphoid hyperplasia in the absence of well-known aetiology and without recurrences, positivity for HHV-6B on FDCs was found in three cases, whereas in seven further patients, a scanty positivity was documented in rare, scattered cells in inter-follicular regions. Immunohistochemistry for HHV-6A and HHV-6B was invariably negative on 134 lymph nodes, with either benign pictures with known aetiology or malignant lymphoproliferative disorders, tested as further controls. Future studies are warranted to investigate a potential association between HHV- 6B reactivation and chronic/recurrent benign lymphadenopathy.

2016 - Circulating functional T cells specific to human herpes virus 6 (HHV6) antigens in individuals with chromosomally integrated HHV6 [Articolo su rivista]
Barozzi, Patrizia; Riva, Giovanni; Vallerini, Daniela; Quadrelli, Chiara; Lagreca, Ivana; Eccheli, Roberta; Forghieri, Fabio; Coluccio, Valeria; Maccaferri, Monica; Paolini, Ambra; Colaci, Elisabetta; Morselli, Monica; Marasca, Roberto; Narni, Franco; Potenza, Leonardo; Luppi, Mario; Comoli, Patrizia; Campioli, Daniele; Trenti, Tommaso
abstract

Circulating functional T cells specific to human herpes virus 6 (HHV6) antigens in individuals with chromosomally integrated HHV6

2016 - Common Genetic Polymorphisms within NFκB-Related Genes and the Risk of Developing Invasive Aspergillosis [Articolo su rivista]
Lupiañez, Carmen B; Villaescusa, María T; Carvalho, Agostinho; Springer, Jan; Lackner, Michaela; Sánchez Maldonado, José M; Canet, Luz M; Cunha, Cristina; Segura Catena, Juana; Alcazar Fuoli, Laura; Solano, Carlos; Fianchi, Luana; Pagano, Livio; Potenza, Leonardo; Aguado, José M; Luppi, Mario; Cuenca Estrella, Manuel; Lass Flörl, Cornelia; Einsele, Hermann; Vázquez, Lourdes; Ríos Tamayo, Rafael; Loeffler, Jurgen; Jurado, Manuel; Sainz, Juan
abstract

Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4 rs12203592T/T genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95%CI 1.25-31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4AATC and IRF4GGTC haplotypes (not including the IRF4 rs12203592T risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4 rs12203592 SNP. Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA.

2016 - Ibrutinib modifies the function of monocyte/macrophage population in chronic lymphocytic leukemia [Articolo su rivista]
Fiorcari, Stefania; Maffei, Rossana; Audrito, Valentina; Martinelli, Silvia; Hacken, Elisa Ten; Zucchini, Patrizia; Grisendi, Giulia; Potenza, Leonardo; Luppi, Mario; Burger, Jan A; Deaglio, Silvia; Marasca, Roberto
abstract

In lymphoid organs, nurse-like cells (NLCs) show properties of tumor-associated macrophages, playing a crucial role in chronic lymphocytic leukemia (CLL) cell survival. Ibrutinib, a potent inhibitor of Bruton's tyrosine kinase (BTK), is able to counteract pro-survival signals in CLL cells. Since the effects on CLL cells have been studied in the last years, less is known about the influence of ibrutinib on NLCs properties. We sought to determine how ibrutinib modifies NLCs functions focusing on the balance between immunosuppressive and inflammatory features. Our data show that ibrutinib targets BTK expressed by NLCs modifying their phenotype and function. Treatment with ibrutinib reduces the phagocytic ability and increases the immunosuppressive profile of NLCs exacerbating the expression of M2 markers. Accordingly, ibrutinib hampers LPS-mediated signaling, decreasing STAT1 phosphorylation, while allows IL-4-mediated STAT6 phosphorylation. In addition, NLCs treated with ibrutinib are able to protect CLL cells from drug-induced apoptosis partially through the secretion of IL-10. Results from patient samples obtained prior and after 1 month of treatment with ibrutinib show an accentuation of CD206, CD11b and Tie2 in the monocytic population in the peripheral blood. Our study provides new insights into the immunomodulatory action of ibrutinib on monocyte/macrophage population in CLL.

2016 - Lenalidomide in chronic lymphocytic leukemia: The present and future in the era of tyrosine kinase inhibitors [Articolo su rivista]
Maffei, Rossana; Colaci, Elisabetta; Fiorcari, Stefania; Martinelli, Silvia; Potenza, Leonardo; Luppi, Mario; Marasca, Roberto
abstract

Lenalidomide is an immunomodulatory agent (IMiD) clinically active in chronic lymphocytic leukemia (CLL), both in heavily pre-treated patients and upfront. Lenalidomide has a unique mechanism of action in CLL. Its efficacy relies on a multifactorial mode-of-action (MOA), comprising a plethora of immunomodulatory actions, the disruption of mutualistic interactions inside CLL microenvironment and direct effects against leukemic cells. In the last few years, a number of new and highly effective drugs appeared in the scenario of CLL therapeutic options, i.e. tyrosine kinase inhibitors (TKIs), showing a good safety profile and impressive clinical response, also in high-risk patients. In this review, we describe the data from clinical studies about lenalidomide efficacy in CLL and we critically dissect the different mechanisms of action of this drug. We point the attention on open issues, including drug dosage and administration schedule, prediction of clinical response to lenalidomide, and combination therapeutic strategies. This overview would be useful to envision a possible role of lenalidomide in the treatment flow-chart of CLL, exploiting its peculiar MOA and also exploring the possible synergetic effect with new drugs.

2016 - Long-term cognitive sequelae in a case of Wernicke’s encephalopathy after allogeneic stem cell transplantation [Articolo su rivista]
Giovannelli, Fabio; Basagni, Benedetta; Potenza, Leonardo; Foschi, Valeria; De Tanti, Antonio
abstract

We describe the case of a non-alcoholic patient with chronic myeloid leukemia who developed iatrogenic Wernicke’s encephalopathy (WE) following stem cell transplantation. Four years after the WE acute event, the patient’s cognitive profile was mainly characterized by moderate memory impairment, and functional and daily-living difficulties. Our report sustains the hypothesis that a iatrogenic form of WE may produce long-term cognitive sequelae even when thiamine therapy is administered in the acute phase until the resolution of the neurological signs.

2016 - Mucorales-specific T cells in patients with hematologic malignancies [Articolo su rivista]
Potenza, Leonardo; Vallerini, Daniela; Barozzi, Patrizia; Riva, Giovanni; Gilioli, Andrea; Forghieri, Fabio; Candoni, Anna; Cesaro, Simone; Quadrelli, Chiara; Maertens, Johan; Rossi, Giulio; Morselli, Monica; Codeluppi, Mauro; Mussini, Cristina; Colaci, Elisabetta; Messerotti, Andrea; Paolini, Ambra; Maccaferri, Monica; Fantuzzi, Valeria; DEL GIOVANE, Cinzia; Stefani, Alessandro; Morandi, Uliano; Maffei, Rossana; Marasca, Roberto; Narni, Franco; Fanin, Renato; Comoli, Patrizia; Romani, Luigina; Beauvais, Anne; Viale, Pier Luigi; Latgè, Jean Paul; Lewis, Russell E.; Luppi, Mario
abstract

Background: Invasive mucormycosis (IM) is an emerging life-threatening fungal infection. It is difficult to obtain a definite diagnosis and to initiate timely intervention. Mucorales-specific T cells occur during the course of IM and are involved in the clearance of the infection. We have evaluated the feasibility of detecting Mucorales-specific T cells in hematological patients at risk for IM, and have correlated the detection of such cells with the clinical conditions of the patients. Methods and Findings: By using an enzyme linked immunospot assay, the presence of Mucorales-specific T cells in peripheral blood (PB) samples has been investigated at three time points during highdose chemotherapy for hematologic malignancies. Mucorales-specific T cells producing interferon-γ, interleukin-10 and interleukin-4 were analysed in order to detect a correlation between the immune response and the clinical picture. Twenty-one (10.3%) of 204 patients, accounting for 32 (5.3%) of 598 PB samples, tested positive for Mucorales-specific T cells. Two groups could be identified. Group 1, including 15 patients without signs or symptoms of invasive fungal diseases (IFD), showed a predominance of Mucorales-specific T cells producing interferon-gamma. Group 2 included 6 patients with a clinical picture consistent with invasive fungal disease (IFD):2 cases of proven IM and 4 cases of possible IFD. The proven patients had significantly higher number of Mucorales-specific T cells producing interleukin-10 and interleukin-4 and higher rates of positive samples by using derived diagnostic cut-offs when compared with the 15 patients without IFD. Conclusions: Mucorales-specific T cells can be detected and monitored in patients with hematologic malignancies at risk for IM. Mucorales-specific T cells polarized to the production of T helper type 2 cytokines are associated with proven IM and may be evaluated as a surrogate diagnostic marker for IM.

2016 - Polymorphisms in host immunity-modulating genes and risk of invasive aspergillosis: Results from the AspBIOmics Consortium [Articolo su rivista]
Lupiañez, C. B.; Canet, L. M.; Carvalho, A.; Alcazar Fuoli, L.; Springer, J.; Lackner, M.; Segura Catena, J.; Comino, A.; Olmedo, C.; Ríos, R.; Fernández Montoya, A.; Cuenca Estrella, M.; Solano, C.; López Nevot, M. Á.; Cunha, C.; Oliveira Coelho, A.; Villaescusa, T.; Fianchi, L.; Aguado, J. M.; Pagano, L.; López Fernández, E.; Potenza, Leonardo; Luppi, Mario; Lass Flörl, C.; Loeffler, J.; Einsele, H.; Vazquez, L.; Jurado, M.; Sainz, J.
abstract

Recent studies suggest that immune-modulating single-nucleotide polymorphisms (SNPs) influence the risk of developing cancer-related infections. Here, we evaluated whether 36 SNPs within 14 immune-related genes are associated with the risk of invasive aspergillosis (IA) and whether genotyping of these variants might improve disease risk prediction. We conducted a case-control association study of 781 immunocompromised patients, 149 of whom were diagnosed with IA. Association analysis showed that the IL4Rrs2107356 and IL8rs2227307 SNPs (using dbSNP numbering) were associated with an increased risk of IA (IL4Rrs2107356 odds ratio [OR], 1.92; 95% confidence interval [CI], 1.20 to 3.09; IL8rs2227307 OR, 1.73; 95% CI, 1.06 to 2.81), whereas the IL12Brs3212227 and IFNγrs2069705 variants were significantly associated with a decreased risk of developing the infection (IL12Brs3212227 OR, 0.60; 95% CI, 0.38 to 0.96; IFNγrs2069705 OR, 0.63; 95% CI, 0.41 to 0.97). An allogeneic hematopoietic stem cell transplantation (allo-HSCT)-stratified analysis revealed that the effect observed for the IL4Rrs2107356 and IFNγrs2069705 SNPs was stronger in allo-HSCT (IL4Rrs2107356 OR, 5.63; 95% CI, 1.20 to 3.09; IFNγrs2069705 OR, 0.24; 95% CI, 0.10 to 0.59) than in non-HSCT patients, suggesting that the presence of these SNPs renders patients more vulnerable to infection, especially under severe and prolonged immunosuppressive conditions. Importantly, in vitro studies revealed that carriers of the IFNγrs2069705C allele showed a significantly increased macrophage-mediated neutralization of fungal conidia (P = 0.0003) and, under stimulation conditions, produced higher levels of gamma interferon (IFNγ) mRNA (P = 0.049) and IFNγ and tumor necrosis factor alpha (TNF-α) cytokines (P value for 96 h of treatment with lipopolysaccharide [PLPS-96 h], 0.057; P value for 96 h of treatment with phytohemagglutinin [PPHA-96 h], 0.036; PLPS+PHA-96 h = 0.030; PPHA-72 h = 0.045; PLPS+PHA-72 h = 0.018; PLPS-96 h = 0.058; PLPS+PHA-96 h = 0.0058). Finally, we also observed that the addition of SNPs significantly associated with IA to a model including clinical variables led to a substantial improvement in the discriminatory ability to predict disease (area under the concentration-time curve [AUC] of 0.659 versus AUC of 0.564; P-2 log likehood ratio test = 5.2 · 10-4 and P50.000 permutation test = 9.34 · 10-5). These findings suggest that the IFNγrs2069705 SNP influences the risk of IA and that predictive models built with IFNγ, IL8, IL12p70, and VEGFA variants can used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.

2016 - Reversal of the glycolytic phenotype of primary effusion lymphoma cells by combined targeting of cellular metabolism and PI3K/Akt/ mTOR signaling [Articolo su rivista]
Mediani, Laura; Gibellini, Federica; Bertacchini, Jessika; Frasson, Chiara; Bosco, Raffaella; Accordi, Benedetta; Basso, Giuseppe; Bonora, Massimo; Calabrò, Maria Luisa; Mattiolo, Adriana; Sgarbi, Gianluca; Baracca, Alessandra; Pinton, Paolo; Riva, Giovanni; Rampazzo, Enrico; Petrizza, Luca; Prodi, Luca; Milani, Daniela; Luppi, Mario; Potenza, Leonardo; De Pol, Anto; Cocco, Lucio; Capitani, Silvano; Marmiroli, Sandra
abstract

PEL is a B-cell non-Hodgkin lymphoma, occurring predominantly as a lymphomatous effusion in body cavities, characterized by aggressive clinical course, with no standard therapy. Based on previous reports that PEL cells display a Warburg phenotype, we hypothesized that the highly hypoxic environment in which they grow in vivo makes them more reliant on glycolysis, and more vulnerable to drugs targeting this pathway. We established here that indeed PEL cells in hypoxia are more sensitive to glycolysis inhibition. Furthermore, since PI3K/Akt/mTOR has been proposed as a drug target in PEL, we ascertained that pathway-specific inhibitors, namely the dual PI3K and mTOR inhibitor, PF-04691502, and the Akt inhibitor, Akti 1/2, display improved cytotoxicity to PEL cells in hypoxic conditions. Unexpectedly, we found that these drugs reduce lactate production/extracellular acidification rate, and, in combination with the glycolysis inhibitor 2-deoxyglucose (2-DG), they shift PEL cells metabolism from aerobic glycolysis towards oxidative respiration. Moreover, the associations possess strong synergistic cytotoxicity towards PEL cells, and thus may reduce adverse reaction in vivo, while displaying very low toxicity to normal lymphocytes. Finally, we showed that the association of 2-DG and PF-04691502 maintains its cytotoxic and proapoptotic effect also in PEL cells co-cultured with human primary mesothelial cells, a condition known to mimic the in vivo environment and to exert a protective and pro-survival action. All together, these results provide a compelling rationale for the clinical development of new therapies for the treatment of PEL, based on combined targeting of glycolytic metabolism and constitutively activated signaling pathways.

2016 - The bone marrow represents an enrichment site of specific T lymphocytes against filamentous fungi [Articolo su rivista]
Vallerini, Daniela; Riva, Giovanni; Barozzi, Patrizia; Forghieri, Fabio; Lagreca, Ivana; Quadrelli, Chiara; Morselli, Monica; Bresciani, Paola; Cuoghi, Angela; Coluccio, Valeria; Maccaferri, Monica; Paolini, Ambra; Colaci, Elisabetta; Marasca, Roberto; Narni, Franco; Latgè, Jean Paul; Romani, Luigina; Comoli, Patrizia; Campioli, Daniele; Trenti, Tommaso; Luppi, Mario; Potenza, Leonardo
abstract

Bone marrow has already been described as an enrichment site for several antigen-specific T lymphocytes, but the presence of mould-specific T cells has never been investigated in the bone marrow. We have previously demonstrated that mould-specific T cells emerge in the peripheral blood of patients with invasive fungal infections (IFI) but tend to become undetectable after disease resolution. In seven patients with a history of IFI, we investigated the presence of mould-specific T cells secreting different cytokines in bone marrow and peripheral blood paired samples. The results showed that the frequencies of mould-specific T cells secreting the protective cytokine IFNI3 are significantly higher in bone marrow (BM) and are mainly represented by CD8+ T lymphocytes with effector phenotype. A putative disappearance of such protective BM responses after myeloablative therapy could contribute to the increased risk of IFI in hematologic patients.

2015 - Antineoplastic effects of liposomal siRNA treatment targeting BLIMP1/PRDM1 in primary effusion lymphoma [Articolo su rivista]
Riva, Giovanni; Lagreca, Ivana; Mattiolo, Adriana; Belletti, Daniela; Lignitto, Laura; Barozzi, Patrizia; Ruozi, Barbara; Vallerini, Daniela; Quadrelli, Chiara; Corradini, Giorgia; Forghieri, Fabio; Marasca, Roberto; Narni, Franco; Tosi, Giovanni; Forni, Flavio; Vandelli, Maria Angela; Amadori, Alberto; Chieco Bianchi, Luigi; Potenza, Leonardo; Calabro', Maria Luisa; Luppi, Mario
abstract

RNA interference (RNAi) has been suggested to represent a promising therapeutic approach in different disease settings. Primary effusion lymphoma (PEL) is a plasmablastic lymphoma consistently expressing B lymphocyte-induced maturation protein 1 (Blimp-1), a pivotal transcriptional regulator during terminal differentiation of B cells into plasma cells. Here we report, for the first time, that transient knockdown of the BLIMP1 gene (also known as PR Domain Containing 1 with ZNF Domain, or PRDM1) using small interfering RNA (siRNA) delivered by liposomes, induced remarkable killing in PEL cell lines. Furthermore, in a murine model of PEL, significantly prolonged survival was achieved by intraperitoneal treatment with such anti-BLIMP1 lipoplexes, while no vector-induced toxicity was observed. This effective and safe RNAi strategy, based on liposomal siRNA targeting a master transcription factor of post-germinal center B cells, may indeed be a potential treatment against plasmablastic lymphoma

2015 - Early Education for Early, Integrated Palliative Medicine [Articolo su rivista]
Potenza, Leonardo; Galli, Lisa; Morselli, Monica; Bandieri, Elena; Luppi, Mario
abstract

Early Education for Early, Integrated Palliative Medicine

2015 - Epidemiology and clinical outcome of lower respiratory tract infections by respiratory syncytial virus or parainfluenza virus type 3 in adults receiving treatment for either acute leukemia or severe aplastic anemia: a retrospective single center study [Articolo su rivista]
Bigliardi, Sara; Morselli, Monica; Potenza, Leonardo; Riva, Giovanni; Coluccio, Valeria; Maccaferri, Monica; Paolini, Ambra; Colaci, Elisabetta; Fantuzzi, Valeria; Soci, Francesco; Nasillo, Vincenzo; Messerotti, Andrea; Arletti, Laura; Pioli, Valeria; Lugli, Elisabetta; Gilioli, Andrea; Quadrelli, Chiara; Vallerini, Daniela; Barozzi, Patrizia; Lagreca, Ivana; Marasca, Roberto; Narni, Franco; Franceschini, Erica; Codeluppi, Mauro; Mussini, Cristina; Luppi, Mario; Forghieri, Fabio
abstract

Epidemiology and clinical outcome of lower respiratory tract infections by respiratory syncytial virus or parainfluenza virus type 3 in adults receiving treatment for either acute leukemia or severe aplastic anemia: a retrospective single center study

2015 - Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia [Articolo su rivista]
Fiorcari, Stefania; Martinelli, Silvia; Bulgarelli, Jenny; Audrito, V; Zucchini, Patrizia; Colaci, Elisabetta; Potenza, Leonardo; Narni, Franco; Luppi, Mario; Deaglio, S; Marasca, Roberto; Maffei, Rossana
abstract

Lenalidomide is an immunomodulatory agent clinically active in chronic lymphocytic leukemia patients. The specific mechanism of action is still undefined, but includes modulation of the microenvironment. In chronic lymphocytic leukemia patients, nurse-like cells differentiate from CD14(+) mononuclear cells and protect chronic lymphocytic leukemia cells from apoptosis. Nurse-like cells resemble M2 macrophages with potent immunosuppressive functions. Here, we examined the effect of lenalidomide on the monocyte/macrophage population in chronic lymphocytic leukemia patients. We found that lenalidomide induces high actin polymerization on CD14(+) monocytes through activation of small GTPases, RhoA, Rac1 and Rap1 that correlated with increased adhesion and impaired monocyte migration in response to CCL2, CCL3 and CXCL12. We observed that lenalidomide increases the number of nurse-like cells that lost the ability to nurture chronic lymphocytic leukemia cells, acquired properties of phagocytosis and promoted T-cell proliferation. Gene expression signature, induced by lenalidomide in nurse-like cells, indicated a reduction of pivotal pro-survival signals for chronic lymphocytic leukemia, such as CCL2, IGF1, CXCL12, HGF1, and supported a modulation towards M1 phenotype with high IL2 and low IL10, IL8 and CD163. Our data provide new insights into the mechanism of action of lenalidomide that mediates a pro-inflammatory switch of nurse-like cells affecting the protective microenvironment generated by chronic lymphocytic leukemia into tissues.

2015 - NPM1 mutations may reveal acute myeloid leukemia in cases otherwise morphologically diagnosed as myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms [Articolo su rivista]
Forghieri, Fabio; Paolini, Ambra; Morselli, Monica; Bigliardi, Sara; Bonacorsi, Goretta; Leonardi, Giovanna; Coluccio, Valeria; Maccaferri, Monica; Fantuzzi, Valeria; Faglioni, Laura; Colaci, Elisabetta; Soci, Francesco; Nasillo, Vincenzo; Messerotti, Andrea; Arletti, Laura; Pioli, Valeria; Zucchini, Patrizia; Quadrelli, Chiara; Corradini, Giorgia; Giacobbi, Francesca; Vallerini, Daniela; Riva, Giovanni; Barozzi, Patrizia; Lagreca, Ivana; Marasca, Roberto; Narni, Franco; Mecucci, Cristina; Ottaviani, Emanuela; Martinelli, Giovanni; Falini, Brunangelo; Luppi, Mario; Potenza, Leonardo
abstract

NPM1 mutations may reveal acute myeloid leukemia in cases otherwise morphologically diagnosed as myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms.

2015 - Philadelphia chromosome-positive acute lymphoblastic leukemia [Articolo su rivista]
Forghieri, Fabio; Luppi, Mario; Potenza, Leonardo
abstract

Philadelphia chromosome-positive Acute Lymphoblastic Leukemia

2015 - Pre-chemotherapy risk factors for invasive fungal diseases: prospective analysis of 1,192 patients with newly diagnosed acute myeloid leukemia (SEIFEM 2010-a multicenter study) [Articolo su rivista]
Caira, Morena; Candoni, Anna; Verga, Luisa; Busca, Alessandro; Delia, Mario; Nosari, Annamaria; Caramatti, Cecilia; Castagnola, Carlo; Cattaneo, Chiara; Fanci, Rosa; Chierichini, Anna; Melillo, Lorella; Mitra, Maria Enza; Picardi, Marco; Potenza, Leonardo; Salutari, Prassede; Vianelli, Nicola; Facchini, Luca; Cesarini, Monica; De Paolis, Maria Rosaria; Di Blasi, Roberta; Farina, Francesca; Venditti, Adriano; Ferrari, Antonella; Garzia, Mariagrazia; Gasbarrino, Cristina; Invernizzi, Rosangela; Lessi, Federica; Manna, Annunziata; Martino, Bruno; Nadali, Gianpaolo; Offidani, Massimo; Paris, Laura; Pavone, Vincenzo; Rossi, Giuseppe; Spadea, Antonio; Specchia, Giorgina; Trecarichi, Enrico Maria; Vacca, Adriana; Cesaro, Simone; Perriello, Vincenzo; Aversa, Franco; Tumbarello, Mario; Pagano, Livio
abstract

Correct definition of the level of risk of invasive fungal infections is the first step in improving the targeting of preventive strategies. We investigated the potential relationship between pre-hospitalization exposure to sources of fungi and the development of invasive fungal infections in adult patients with newly diagnosed acute myeloid leukemia after their first course of chemotherapy. From January 2010 to April 2012, all consecutive acute myeloid leukemia patients in 33 Italian centers were prospectively registered. Upon first admission, information about possible pre-chemotherapy risk factors and environmental exposure was collected. We recorded data regarding comorbid conditions, employment, hygienic habits, working and living environment, personal habits, hobbies, and pets. All invasive fungal infections occurring within 30 days after the first course of chemotherapy were recorded. Of the 1,192 patients enrolled in this study, 881 received intensive chemotherapy and were included in the present analysis. Of these, 214 developed an invasive fungal infection, including 77 proven/probable cases (8.7%). Of these 77 cases, 54 were proven/probable invasive mold infections (6.1%) and 23 were proven yeast infections (2.6%). Upon univariate analysis, a significant association was found between invasive mold infections and age, performance status, diabetes, chronic obstructive pulmonary disease, smoking, cocaine use, job, hobbies, and a recent house renovation. Higher body weight resulted in a reduced risk of invasive mold infections. Multivariate analysis confirmed the role of performance status, job, body weight, chronic obstructive pulmonary disease, and house renovation. In conclusion, several hospital-independent variables could potentially influence the onset of invasive mold infections in patients with acute myeloid leukemia. Investigation of these factors upon first admission may help to define a patient's risk category and improve targeted prophylactic strategies.

2015 - Risk of invasive fungal infection in patients affected by acute promyelocytic leukaemia. A report by the SEIFEM-D registry [Articolo su rivista]
Pagano, Livio; Stamouli, Maria; Tumbarello, Mario; Verga, Luisa; Candoni, Anna; Cattaneo, Chiara; Nadali, Gianpaolo; Mitra, Maria Enza; Mancini, Valentina; Nosari, Annamaria; Garzia, Maria Grazia; Delia, Mario; Storti, Sergio; Spadea, Antonio; Caramatti, Cecilia; Perriello, Vincenzo; Sanna, Marco; Vacca, Adriana; De Paolis, Maria Rosaria; Potenza, Leonardo; Salutari, Prassede; Castagnola, Carlo; Fanci, Rosa; Chierichini, Anna; Melillo, Lorella; Picardi, Marco; Facchini, Luca; Martino, Bruno; Di Blasi, Roberta; Cesarini, Monica; Offidani, Massimo; Vianelli, Nicola; Caira, Morena; Lessi, Federica; Ferrari, Antonella; Venditti, Adriano; Pavone, Vincenzo; Lo Coco, Francesco; Aversa, Franco; Busca, Alessandro
abstract

Patients with acute promyelocytic leukaemia (APL) are usually considered at lower risk for developing an infectious complication (Girmenia et al, 2003), principally because current treatments are mainly based on the induction of myeloid differentiation rather than the highly myeloablative properties of standard chemotherapy used in patients with acute myeloid leukaemia (AML). This prospective study, conducted in 33 locations throughout Italy, evaluated the incidence of invasive fungal infection (IFI) and the clinical characteristics in patients with APL compared to patients affected by other AML subtypes treated with intensive chemotherapy.

2015 - Safety profile of Erwinia asparaginase treatment in adults with newly diagnosed acute lymphoblastic leukemia: a retrospective monocenter study [Articolo su rivista]
Bigliardi, Sara; Morselli, Monica; Potenza, Leonardo; Coluccio, Valeria; Maccaferri, Monica; Paolini, Ambra; Colaci, Elisabetta; Fantuzzi, Valeria; Faglioni, Laura; Soci, Francesco; Nasillo, Vincenzo; Messerotti, Andrea; Pedrazzi, Paola; Marietta, Marco; Luppi, Mario; Forghieri, Fabio
abstract

Safety profile of Erwinia asparaginase treatment in adults with newly diagnosed acute lymphoblastic leukemia: a retrospective monocenter study.

2015 - Targeting neoplastic B cells and harnessing microenvironment: the “double face” of ibrutinib and idelalisib [Articolo su rivista]
Maffei, Rossana; Fiorcari, Stefania; Martinelli, Silvia; Potenza, Leonardo; Luppi, Mario; Marasca, Roberto
abstract

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not suitable for high dose chemotherapy with autologous stem cell transplantation (ASCT) has a dismal prognosis and no standard therapy. We designed an Italian multicenter retrospective study aimed at evaluating the safety and efficacy of rituximab plus bendamustine (R–B) as salvage treatment in patients not eligible for ASCT because of age and/or comorbidity or in patients with post-ASCT recurrence. Fifty-five patients with a median age of 76 years were included. The overall response rate was 50%, including 28% complete remission and 22% partial remission. The median overall survival (OS) was 10.8 months. The median progression free survival (PFS) was 8.8 months. Eleven patients are still alive and in complete remission at last follow-up (12–71 months). Toxicity was moderate, mainly grades 1 and 2. R–B showed promising efficacy results with an acceptable toxicity profile and should be further investigated, possibly in combination with novel drugs.

2014 - An unusual case of B-ALL occurring in a patient with acute promyelocytic leukemia in remission after two hematopoietic SCTs: whose are the leukemic cells? [Articolo su rivista]
Bigliardi, S; Morselli, M; Potenza, Leonardo; Bresciani, P; Cuoghi, A; Coluccio, Valeria; Riva, Giovanni; Paolini, Ambra; Fantuzzi, Valeria; Faglioni, Laura; Nasillo, Vincenzo; Messerotti, Andrea; Marasca, Roberto; Narni, Franco; Luppi, Mario; Forghieri, Fabio
abstract

We read with interest the recent article by Shiozaki H, et al. (Bone Marrow Transplant 2014; 49: 102–109) reporting a case of donor cell leukemia (DCL) occurring in a patient who previously underwent cord blood (CB) transplantation for myelodysplastic syndrome and describing the clinical and biological differences between DCL arising after hematopoietic SCT (HSCT) from either CB or BM sources. We would like to comment on these issues, reporting an unusual case of DCL in a patient with a long history of acute promyelocytic leukemia (APL).

2014 - An unusual case of splenomegaly and increased lactate dehydrogenase heralding acute myeloid leukemia with eosinophilia and RUNX1-MECOM fusion transcripts [Articolo su rivista]
Forghieri, Fabio; Bigliardi, Sara; Morselli, Monica; Potenza, Leonardo; Fantuzzi, Valeria; Faglioni, Laura; Nasillo, Vincenzo; Messerotti, Andrea; Paolini, Ambra; Luppi, Mario
abstract

We report the first case of acute myeloid leukemia (AML) with RUNX1-MECOM fusion transcripts, showing marked eosinophilia. A 63-year old man admitted in August 2013, had previously been observed in April 2013, because of persisting homogeneous splenomegaly and increased LDH, which were initially attributed to both minor β-thalassemia and previous acute myocardial infarction. However, based upon the retrospective analysis of clinical features combined with the documentation of both JAK2 V617F and c-KIT D816V mutations at AML diagnosis, an aggressive leukemic transformation with eosinophilia of a previously unrecognized myeloproliferative neoplasm, rather than the occurrence of de novo AML, may be hypothesized.

2014 - Chromosomally Integrated HHV-6 [Capitolo/Saggio]
Luppi, M.; Potenza, L.; Morissette, G.; Flamand, L.
abstract

Herpesviruses are members of a diverse family of viruses that colonize all vertebrates from fish to mammals. Interestingly, certain oncogenic herpesviruses such as the Marek's disease virus can be found integrated at low frequencies in the host's chromosomes. In recent years, the consistent and rather frequent detection (in approximately 1% of the human population) of human herpesvirus 6 (HHV-6) viral DNA integrated into human chromosomes has spurred renewed interest in our understanding of how these viruses infect, replicate, and propagate themselves. In this chapter, we provide a historical perspective on chromosomal integration by HHV-6 and present the current state of knowledge on integration and the possible clinical implications associated with HHV-6 chromosomal integration. © 2014 Elsevier B.V. All rights reserved.

2014 - Endothelin-1 promotes survival and chemoresistance in chronic lymphocytic leukemia B cells through eta receptor [Articolo su rivista]
Maffei, Rossana; Bulgarelli, Jenny; Fiorcari, Stefania; Martinelli, Silvia; Castelli, Ilaria; Valenti, Vanessa; Rossi, Davide; Bonacorsi, Goretta; Zucchini, Patrizia; Potenza, Leonardo; Vallisa, Daniele; Gattei, Valter; Del Poeta, Giovanni; Forconi, Francesco; Gaidano, Gianluca; Narni, Franco; Luppi, Mario; Marasca, Roberto
abstract

The endothelin axis, comprising endothelins (ET-1, ET-2 and ET-3) and their receptors (ET(A)R and ETBR), has emerged as relevant player in tumor growth and metastasis. Here, we investigated the involvement of ET-1/ET(A)R axis in chronic lymphocytic leukemia (CLL). CLL cells expressed higher levels of ET-1 and ETA receptor as compared to normal B cells. ET-1 peptide stimulated phosphoinositide-3-kinase and mitogen-activated protein kinase signaling pathways, improved survival and promoted proliferation of leukemic cells throughout ET(A)R triggering. Moreover, the blockade of ET(A)R by the selective antagonist BQ-123 inhibited the survival advantage acquired by CLL cells in contact with endothelial layers. We also found that blocking ET(A)R via BQ-123 interferes with ERK phosphorylation and CLL pro-survival effect mediated by B-cell receptor (BCR) activation. The pro-apoptotic effect of phosphoinositide-3-kinase δ inhibitor idelalisib and mitogen-activated protein kinase inhibitor PD98059 was decreased by the addition of ET-1 peptide. Then, ET-1 also reduced the cytotoxic effect of fludarabine on CLL cells cultured alone or co-cultured on endothelial layers. ET(A)R blockade by BQ-123 inhibited the ET-1-mediated protection against drug-induced apoptosis. Lastly, higher plasma levels of big ET-1 were detected in patients (n = 151) with unfavourable prognostic factors and shorter time to first treatment. In conclusion, our data describe for the first time a role of ET-1/ET(A)R signaling in CLL pathobiology. ET-1 mediates survival, drug-resistance, and growth signals in CLL cells that can be blocked by ET(A)R inhibition.

2014 - Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation [Articolo su rivista]
Cunha, Cristina; Aversa, Franco; Lacerda, João F; Busca, Alessandro; Kurzai, Oliver; Grube, Matthias; Löffler, Jürgen; Maertens, Johan A; Bell, Alain S; Inforzato, Antonio; Barbati, Elisa; Almeida, Bruno; Santos e. Sousa, Pedro; Barbui, Anna; Potenza, Leonardo; Caira, Morena; Rodrigues, Fernando; Salvatori, Giovanni; Pagano, Livio; Luppi, Mario; Mantovani, Alberto; Velardi, Andrea; Romani, Luigina; Carvalho, Agostinho
abstract

BACKGROUND: The soluble pattern-recognition receptor known as long pentraxin 3 (PTX3) has a nonredundant role in antifungal immunity. The contribution of single-nucleotide polymorphisms (SNPs) in PTX3 to the development of invasive aspergillosis is unknown. METHODS: We screened an initial cohort of 268 patients undergoing hematopoietic stem-cell transplantation (HSCT) and their donors for PTX3 SNPs modifying the risk of invasive aspergillosis. The analysis was also performed in a multicenter study involving 107 patients with invasive aspergillosis and 223 matched controls. The functional consequences of PTX3 SNPs were investigated in vitro and in lung specimens from transplant recipients. RESULTS: Receipt of a transplant from a donor with a homozygous haplotype (h2/h2) in PTX3 was associated with an increased risk of infection, in both the discovery study (cumulative incidence, 37% vs. 15%; adjusted hazard ratio, 3.08; P=0.003) and the confirmation study (adjusted odds ratio, 2.78; P=0.03), as well as with defective expression of PTX3. Functionally, PTX3 deficiency in h2/h2 neutrophils, presumably due to messenger RNA instability, led to impaired phagocytosis and clearance of the fungus. CONCLUSIONS: Genetic deficiency of PTX3 affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated with HSCT. (Funded by the European Society of Clinical Microbiology and Infectious Diseases and others.).

2014 - Long-term molecular remission with persistence of BCR-ABL1-specific cytotoxic T cells following imatinib withdrawal in an elderly patient with Philadelphia-positive ALL [Articolo su rivista]
Riva, Giovanni; Luppi, Mario; Lagreca, Ivana; Barozzi, Patrizia; Quadrelli, Chiara; Vallerini, Daniela; Zanetti, Eleonora; Basso, Sabrina; Forghieri, Fabio; Morselli, Monica; Maccaferri, Monica; Paolini, Ambra; Fantuzzi, Valeria; Messerotti, Andrea; Maffei, Rossana; Iacobucci, Ilaria; Martinelli, Giovanni; Marasca, Roberto; Narni, Franco; Comoli, Patrizia; Potenza, Leonardo
abstract

Long-term molecular remission with persistence of BCR-ABL1-specific cytotoxic T cells following imatinib withdrawal in an elderly patient with Philadelphia-positive ALL

2014 - Ruxolitinib for pulmonary extramedullary hematopoiesis in myelofibrosis [Articolo su rivista]
Maccaferri, Monica; Leonardi, Giovanna; Marasca, Roberto; Colaci, Elisabetta; Paolini, Ambra; Soci, Francesco; Forghieri, Fabio; Potenza, Leonardo; Narni, Franco; Luppi, Mario
abstract

Here we report an uncommon case of a patient with MF and pulmonary EMH treated with ruxolitinib

2014 - Use of a high sensitive nanofluidic array for the detection of rare copies of BCR-ABL1 transcript in patients with Philadelphia-positive acute lymphoblastic leukemia in complete response [Articolo su rivista]
Iacobucci, Ilaria; Lonetti, Annalisa; Venturi, Claudia; Ferrari, Anna; Papayannidis, Cristina; Ottaviani, Emanuela; Abbenante, Maria Chiara; Paolini, Stefania; Bresciani, Paola; Potenza, Leonardo; Parisi, Sarah; Cattina, Federica; Soverini, Simona; Russo, Domenico; Luppi, Mario; Martinelli, Giovanni
abstract

Monitoring of minimal residual disease (MRD) by quantification of BCR-ABL1 transcript levels has become a main part of the management of patients with BCR-ABL1-positive acute lymphoblastic leukemia (ALL) in treatment with tyrosine kinase inhibitors (TKIs). The failure to achieve molecular negativity shortly after starting TKI has been demonstrated to be predictive of relapse, suggesting that an accurate measurement of low BCR-ABL1 levels may have a role in preventing hematological relapse. Despite the big efforts made by many European laboratories within the European Study Group, at the time of writing a standardized procedure to quantify and express results is still missing for BCR-ABL1-positive ALL. In this study, in order to detect with high sensitivity low levels of BCR-ABL1 transcripts, we used a new technology and a new molecular approach based on microfluidic digital polymerase chain reaction (dPCR) using Taqman chemistry and we compared obtained results with those generated by the conventional method based on reverse transcriptase PCR reaction (RQ-PCR) for BCR-ABL1 and total ABL1, with TaqMan chemistry and with Applied Biosystems instrument. We demonstrated the dPCR is high-sensitive (able to detect a single copy of BCR-ABL1) and reliable (results are comparable to those obtained by BCR-ABL1 quantification with conventional technology), allowing an accurate monitoring of BCR-ABL1-positive ALL patients in complete remission.

2013 - Characterization of Specific Immune Responses to Different Aspergillus Antigens during the Course of Invasive Aspergillosis in Hematologic Patients [Articolo su rivista]
Potenza, Leonardo; Vallerini, Daniela; Barozzi, Patrizia; Riva, Giovanni; Forghieri, Fabio; Beauvais, Anne; Beau, Remi; Candoni, Anna; Maertens, Johan; Rossi, Giulio; Morselli, Monica; Zanetti, Eleonora; Quadrelli, Chiara; Codeluppi, Mauro; Guaraldi, Giovanni; Pagano, Livio; Caira, Morena; DEL GIOVANE, Cinzia; Maccaferri, Monica; Stefani, Alessandro; Morandi, Uliano; Tazzioli, Giovanni; Girardis, Massimo; Delia, Mario; Specchia, Giorgina; Longo, Giuseppe; Marasca, Roberto; Narni, Franco; Merli, Francesco; Imovilli, Annalisa; Apolone, Giovanni; Carvalho, Agostinho; Comoli, Patrizia; Romani, Luigina; Latgè, Jean Paul; Luppi, Mario
abstract

Several studies in mouse model of invasive aspergillosis (IA) and in healthy donors have shown that different Aspergillus antigens may stimulate different adaptive immune responses. However, the occurrence of Aspergillus-specific T cells have not yet been reported in patients with the disease. In patients with IA, we have investigated during the infection: a) whether and how specific T-cell responses to different Aspergillus antigens occur and develop; b) which antigens elicit the highest frequencies of protective immune responses and, c) whether such protective T cells could be expanded ex-vivo. Forty hematologic patients have been studied, including 22 patients with IA and 18 controls. Specific T cells producing IL-10, IFN-γ, IL-4 and IL-17A have been characterized through enzyme linked immunospot and cytokine secretion assays on 88 peripheral blood (PB) samples, by using the following recombinant antigens: GEL1p, CRF1p, PEP1p, SOD1p, α1-3glucan, β1-3glucan, galactomannan. Specific T cells were expanded through short term culture. Aspergillus-specific T cells producing non-protective interleukin-10 (IL-10) and protective interferon-gamma (IFN-γ) have been detected to all the antigens only in IA patients. Lower numbers of specific T cells producing IL-4 and IL-17A have also been shown. Protective T cells targeted predominantly Aspergillus cell wall antigens, tended to increase during the IA course and to be associated with a better clinical outcome. Aspergillus-specific T cells could be successfully generated from the PB of 8 out of 8 patients with IA and included cytotoxic subsets able to lyse Aspergillus hyphae. Aspergillus specific T-cell responses contribute to the clearance of the pathogen in immunosuppressed patients with IA and Aspergillus cell wall antigens are those mainly targeted by protective immune responses. Cytotoxic specific T cells can be expanded from immunosuppressed patients even during the infection by using the above mentioned antigens. These findings may be exploited for immunotherapeutic purposes in patients with IA. © 2013 Potenza et al.

2013 - Combined antifungal approach for the treatment of invasive mucormycosis in patients with hematologic diseases: a report from the SEIFEM and FUNGISCOPE registries. [Articolo su rivista]
Pagano, L; Cornely, Oa; Busca, A; Caira, M; Cesaro, S; Gasbarrino, C; Girmenia, C; Heinz, Wj; Herbrecht, R; Lass Flörl, C; Nosari, A; Potenza, Leonardo; Racil, Z; Rickerts, V; Sheppard, Dc; Simon, A; Ullmann, Aj; Valentini, Cg; Vehreschild, Jj; Candoni, A; Vehreschild, Mj
abstract

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2013 - Human Herpesvirus 8 (HHV8) Infection and Related Diseases in Italian Transplant Cohorts. [Articolo su rivista]
Riva, Giovanni; Barozzi, Patrizia; Quadrelli, Chiara; Vallerini, Daniela; Zanetti, Eleonora; Forghieri, Fabio; Chiereghin, A; Libri, I; Maggiore, U; Buzio, C; Lazzarotto, T; Narni, Franco; Luppi, Mario; Potenza, Leonardo
abstract

Human Herpesvirus 8 (HHV8) Infection and Related Diseases in Italian Transplant Cohorts

2013 - Immunity to Polyomavirus BK Infection: Immune Monitoring to Regulate the Balance between Risk of BKV Nephropathy and Induction of Alloimmunity. [Articolo su rivista]
Comoli, P; Cioni, M; Basso, S; Gagliardone, C; Potenza, Leonardo; Verrina, E; Luppi, Mario; Zecca, M; Ghiggeri, Gm; Ginevri, F.
abstract

Polyomavirus BK-associated nephropathy (PyVAN) is the main infectious cause of allograft damage after kidney transplantation. A number of studies revealed an association between the presence of BKV-specific cellular immunity and BK viral clearance, with patients failing to recover specific T cells progressing to PyVAN. Evolution to allograft dysfunction can be prevented by restoration of BKV-specific immunity through a stepwise reduction of maintenance immunosuppressive drugs. Prospective monitoring of BK viral load and specific immunity, together with B-cell alloimmune surveillance, may allow a targeted modification/reduction of immunosuppression, with the aim of obtaining viral clearance while preventing graft injury due to deposition of de novo donor-specific HLA antibodies and late/chronic antibody-mediated allograft injury. Innovative, immune-based therapies may further contribute to BKV infection prevention and control.

2013 - Pain and emozional distress in hematological patients throughout all phases of disease: results from a multidisciplinary research team in Modena University Hospital [Abstract in Rivista]
Alfieri, P; Bandieri, E; Berti, A; Bulgarelli, C; Rizzello, F; Favale, V; Forghieri, Fabio; Galli, L; Morselli, M; Potenza, Leonardo; Zanin, R; Artioli, F; Narni, Franco; Luppi, Mario
abstract

Background: According to some outdated reports, physical pain has been considered for many years a rare feature in the majority of blood malignancies, especially in acute leukemias, with the exception of advanced and terminal phases of disease. Unlike myeloma and lymphoma, there are few published data regarding the frequency of pain in patients with leukemia. Based on the modern concept of total cancer pain and on the importance of patient-reported outcomes, routine symptom assessment for hematologic patients should include, together with pain, even emotional distress, expressed in terms of anxiety and depression. Aims: In order to investigate prevalence and clinical relevance of pain and emotional distress in patients with acute myeloid (AML) and lymphoid (ALL) leukemia referred to our center, a multidisciplinary team consisting of nurses, physicians and psychologists has adopted two validated tools in the daily clinical practice: NRS (Numeral Rating Scale) and HADS (Hospital Anxiety and Depression Scale). ESAS (Edmonton Symptom Assessment System) has been compared with HADS with the aim to evaluate its diagnostic accuracy. Methods: NRS, HADS and ESAS scales were administered to newly diagnosed AML and ALL patients at diagnosis (T0), during the neutropenic phase (T15) and at discharge (T30), throughout hospital admissions and different phases of treatment. According to NRS scale pain intensity was classified as absent (0), mild (1-3), moderate (4-6) or severe (7-10). HADS is 14-item scale given by 7 ques- tions related to anxiety and 7 to depression, determining a score from 0 to 21. ESAS is a multiple-item visual analogue scale from 0 to 10. Anxiety and depression were considered positive with HADS 8 and ESAS 2 or more. Sensitivity and specificity tests were also performed. Results were mainly focused on induction phase, bone marrow transplation (BMT) and home care. Results: From June 2007 to December 2011 137 patients with AML and ALL were enrolled in the study (AML=109, ALL=28, M=85, F=52, median age=60). Another cohort of 31 patients referred to the home care program and affected by several blood disorders (NHL=8, MM=6, AML=5, MF=3, ITP=2, MDS=2, AA=1, ALL=1, CLL=1, CML=1, ET=1) was evaluated in parallel (M=18, F=13, median age=79) on monthly basis. 842 questionnaires were collected in the AML-ALL group. At diagnosis pain was reported in 46.2% of cases (mild=30.3%, moderate-severe=15.9%). The highest prevalence and intensi- ty of pain was observed in post-BMT neutropenic phase associated to mucositis (overall pain=61.5%, severe=30.8%). At diagnosis anxiety scores were positive in 33.6% for HADS and 51.1% for ESAS, while depression was present in 22.4% and 42.4% of cases, respectively. A higher prevalence of anxiety and depression was documented at T15 both in induction and post-BMT phases. Considering all HADS questionnaires anxiety and depression were positive in 26.7% and 25.2% of cases, respectively (10% with HADS from 11 upward, accounting for more severe symptoms), while an ESAS score of 2 or more was reported in 36.5% (anxiety) and 31.9% (depression) of cases. In the home care group pain was reported in 78 of all 157 questionnaires (overall pain=49.7%, mild=26.1%, moderate-severe=23.6%). Anxiety and depression were positive in 31.2% and 45.2% of HADS and in 45.9% and 49% of ESAS questionnaires, respectively. Overall test accuracy of ESAS (score of 2 or more) was 77.5% for anxiety and 76.4% for depression. Summary and Conclusions: Pain, anxiety and depression are common symptoms in a significant proportion of acute leukemia patients, impacting quality of life, clinical decisions and outcomes. Compared with HADS, ESAS showed adequate diagnostic accuracy in screening for anxiety and depression, and could be an excellent candidate for large-scale and routine assessment of physical pain, emotional distress and other symptoms, at diagnosis and during the ac

2012 - Atraumatic splenic rupture in patients with myelodysplastic syndromes: Report of a case occurred during treatment with 5-azacitidine and review of the literature. [Articolo su rivista]
Forghieri, Fabio; Morselli, M; Leonardi, G; Potenza, Leonardo; Bonacorsi, G; Coluccio, V; Paolini, Ambra; Maccaferri, Monica; Colaci, Elisabetta; Fantuzzi, Valeria; Bigliardi, Sara; Zaldini, Piera; Riva, Giovanni; Barozzi, Patrizia; Leonardi, L; Rossi, A; Marasca, Roberto; Narni, Franco; Luppi, Mario
abstract

No abstract available

2012 - Chronic/relapsing lymphadenopathy associated with HHV-6B infection: a new benign clinico-pathologic entity occurring in immunocompetent individuals [Abstract in Rivista]
Forghieri, Fabio; Potenza, Leonardo; Barozzi, Patrizia; Vallerini, Daniela; Riva, Giovanni; Zanetti, E; Quadrelli, C; Morselli, M; Leonardi, G; Maccaferri, M; Paolini, Ambra; Coluccio, Valeria; Colaci, Elisabetta; Pedrazzi, Letizia; Fantuzzi, Valeria; Bigliardi, Sara; Soci, Francesco; Bonacorsi, G; Zaldini, P; Rossi, G; Milani, M; Rivasi, Francesco; Gennari, W; Pecorari, M; Grottola, Antonella; Tagliazucchi, S; Rumpianesi, F; Mattioli, F; Presutti, Livio; Franzoni, Chiara; Gelmini, Roberta; Saviano, Massimo; Cermelli, Claudio; Marasca, Roberto; Narni, Franco; Luppi, Mario
abstract

Background. HHV-6 DNA sequences were disclosed in lymph node (LN) tis- sues of several patients with lymphoid malignancies, but a direct major role of HHV-6 in lymphoid malignant transformation has so far not been confirmed. In contrast, active HHV-6 infection has been associated to either infectious mononucleosis-like syndrome or acute lymphadenitis occurring in febrilepatients with systemic symptoms, or to Rosai-Dorfman disease in which viral antigens have been detected by immunohistochimical (IHC) analyses in both histiocytes and follicular dendritic cells (FDCs). Methods. We have retrospec- tively analyzed clinical and pathological data of 365 adult patients, consecutive- ly observed at our Institution over a period of 5 years (2006-2010), because of enlarged superficial lymph nodes and subsequently undergoing lymphadenec- tomy. In the benign/reactive cases in which well-recognized etiologies have been excluded, an involvement of HHV-6 active infection or reactivation was investigated by molecular and immunohistochemical examinations. Results. Malignant disorders, namely malignant lymphoproliferative disorders or solid cancer metastases, were found in 227 cases (62%), whereas in 138 cases (38%) benign/reactive pictures were documented on lymph node examination. Among these latter cases, a well-recognized etiology was demonstrated in 84 patients (61%), while in 54 cases (39%), a well-defined non-malignant reactive/infectious cause could not be documented. Immunohistochemical analyses resulted negative for both HHV-6A and HHV-6B in 38 of these latter lymph nodes (70%). In 7 patients (13%), a scattered, scanty and aspecific pos- itivity for HHV-6B late protein was documented in rare interfollicular plasma cells and histiocytes. Surprisingly, in 9 patients (17%), immunohistochemical analyses showed HHV-6B positive staining of FDCs, together with scattered positivity of interfollicular cells. These 9 HIV-negative adult patients (median age 42 years, range 18-76 years), with either localized or generalized LAP, were observed for a median follow-up of 38 months (range 28-166). Of note, six of them presented with recurrent LAP (one to 3 recurrences), without evolving into lymphoma. A common LN histological pattern at presentation showed florid fol- licular hyperplasia with concurrent mild paracortical expansion. Three cases also showed features consistent with PTGC. Constitutional symptoms were absent in all patients. The IHC reactions for both HHV-6A and HHV-6B, per- formed on further control cases, represented by 131 LN tissues from patients with either benign LAP induced by other known etiologies or lymphoma, were invariably negative. Serology was positive for both IgM and IgG with high avid- ity suggesting viral reactivation/reinfection. However, the molecular analyses failed to detect HHV-6 viremias in cell-free-serum samples of all the 9 patients with positive HHV-6B IHC staining, while positivity for HHV-6B DNA was dis- closed by PCR analyses in 7 out of the 7 LN tissues studied. Conclusions. We show for the first time that local reactivation/infection of HHV-6B should be con- sidered among the possible causes of chronic/relapsing benign LAP in immuno- competent individuals. IHC is the method of choice for investigating the pres- ence of HHV-6 infection in such cases. HHV-6B may indirectly modulate and trigger the proliferation of lymphocytes, by locally affecting FDCs and LN microenvironment. FDCs may indeed be involved in presenting HHV-6B anti- gens to other immune cells, mainly cortical B lymphocytes.

2012 - Evaluation of the practice of antifungal prophylaxis use in patients with newly diagnosed acute myeloid leukemia: results from the SEIFEM 2010-B registry. [Articolo su rivista]
Pagano, L; Caira, M; Candoni, A; Aversa, F; Castagnola, C; Caramatti, C; Cattaneo, C; Delia, M; De Paolis, Mr; Di Blasi, R; Di Caprio, L; Fanci, R; Garzia, M; Martino, B; Melillo, L; Mitra, Me; Nadali, G; Nosari, A; Picardi, M; Potenza, Leonardo; Salutari, P; Trecarichi, Em; Tumbarello, M; Verga, L; Vianelli, N; Busca, A; Seifem, Group
abstract

BACKGROUND: To analyze the efficacy of antifungal prophylaxis (AFP) with posaconazole and itraconazole in a real-life setting of patients with acute myeloid leukemia (AML) during the first induction of remission. METHODS: From January 2010 to June 2011, all patients with newly diagnosed AML were consecutively registered and prospectively monitored at 30 Italian hematological centers. Our analysis focused on adult patients who received intensive chemotherapy and a mold-active AFP for at least 5 days. To determine the efficacy of prophylaxis, invasive fungal disease (IFD) incidence, IFD-attributable mortality, and overall survival were evaluated. RESULTS: In total, 515 patients were included in the present analysis. Posaconazole was the most frequently prescribed drug (260 patients [50%]) followed by fluconazole (148 [29%]) and itraconazole (93 [18%]). When comparing the groups taking posaconazole and itraconazole, there were no significant differences in the baseline clinical characteristics, whereas there were significant differences in the percentage of breakthrough IFDs (18.9% with posaconazole and 38.7% with itraconazole, P< .001). The same trend was observed when only proven/probable mold infections were considered (posaconazole, 2.7% vs itraconazole, 10.7%, P= .02). There were no significant differences in the IFD-associated mortality rate, while posaconazole prophylaxis had a significant impact on overall survival at day 90 (P= .002). CONCLUSIONS: During the last years, the use of posaconazole prophylaxis in high-risk patients has significantly increased. Although our study was not randomized, it demonstrates in a real-life setting that posaconazole prophylaxis confers an advantage in terms of both breakthrough IFDs and overall survival compared to itraconazole prophylaxis. Clinical Trials Registration: NCT01315925.

2012 - How I treat HHV8/KSHV-related diseases in posttransplant patients. [Articolo su rivista]
Riva, Giovanni; Luppi, Mario; Barozzi, Patrizia; Forghieri, Fabio; Potenza, Leonardo
abstract

Posttransplantation human herpesvirus-8 (HHV8)/Kaposi sarcoma herpesvirus (KSHV) primary infection and/or reactivations are associated with uncommon and sometimes fatal, neoplastic, and non-neoplastic diseases. HHV8-related clinical manifestations notably range from Kaposi sarcoma (KS) to either primary effusion lymphoma or multicentric Castleman disease B-cell malignancies, and from polyclonal HHV8-positive plasmacytic lymphoproliferative disorders to bone marrow failure and peripheral cytopenias, associated or not with hemophagocytic syndromes, and to acute hepatitis syndromes. We reviewed the patient series reported in the literature and summarized clinical management aspects, in terms of diagnosis, follow-up, and treatment. We described typical clinical presentations and histopathologic diagnostic features of these diseases, and we discussed the role of HHV8-specific serologic, molecular, and immunologic assays, particularly focusing on recent data from HHV8-specific T-cell monitoring in posttransplantation KS patients. We finally discussed actual therapeutic options, namely, the reduction or discontinuation of immunosuppressive therapy or the switch from calcineurin inhibitors to mTOR inhibitors, as alternatives to antineoplastic chemotherapy, along with the use of antiherpesvirus agents as prophylactic or therapeutic measures, and treatment with rituximab in posttrans-plantation multicentric Castleman disease patients and non-neoplastic HHV8-associated syndromes.

2012 - Pathogenetic mechanisms of hepatitis C virus-induced B-cell lymphomagenesis. [Articolo su rivista]
Forghieri, Fabio; Luppi, Mario; Barozzi, Patrizia; Maffei, Rossana; Potenza, Leonardo; Narni, Franco; Marasca, Roberto
abstract

Hepatitis C virus (HCV) infection is probably the most common chronic viral infection and affects an estimated 180 million people worldwide, accounting for 3% of the global population. Although the liver is considered to be the primary target, extrahepatic manifestations are well recognized among patients with chronic HCV infection. Epidemiological studies have clearly demonstrated a correlation between chronic HCV infection and occurrence of B-cell non-Hodgkin's lymphomas (B-NHL). The clinical evidence that antiviral therapy has a significant role in the treatment at least of some HCV-associated lymphoproliferative disorders, especially indolent B-NHL, further supports the existence of an etiopathogenetic link. However, the mechanisms exploited by HCV to induce B-cell lymphoproliferation have so far not completely clarified. It is conceivable that different biological mechanisms, namely, chronic antigen stimulation, high-affinity interaction between HCV-E2 protein and its cellular receptors, direct HCV infection of B-cells, and "hit and run" transforming events, may be combined themselves and cooperate in a multifactorial model of HCV-associated lymphomagenesis.

2012 - Severe pneumonia caused by Legionella pneumophila serogroup 11, Italy. [Articolo su rivista]
Grottola, Antonella; Forghieri, Fabio; Meacci, M; Fabio, A; Pozzi, L; Marchegiano, P; Codeluppi, M; Morselli, M; Potenza, Leonardo; Paolini, Ambra; Coluccio, V; Luppi, Mario; Rumpianesi, F; Pecorari, M.
abstract

Legionella pneumophila serogroups (SGs) 1–16 cause pneumonia in humans. Although SG 1 is the serogroup most commonly associated with disease, we report a case of community-acquired legionellosis caused by SG 11.

2012 - Successful generation of p190-BCR ABL-specific T-cell lines for prophylaxis/treatment of minimal residual disease in HSCT recipients with Ph+ acute lymphoblastic leukaemia [Abstract in Rivista]
Basso, S.; Quartuccio, G.; Guido, I.; Quadrelli, C.; Gurrado, A.; Piantoni, L.; Zavras, N.; Cantoni, F.; Falcone, R.; Riva, Giovanni; Barozzi, Patrizia; Potenza, Leonardo; Maccario, R.; Zecca, M.; Luppi, Mario; Comoli, P.
abstract

Recent studies by our groups have demonstrated the presence of BM-homing, BCR-ABL specific cytotoxic T cells (CTL) in Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) patients during sole Imatinib mesylate maintenance treatment, that inversely correlated with minimal residual disease (MRD). This observation supports the notion that anti-tumor T lymphocytes may effectively participate in the control of Ph+ leukemic proliferation, and represents the rationale for a BCR-ABL-targeted cell therapy approach to prophylactically treat leukemic relapse after HSCT in patients with Ph+ALL. The aim of this study was to evaluate the feasibility of expanding BCR-ABL specific CTL from HSCT donors, to be employed as specific DLI after HSCT for Ph+ALL. We conducted scale-up experiments to validate an in vitro culture method to expand BCR-ABL specific CTL from HSCT donors, by peripheral blood mononuclear cell (PBMC) stimulation with 9-20mer peptide pools derived from the p190 BCR-ABL fusion region. T-cell lines, that included a median 70% CD4+ and 29% CD8+ T lymphocytes, were successfully generated from 5/6 individuals. The T-cell lines showed specific INFg production in Elispot assays consistently higher (median 130 SFU/10e5 cells, range 0-198) than non-cultured donor PBMC (median 4 SFU/10e5 cells). In a standard 51chromium release assay, 5 of 6 T-cell lines presented specific cytotoxic activity against PHA blasts pulsed with BCR-ABL peptide mix (median lysis 30%, range 6-65), CD3-redirected activity against P815 cells (median lysis 38%, range 36-52) with minimal residual alloreactivity (median lysis 4%, range 0-15). Our data indicate that BCR-ABL-specific T-cell lines with limited alloreactivity may be expanded from HSCT donors after stimulation with BCR-ABL fusion region-derived peptides. Their efficacy in containment of MRD after allogeneic HSCT for Ph+ALL remains to be evaluated in clinical trials.

2011 - A case of JAK2 V617F-positive myelodysplastic/myeloproliferative neoplasm with unusual morphology, resembling acute promyelocytic leukemia-like disorder with a chronic course. [Articolo su rivista]
Forghieri, Fabio; Morselli, M; Potenza, Leonardo; Maccaferri, Monica; Pedrazzi, Letizia; Coluccio, Valeria; Barozzi, Patrizia; Vallerini, Daniela; Riva, Giovanni; Zanetti, Eleonora; Quarelli, C; Bonacorsi, G; Artusi, Tullio; Zaldini, Piera; Zucchini, Patrizia; Marasca, Roberto; Narni, Franco; Falini, B; Torelli, Giuseppe; Luppi, Mario
abstract

An atypical case of myelodysplastic syndrome with morphologic aspect resempling acute promyelocytic leukemia, carring JA2 mutations.

2011 - BCR-ABL-specific cytotoxic T cells in the bone marrow of patients with Ph(+) acute lymphoblastic leukemia during second-generation tyrosine-kinase inhibitor therapy. [Articolo su rivista]
Riva, Giovanni; Luppi, Mario; Quadrelli, Chiara; Barozzi, Patrizia; Basso, S; Vallerini, Daniela; Zanetti, E; Morselli, M; Forghieri, Fabio; Maccaferri, M; Paolini, Ambra; DEL GIOVANE, Cinzia; D'Amico, Roberto; Marasca, Roberto; Narni, Franco; Iacobucci, I; Martinelli, G; Baccarani, M; Comoli, P; Potenza, Leonardo
abstract

BCR-ABL-specific cytotoxic T cells in the bone marrow of patients with Ph+ acute lymphoblastic leukemia during second-generation tyrosine-kinase inhibitor therapy

2011 - CDKN2A/B alterations impair prognosis in adult BCR-ABL1-positive acute lymphoblastic leukemia patients. [Articolo su rivista]
Iacobucci, I; Ferrari, A; Lonetti, A; Papayannidis, C; Paoloni, F; Trino, S; Storlazzi, Ct; Ottaviani, E; Cattina, F; Impera, L; Abbenante, Mc; Vignetti, M; Vitale, A; Potenza, Leonardo; Paolini, S; Soverini, S; Pane, F; Luppi, Mario; Foà, R; Baccarani, M; Martinelli, G.
abstract

PURPOSE: The 9p21 locus, encoding three important tumor suppressors (p16/CDKN2A, p14/ARF, and p15/CDKN2B), is a major target of inactivation in the pathogenesis of many human tumors.PATIENTS AND METHODS: To explore, at high resolution, the frequency and size of alterations affecting this locus in adult BCR-ABL1-positive acute lymphoblastic leukemia (ALL) and to investigate their prognostic value, 112 patients (101 de novo and 11 relapsed cases) were analyzed by genome-wide single-nucleotide polymorphism arrays and gene candidate deep exon sequencing. Paired diagnosis-relapse samples were further available and analyzed for 19 (19%) cases.RESULTS: CDKN2A/ARF and CDKN2B genomic alterations were identified in 29% and 25% of newly diagnosed patients, respectively. Deletions were monoallelic in 72% of cases, and in 43% of them, the minimal overlapping region of the lost area spanned only the CDKN2A/B gene locus. An analysis conducted at relapse showed an increase in the detection rate of CDKN2A/ARF loss (47%) compared with the time of diagnosis (P = 0.06). Point mutations within the 9p21 locus were found at very low levels, with only a nonsynonymous substitution in the exon 2 of CDKN2A. Of note, deletions of CDKN2A/B were significantly associated with poor outcomes in terms of overall survival (P = 0.0206), disease free-survival (P = 0.0010), and cumulative incidence of relapse (P = 0.0014).CONCLUSIONS: Inactivation of the 9p21 locus by genomic deletion is a frequent event in BCR-ABL1-positive ALL. Deletions are frequently acquired during leukemia progression and are a poor prognostic marker of long-term outcomes.

2011 - Chronic eosinophilic leukaemia with ETV6-NTRK3 fusion transcript in an elderly patient affected with pancreatic carcinoma [Articolo su rivista]
Forghieri, Fabio; Morselli, M; Potenza, Leonardo; Maccaferri, Monica; Pedrazzi, Letizia; Paolini, Ambra; Bonacorsi, G; Artusi, Tullio; Giacobbi, F; Corradini, G; Barozzi, Patrizia; Zucchini, Patrizia; Marasca, Roberto; Narni, Franco; Crescenzi, B; Mecucci, C; Falini, B; Torelli, Giuseppe; Luppi, Mario
abstract

Chronic eosinophilic leukaemia with ETV6-NTRK3 fusion transcript in an elderly patient affected with pancreatic carcinoma.A case report

2011 - Identification and characterization of Aspergillus-specific immune responses to diagnose invasive aspergillosis in high risk patients: a multicenter study [Abstract in Rivista]
Potenza, Leonardo; Vallerini, Daniela; Barozzi, Patrizia; Riva, Giovanni; Maertens, J; Candoni, A; Beauvais, A; Zanetti, Eleonora; Quadrelli, C; Morselli, M; Forghieri, Fabio; Maccaferri, M; Paolini, Ambra; Marasca, Roberto; DEL GIOVANE, Cinzia; D'Amico, Roberto; Ciceri, F; Comoli, P; Cesaro, S; Caira, M; Pagano, L; Romani, L; Narni, Franco; Latgè, Jp; Luppi, Mario
abstract

Background. The mortality of Invasive Aspergillosis (IA) still affects from 27% to 55% of high risk hematologic patients. The reasons of such a poor outcome also rely on several drawbacks limiting the di- agnostic accuracy of non cultural based diagnostic methods (NCBDM) and hampering the opportunities for an early intervention. Studies in mice model of IA and in healthy subjects have shown that Aspergillus-specific T-cells producing interferon-gamma (IFN- gamma-T1) are protective, while Aspergillus-specific T-cells pro- ducing interleukin-10 (IL-10-T2) are non-protective to IA. Aims. We have investigated whether the identification of Aspergillus-specific IFN-gamma-T1 and/or IL-10-T2 through an ex-vivo enzyme linked immunospot (ELISPOT) assay may be effective in the diagnosis of IA in high risk patients. Furthermore, in the proven IA patients, we have functionally and phenotipically characterized such T cells through the cytokine secretion assay (CSA). Methods. 180 patients (168 hemato- logic and 12 solid organ transplant patients) have been enrolled. They were classified, according the revised EORTC/MSG criteria, as fol- lows: 18 proven, 35 probable, 17 possible IA cases and 110 controls. The control patients were divided in two groups: group 1 included 86 (78.2%) patients with hystological and/or cultural verified infec- tious/inflammatory/neoplastic diseases, but other than IA; group 2 in- cluded 24 (21.8%) patients without clinical and/or microbiological features of IA. ELISPOT has been performed, as described [Potenza et al. Leukemia 2007; 21: 578-81], by using as antigens Aspergillus either conidia or recombinant antigens, namely CRF1p, GEL1p, PEP1p, SOD1p, α1-3 glucan, β1-3 glucan and galactomannan (GM). Results. The patient and sample positivity rates were 94.4%/89.5% in proven, 45.7%/35.3% in probable, 35.3%/50% in possible IA cases and 1.8%/4.5% in the controls, respectively. The sensitivity and speci- ficity of ELISPOT for the diagnosis of IA resulted 94.4% (95% CI, 73%-99%) and 98.2% (95% CI, 93%-99%), respectively. The PPV of the test was 89.5% (95% CI, 67%-99%), the NPV was 99.1% (95% CI, 94%-100%) and the efficiency was 97.6% (95% CI, 92.3%- 99.4%). The positive likelihood ratio (LR) resulted 51.89, the negative LR was 0.06 (Table 1A,B). In proven IA patients, CSA demonstrated that Aspergillus-specific IL-10-T2 were predominantly central memory (CM) CD4+ T cells (median frequency 0.37%/0.22%), while Aspergillus-specific IFN-gamma-T1 were either CD4+ or CD8+ cells of either effector memory (EM) or CM phenotype (median frequen- cies 0.24%/0.20%). Also lower frequencies of Aspergillus-specific ei- ther CD4+ or CD8+ T cells producing IL-4 (0.11%/0.19%) of EM phenotype, and EM CD8+ cells producing IL-17 (0.18%), were de- tected. Moreover, although CRF1p, GEL1p, α1-3 glucan and SOD1p resulted the antigens eliciting the highest number of Aspergillus-spe- cific IFN-gamma-T1, only GEL1p and α1-3 glucan were those most constantly targeted by protective immune responses along the entire course of the IA. Conclusions. Our findings demonstrate the potential of ELISPOT in the diagnosis of IA, suggesting that it may comple- ment the other NCBDM, enabling a more consistent diagnosis of IA. Furthermore, this study describes for the first time the Aspergillus- specific immune responses in patients with proven IA, identifying also the antigens predominantly targeted by protective IFN-gamma- T1, with possible consequences in designing strategies of either adoptive cell infusion or vaccine therapies.

2011 - May the indirect effects of CIHHV-6 in transplant patients be exerted through the reactivation of the viral replicative machinery? [Articolo su rivista]
Potenza, Leonardo; Barozzi, Patrizia; Rossi, G; Riva, Giovanni; Vallerini, Daniela; Zanetti, Eleonora; Quadrelli, Chiara; Morselli, M; Forghieri, Fabio; Maccaferri, Monica; Paolini, Ambra; Marasca, Roberto; Narni, Franco; Luppi, Mario
abstract

Indirect effects of CIHHV-6 in transplant patients

2011 - Mucorles-specific T cells emerge in the course of invasive mucormucosis and may be used as a surrogate diagnostic marker in high-risk patients [Articolo su rivista]
Potenza, Leonardo; Vallerini, Daniela; Barozzi, Patrizia; Riva, Giovanni; Forghieri, Fabio; Zanetti, Eleonora; Quadrelli, Chiara; Candoni, A; Maertens, J; Rossi, Giulio; Morselli, M; Codeluppi, M; Paolini, Ambra; Maccaferri, Monica; DEL GIOVANE, Cinzia; D'Amico, Roberto; Rumpianesi, F; Pecorari, M; Cavalleri, F; Marasca, Roberto; Narni, Franco; Luppi, Mario
abstract

Mucorales-specific T cells have been investigated in 28 hematologic patients during the course of their treatment. Three developed proven invasive mucormycosis (IM), 17 infections of known etiologies but other than IM, and 8 never showed fever upon the period of observation. The Mucorales-specific T cells may be detected only in patients with IM, at diagnosis and along the entire course of the IM, but neither before nor long time after the resolution of the infection. Such T cells produced predominantly interleukin-4, interferon-gamma (IFN-γ), interleukin-10, and to a lesser extent also interleukin-17, and belonged to either CD4+ or CD8+ subsets. The specific T cells producing IFN-γ were able to directly induce damage of Mucorales hyphae. None of the 25 patients without IM showed Mucorales-specific T cells. Specific T cells contribute to human immune responses against fungi of the order Mucorales and could be evaluated as a surrogate diagnostic marker of IM.

2011 - Tumor-targeted immunoliposomal nanosystems to deliver either Cidofovir or Antineoplastic SiRNA against Primary Effusion Lymphoma (PEL) [Relazione in Atti di Convegno]
Riva, Giovanni; Belletti, Daniela; Ruozi, Barbara; Barozzi, Patrizia; Vallerini, Daniela; Quadrelli, Chiara; Zanetti, Eleonora; Morselli, M; Forghieri, Fabio; Marasca, Roberto; Narni, Franco; Tosi, Giovanni; Forni, Flavio; Vandelli, Maria Angela; Potenza, Leonardo; Luppi, Mario
abstract

Therapeutic applications of siRNA-mediated gene silencing appear to be highly dependent on the use of pharmaco-technologic carrier systems, able to protect siRNAs from rapid degradation upon administration, as well as to specifically deliver them to target cells. Actually, while siRNA-expressing viral vectors are burdened with safety concerns for their clinical use, the development of modified liposomal nanocarriers may represent a feasible option to harness the therapeutic potential of targetedantineoplastic siRNAs. Recently, we have successfully developed and characterized effective immunoliposomal nanosystems (ILNs) for targeted delivery of Cidofovir (an anti-herpesviral nucleotideanalogue, also showing antitumor activity) against PEL cell lines, demonstrating a significant improvement of the antineoplastic activity of the drug, especially at lower doses (less than 1nM). Thus, we tried to adapt such PEL-specific ILNs (PEGilated nanovescicles made of cationic/neutral lipids, engineered with anti-CD138 moAb on their surface) to efficiently encapsulate siRNAs and deliver them into PEL cell lines (highly expressing CD138 membrane protein). Our preliminary data showed thatsingle treatments with anti-PEL ILNs, delivering specific siRNAs against Blimp1 (Prdm1), which is a master transcription factor in PEL (a plasmablast/pre-plasmacell lymphoma, consistently Bcl-6 neg, Blimp1 pos), were able to induce a dose-dependent (50-200nM) inhibition of Blimp1 production (as assessed by Blimp1 mRNA and protein levels using RT-PCR and Western Blot, respectively), and this was strongly associated with enhanced cell death (more than 80%, using Annexin V/PI test). In particular, we observed a massive reduction of PEL viability (mean viable cells 8%, range 3-15%) as soon as 48-72 hours after treatment with 100nM anti-Blimp1 siRNAs. Interestingly, these data may resemble those described in multiple myeloma cell lines, after transduction with lentiviral vector constitutively expressing anti-Blimp1 shRNAs. Further studies on PEL murine models are now warranted to assess the efficacy and toxicity profile of in-vivo treatment with PEL-specific ILNs, loadedwith either Cidofovir or anti-Blimp1 siRNAs.

2011 - β-HHVs and HHV-8 in Lymphoproliferative Disorders. [Articolo su rivista]
Quadrelli, Chiara; Barozzi, Patrizia; Riva, Giovanni; Vallerini, Daniela; E., Zanetti; Potenza, Leonardo; Forghieri, Fabio; Luppi, Mario
abstract

Similarly to Epstein-Barr virus (EBV), the human herpesvirus-8 (HHV-8) is a γ-herpesvirus, recently recognized to be associated with the occurrence of rare B cell lymphomas and atypical lymphoproliferations, especially in the human immunodeficiency virus (HIV) infected subjects. Moreover, the human herpesvirus-6 (HHV-6), a β-herpesvirus, has been shown to be implicated in some non-malignant lymph node proliferations, such as the Rosai Dorfman disease, and in a proportion of Hodgkin's lymphoma cases. HHV-6 has a wide cellular tropism and it might play a role in the pathogenesis of a wide variety of human diseases, but given its ubiquity, disease associations are difficult to prove and its role in hematological malignancies is still controversial. The involvement of another β-herpesvirus, the human cytomegalovirus (HCMV), has not yet been proven in human cancer, even though recent findings have suggested its potential role in the development of CD4(+) large granular lymphocyte (LGL) lymphocytosis. Here, we review the current knowledge on the pathogenetic role of HHV-8 and human β-herpesviruses in human lymphoproliferative disorders.

2010 - Common vascular endothelial growth factor variants and risk for posttransplant Kaposi sarcoma. [Articolo su rivista]
Zanetti, E; Barozzi, Patrizia; Brown, Ee; Bosco, R; Vallerini, Daniela; Riva, Giovanni; Quadrelli, Chiara; Potenza, Leonardo; Forghieri, Fabio; Montagnani, G; D'Amico, Roberto; Del Giovane, Cinzia; Duraes, C; Whitby, D; Machado, Jc; Schulz, Tf; Torelli, G; Luppi, Mario
abstract

No abstract available

2010 - Emergence of BCR-ABL-specific cytotoxic T cells in the bone marrow of patients with Ph+ acute lymphoblastic leukemia during long-term Imatinib mesylate treatment. [Articolo su rivista]
Riva, Giovanni; Luppi, Mario; Barozzi, Patrizia; Quadrelli, Chiara; Basso, S; Vallerini, Daniela; Zanetti, Eleonora; Morselli, M; Forghieri, Fabio; Maccaferri, M; Volzone, F; DEL GIOVANE, Cinzia; D'Amico, Roberto; Locatelli, F; Torelli, Giuseppe; Comoli, P; Potenza, Leonardo
abstract

Imatinib mesylate (IM) has been demonstrated to be permissive for the emergence of T cells directed against chronic myeloid leukemia cells. Ten Philadelphia chromosome-positive acute lymphoblastic leukemia patients, receiving high dose IM maintenance, underwent a long-term immunological monitoring (range 2-65 months) of (p190)BCR-ABL-specific T cells in the bone marrow (BM) and peripheral blood (PB). (p190)BCR-ABL-specific T lymphocytes were detected in all patients, more frequently in BM than in PB samples (67% vs 25%, p&lt;0.01), and resulted significantly associated with lower minimal residual disease values (p&lt;0.001), while absent at leukemia relapse. Specific T cells were mainly effector memory CD8+ and CD4+ T cells, producing IFNgamma, TNFalpha and IL-2 (median % positive cells: 3.34, 3.04, 3.58, respectively). Cytotoxic subsets able to lyse BCR-ABL-positive leukemia blasts were also detectable. Whether these autologous (p190)BCR-ABL-specific T cells may be detectable under other tyrosine-kinase inhibitors, expanded ex vivo and exploited for immunotherapy remains to be addressed.

2010 - HHV-6 and atypical lymphoproliferative disorders: are only qualitative molecular examinations sufficient to support a pathogenetic role? [Articolo su rivista]
Forghieri, Fabio; Potenza, Leonardo; Barozzi, Patrizia; Vallerini, Daniela; Riva, Giovanni; Zanetti, Eleonora; Quadrelli, Chiara; Torelli, Giuseppe; Luppi, Mario
abstract

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2010 - Organising pneumonia mimicking invasive fungal disease in patients with leukaemia. [Articolo su rivista]
Forghieri, Fabio; Potenza, Leonardo; Morselli, M; Maccaferri, Monica; Pedrazzi, L; Barozzi, Patrizia; Vallerini, Daniela; Riva, Giovanni; Zanetti, Eleonora; Quadrelli, Chiara; Rossi, G; Rivasi, Francesco; Messino', M; Rumpianesi, F; Grottola, Antonella; Venturelli, C; Pecorari, M; Codeluppi, M; Torelli, Giuseppe; Luppi, Mario
abstract

Clinical charts from 63 consecutive highly immunocompromised haematologic patients presenting with pulmonary nodular lesions on CT scan, classified as either probable or possible invasive fungal disease (IFD) according to the revised EORTC/MSG classification, were retrospectively studied. Histopathological analysis of lung tissues, available for 23 patients, demonstrated proven IFD in 17 cases (14 invasive aspergillosis and 3 invasive zygomycosis), diffuse alveolar damage in one and organising pneumonia (OP) in five cases. In the OP cases, three of which have been defined as probable IFD according to EORTC/MSG classification, extensive immunohistochemical, molecular and immunological analyses for fungi were negative. Our case descriptions extend the notion that OP may be encountered as a distinct histopathological entity in pulmonary nodular lesions in patients with leukaemia with probable/possible IFD.

2010 - Pain and emotional distress in leukemia patients at diagnosis. [Articolo su rivista]
Morselli, M; Bandieri, E; Zanin, R; Buonaccorso, L; D'Amico, Roberto; Forghieri, Fabio; Pietramaggiori, A; Potenza, Leonardo; Berti, A; Cacciapaglia, G; Molitierno, A; Galli, L; Artioli, F; Ripamonti, C; Bruera, E; Torelli, Giuseppe; Luppi, Mario
abstract

Pain and emotional distress in leukemia patients at diagnosis.

2010 - Splenic hyalohyphomycosis, molecularly and immunologically consistent with invasive aspergillosis, in a patient with acute lymphoblastic leukemia. [Articolo su rivista]
Forghieri, Fabio; Rossi, G; Potenza, Leonardo; Morselli, M; Barozzi, Patrizia; Vallerini, Daniela; Messino, M; Rumpianesi, F; Pecorari, M; Torelli, Giuseppe; Luppi, Mario
abstract

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2010 - Translational challenges of human herpesvirus 6 chromosomal integration. [Articolo su rivista]
Potenza, Leonardo; Barozzi, Patrizia; Torelli, G; Luppi, Mario
abstract

No abstract available

2010 - invasive aspergillosis in patients with acute myeloid leukemia: SEIFEM-2008 registry study. [Articolo su rivista]
Pagano, L; Caira, M; Candoni, A; Offidani, M; Martino, B; Specchia, G; Pastore, D; Stanzani, M; Cattaneo, C; Fanci, R; Caramatti, C; Rossini, F; Luppi, Mario; Potenza, Leonardo; Ferrara, F; Mitra, Me; Fadda, Rm; Invernizzi, R; Aloisi, T; Picardi, M; Bonini, A; Vacca, A; Chierichini, A; Melillo, L; de Waure, C; Fianchi, L; Riva, M; Leone, G; Aversa, F; Nosari, A.
abstract

Background This study evaluated prognostic factors, treatments and outcome of invasive aspergillosis (IA) in patients with acute myeloid leukemia (AML). DESIGN AND METHODS: The registry, which was activated in 2004 and closed in 2007, collected data on AML patients admitted to 21 hematological divisions in tertiary care centres or university hospitals in Italy, who developed proven or probable IA. RESULTS: 140 cases of IA were collected, with most cases occurring in post-induction aplasia, the highest risk phase in AML. IA-attributable mortality rate was 27%, confirming previous reports of a downward trend. Univariate and multivariate analyses revealed AML stage, duration of, and recovery from, neutropenia as independent prognostic factors. We analyzed outcomes after treatment with the three most frequently used drugs (liposomal amphotericin B, caspofungin, voriconazole). No differences emerged in survival on the 120th day or in the overall response rate which was 71%, ranging from 61% with caspofungin to 84% with voriconazole. Conclusions Our series confirms the downward trend in mortality rates reported in previous series, with all new drugs providing similar survival and response rates. Recovery from neutropenia and disease stage are crucial prognostic factors. Efficacious antifungal drugs bridge the gap due to poor hematological and immunological reconstitution.

2009 - Acute promyelocytic leukemia in very elderly patients: still aclinical challenge. [Articolo su rivista]
Forghieri, Fabio; Luppi, Mario; Morselli, M; Favale, V; Potenza, Leonardo; Volzone, F; Maccaferrim, ; Torelli, Giuseppe
abstract

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2009 - Changes in T-Cell Responses Against Human Herpesvirus-8 Correlate with the Disease Course of Iatrogenic Kaposi's Sarcoma in a Patient with Undifferentiated Arthritis [Articolo su rivista]
Barozzi, Patrizia; Potenza, Leonardo; Riva, Giovanni; Vallerini, Daniela; Quadrelli, Chiara; Bosco, Raffaella; Morselli, M; Forghieri, F; Volzone, F; Rossi, G; Ferri, Clodoveo; Bovini, C; Ciceri, F; Bordignon, C; Whitby, D; Schulz, Tf; Torelli, Giuseppe; Luppi, Mario
abstract

OBJECTIVES: To describe the first in-depth analysis of both the T-cell responses against human herpesvirus-8 (HHV-8) and the HHV-8 viral load in 1 patient who developed iatrogenic HHV-8-associated-Kaposi's sarcoma (KS) following immunosuppressive treatment for undifferentiated arthritis and to review the literature on iatrogenic KS (IKS). METHODS: T-cell responses against HHV-8 lytic and latent antigens were analyzed by ex vivo enzyme-linked immunospot (Elispot) and HHV-8 viral load was assessed by quantitative polymerase chain reaction, in sequential peripheral blood samples from a 55-year-old woman who developed skin/mucosal and visceral KS, while receiving treatment with cyclosporine, methotrexate, and methylprednisolone for undifferentiated arthritis. RESULTS: KS may result from HHV-8 infection in patients undergoing immunosuppressive treatment for rheumatic diseases and this is the first case of IKS occurring in undifferentiated arthritis. A role for immune surveillance in the pathogenesis of IKS is supported by the observation of disease regression following discontinuation of immunosuppressive therapy. In a 4-year follow-up, we showed that variations of the virus-specific immune responses but not of the viral load correlated well with the disease course, characterized by 2 remission and subsequent relapse phases, following changes of immunosuppressive therapy. CONCLUSIONS: We have provided evidence of a clear-cut correlation between changes in immunologic markers of HHV-8 infection and the disease course of this viral associated tumor, concomitant with variations of immunosuppressive treatment. Thus, ex vivo enzyme-linked immunospot for HHV-8-specific T-cell responses represents a new tool for the clinical management of rheumatic patients with IKS.

2009 - Diagnosis of aspergillosis: Role of proteomics [Articolo su rivista]
Potenza, Leonardo; Barozzi, Patrizia; Vallerini, Daniela; Zanetti, Eleonora; Torelli, Giuseppe; Luppi, Mario
abstract

The expansion of the antifungal armamentarium and the implementation of imaging techniques and new nonculture-based fungal diagnostics (NCBFDs) have improved the survival of patients with invasive aspergillosis (IA). However, mortality rates still remain high, possibly influenced by several pitfalls, affecting NCBFDs and reducing the window of opportunity for earlier treatment. A large body of in vitro and in vivo studies has demonstrated that several fungal proteic components are strongly immunogenic, and both the adaptive immunity and the innate branch are heavily involved in the recognition and clearance of fungal pathogens, resulting, on occasion, in a useful tool for the treatment of IA. By evaluating these studies, this review considers the possibility of exploiting either components of the innate or adaptive immunity to support the rapid and early diagnosis of IA. Copyright © 2009 by Current Medicine Group LLC.

2009 - Indirect Antitumor Effects of Mammalian Target of Rapamycin Inhibitors Against Kaposi Sarcoma in Transplant Patients [Articolo su rivista]
Barozzi, Patrizia; Riva, Giovanni; Vallerini, Daniela; Bosco, Raffaella; Quadrelli, Chiara; Zanetti, Eleonora; Potenza, Leonardo; Forghieri, Fabio; Torelli, Giuseppe; Luppi, Mario
abstract

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2009 - Interferon-alpha may restore sensitivity to tyrosine-kinase inhibitors in Philadelphia chromosome positive acute lymphoblastic leukaemia with F317L mutation [Articolo su rivista]
Potenza, Leonardo; Volzone, F; Riva, Giovanni; Soverini, S; Martinelli, S; Iacobucci, I; Gnani, A; Barozzi, Patrizia; Forghieri, Fabio; Morselli, M; Zanetti, E; Maccaferri, Monica; Baccarani, M; Martinelli, G; Torelli, Giuseppe; Luppi, Mario
abstract

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2009 - Persistent hiccups as an adverse event to FLAG-IDA regimenfor leukemia. [Articolo su rivista]
Forghieri, Fabio; Maccaferri, M; Morselli, M; Potenza, Leonardo; Volzone, F; Bandieri, E; Torelli, Giuseppe; Luppi, Mario
abstract

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2009 - Prevalence of Human Herpesvirus-6 Chromosomal Integration (CIHHV-6) in Italian Solid Organ and Allogeneic Stem Cell Transplant Patients [Articolo su rivista]
Potenza, Leonardo; Barozzi, Patrizia; Masetti, M; Pecorari, M; Bresciani, P; Gautheret Dejean, A; Riva, Giovanni; Vallerini, Daniela; Tagliazucchi, S; Codeluppi, M; DI BENEDETTO, Fabrizio; Gerunda, Giorgio Enrico; Narni, Franco; Torelli, Giuseppe; Luppi, Mario
abstract

The unique phenomenon of human herpesvirus-6 (HHV-6) chromosomal integration (CIHHV-6) may account for clinical drawbacks in transplant setting, being misinterpreted as active infection and leading to unnecessary and potentially harmful treatments. We have investigated the prevalence of CIHHV-6 in 205 consecutive solid organ (SO) and allogeneic stem cell transplant (alloSCT) Italian patients. Fifty-two (38.5%) of 135 solid organ transplant (SOT) and 16 (22.8%) of 70 alloSCT patients resulted positive for plasma HHV-6 DNA by real-time polymerase chain reaction. Seven SOT and three alloSCT patients presented HHV-6-related diseases, requiring antivirals. Two further patients (0.9%) were identified, presenting high HHV-6 loads. The quantification of HHV-6 on hair follicles disclosed the integrated state, allowing the discontinuation of antivirals. Before starting specific treatments, CIHHV-6 should be excluded in transplant patients with HHV-6 viremia by the comparison of HHV-6 loads on different fluids and tissues. Pretransplantation screening of donors and recipients may further prevent the misdiagnosis of CIHHV-6.

2008 - A possible role for low-dose cyclosporine in refractory immune thrombocytopenic purpura. [Articolo su rivista]
Emilia, Giovanni; Luppi, Mario; Morselli, M; Forghieri, F; Potenza, Leonardo; Torelli, Giuseppe
abstract

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2008 - Acute appendicitis in adult neutropenic patients with hematologic malignancies [Articolo su rivista]
Forghieri, Fabio; Luppi, Mario; Narni, Franco; Morselli, M.; Potenza, Leonardo; Bresciani, Paola; Volzone, Francesco; Rossi, Giulio; Rossi, Aldo; Trenti, Loris; Barozzi, Patrizia; Torelli, Giuseppe
abstract

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2008 - Assessment of aspergillus-specific T cells for diagnosis of invasive aspergillosis in a leukemic child with liver lesions mimicking hepatosplenic candidiasis [Articolo su rivista]
Potenza, Leonardo; Barozzi, Patrizia; Rossi, Giulio; Palazzi, G; Vallerini, Daniela; Riva, Giovanni; Cellini, M; Morselli, M; Volzone, Francesco; Venturelli, C; Quadrelli, Chiara; Di Pancrazio, L; Cano, Mc; Paolucci, Paolo; Torelli, Giuseppe; Luppi, Mario
abstract

A child with acute myeloid leukemia presented with multiple liver lesions mimicking hepatosplenic candidiasis during the neutropenic phase following the induction chemotherapy. All the available diagnostic tools showed repeatedly negative results, including galactomannan. An enzyme-linked immunospot (ELISPOT) assay showed a high number of Aspergillus-specific T cells producing interleukin-10 [TH2(IL-10)] and a low number of Aspergillus-specific T cells producing gamma interferon [TH1(IFN-γ)], revealing invasive aspergillosis (IA) before the confirmatory biopsy. A progressive skewing from the predominance of TH2(IL-10) to a predominance of TH1(IFN-γ) was observed close to the complete resolution of the infection and foreshadowed the outcome. The ELISPOT assay holds promise for diagnosing pediatric IA.

2008 - BK virus infection and neurologic dysfunctions in a patient with lymphoma treated with chemotherapy and rituximab [Articolo su rivista]
Ferrari, A; Luppi, Mario; Marasca, Roberto; Potenza, Leonardo; Morselli, M; Volzone, F; Santachiara, R; Forghieri, Fabio; Barozzi, Patrizia; Torelli, Giuseppe
abstract

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2008 - Changes in the immune responses against human herpesvirus-8 in the disease course of posttransplant Kaposi sarcoma [Articolo su rivista]
Barozzi, Patrizia; Bonini, C; Potenza, Leonardo; Masetti, Michele; Cappelli, Gianni; Gruarin, P; Whitby, D; Gerunda, Giorgio Enrico; Mondino, A; Riva, Giovanni; Vallerini, Daniela; Quadrelli, Chiara; Bosco, Raffaella; Ciceri, F; Bordignon, C; Schulz, Tf; Torelli, Giuseppe; Luppi, Mario
abstract

In nine patients with posttransplant Kaposi sarcoma (KS) T-cell responses to human herpesvirus (HHV)-8 latent and lytic antigens, as detected by enzyme-linked-immunospot (Elispot) assay, were absent at disease onset. Virus-specific T-cell responses were detected in six renal recipients at remission after a reduction of calcineurin inhibitors (CIs), and in two HHV-8 seropositive renal recipients without KS. In two liver recipients undergoing switch from CIs to sirolimus (SRL), normalization of the T-cell repertoire and recovery of both HHV-8-specific effector and memory T lymphocytes were associated with complete KS remission. In a renal recipient undergoing SRL conversion, the early recovery of HHV-8-specific effector but not of memory T lymphocytes, was associated only with partial remission. Neither rejection nor changes in graft function were observed after SRL conversion. HHV-8-specific T-cell responses are required to achieve posttransplant KS remission, and may be restored under SRL, while maintaining effective immunosuppression.

2008 - HHV-6A in syncytial giant-cell hepatitis [Articolo su rivista]
Potenza, Leonardo; Luppi, Mario; Barozzi, Patrizia; Rossi, Giulio; Cocchi, Stefania; Codeluppi, Mauro; Pecorari, Monica; Masetti, Michele; DI BENEDETTO, Fabrizio; Gennari, William; Portolani, Marinella; Gerunda, Giorgio Enrico; Lazzarotto, Tiziana; Landini, Maria Paola; Schulz, Thomas F.; Torelli, Giuseppe; Guaraldi, Giovanni
abstract

Syncytial giant-cell hepatitis is a rare but severe form of hepatitis that is associated with autoimmune diseases, drug reactions, and viral infections. We used serologic, molecular, and immunohistochemical methods to search for an infectious cause in a case of syncytial giant-cell hepatitis that developed in a liver-transplant recipient who had latent infection with variant B of human herpesvirus 6 (HHV-6B) and who had received the organ from a donor with variant A latent infection (HHV-6A). At the onset of the disease, the detection of HHV-6A (but not HHV-6B) DNA in plasma, in affected liver tissue, and in single micromanipulated syncytial giant cells with the use of two different polymerase-chain-reaction (PCR) assays indicated the presence of active HHV-6A infection in the patient. Expression of the HHV-6A-specific early protein, p41/38, but not of the HHV-6B-specific late protein, p101, was demonstrated only in liver syncytial giant cells in the absence of other infectious pathogens. The same markers of HHV-6A active infection were documented in serial follow-up samples from the patient and disappeared only at the resolution of syncytial giant-cell hepatitis. Neither HHV-6B DNA nor late protein was identified in the same follow-up samples from the patient. Thus, HHV-6A may be a cause of syncytial giant-cell hepatitis.

2008 - Kaposi's sarcoma after liver transplantation [Articolo su rivista]
DI BENEDETTO, Fabrizio; Di Sandro, S; De Ruvo, N; Berretta, M; Masetti, Michele; Montalti, R; Ballarin, Roberto; Cocchi, S; Potenza, Leonardo; Luppi, Mario; Gerunda, Giorgio Enrico
abstract

INTRODUCTION: Kaposi's Sarcoma (KS) is a malignant neoplasm arising from endothelial cells. HHV8-infection represents a key pathogenic determinant for the development of KS. There are no standard criteria to treat KS in immunosuppressed-individuals. Six cases (2.1%) of KS occurred in our Center among 285-recipients who underwent liver transplantation (LT) between October 2000 and November 2006. METHODS: Patients were four males and two females. Mean age was 57 years (range 44-65). Indication for LT was ESLD associated/non-associated with hepatocellular carcinoma (HCC). The immunosuppressive regimen consisted of cyclosporine/tacrolimus associated with steroids or daclizumab. HHV8-detection was performed by the serological method before LT, and by polymerase chain reaction (PCR)-analysis after KS. RESULTS: One patient had HCV-related cirrhosis and coinfection from HIV, three had HBV-related cirrhosis, two of these with coexistent HCC. The last two patients had alcoholic-cirrhosis, one with coexistent HCC. Mean time from transplantation to KS was 6.2 months (range 3.8-8.8). Three patients were treated with doxorubicin and three with switch from calcineurin-inhibitors to sirolimus. Three patients expired after 11.5, 8.8, and 7.4 months from KS diagnosis. DISCUSSION: KS should be treated by a multidisciplinary approach to obtain an early diagnosis and best management. Effective treatment with immunosuppression reduction or switch to sirolimus is mandatory and can induce complete regression.

2008 - Parvoviruses in blood donors and transplant patients, Italy [Articolo su rivista]
Vallerini, Daniela; Barozzi, Patrizia; Quadrelli, Chiara; Bosco, Raffaella; Potenza, Leonardo; Riva, Giovanni; Gregorini, G; Sandrini, S; Tironi, A; Montagnani, Giuliano; De Palma, M; Torelli, Giuseppe; Delwart, E; Luppi, Mario
abstract

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2008 - Reply to: [Efficacy of cyclosporine as a single agent therapy in chronic idiopathic thrombocytopenic purpura". Haematologica 2008; 93:e61] [Articolo su rivista]
Emilia, G.; Luppi, M.; Morselli, M.; Forghieri, F.; Potenza, L.; Torelli, G.
abstract

2008 - Veicolazione liposomiale del cidofovir nel trattamento del PEL (Primary Effusion Lynphoma) [Abstract in Rivista]
Barozzi, Patrizia; Riva, Giovanni; Ruozi, Barbara; Tosi, Giovanni; Belletti, Daniela; Potenza, Leonardo; Quadrelli, Chiara; Vallerini, Daniela; Zanetti, Eleonora; M., Morselli; Forghieri, Fabio; Maccaferri, Monica; A., Paolini; F., Volzone; Vandelli, Maria Angela; Forni, Flavio; Torelli, Giuseppe; Luppi, Mario
abstract

Veicolazione liposomiale del cidofovir nel trattamento del PEL (Primary Effusion Lynphoma)

2007 - B cells and herpesviruses: a model of lymphoproliferation [Articolo su rivista]
Barozzi, Patrizia; Potenza, Leonardo; Riva, Giovanni; Vallerini, Daniela; Quadrelli, Chiara; Bosco, Raffaella; Forghieri, Fabio; Torelli, Giuseppe; Luppi, Mario
abstract

Unlike alpha- and beta-herpesviruses, human gamma-herpesviruses, including the Epstein-Barr virus (EBV) and the human herpesvirus-8 (HHV-8), are B lymphotropic viruses. Primary infection with EBV, in otherwise healthy subjects, causes a benign lymphoproliferative syndrome, the mononucleosis syndrome. However, several epidemiologic and biologic studies have shown a pathogenetic role of EBV in the development of human B cell lymphomas, both in immunocompetent and in immunosuppressed individuals. HHV-8 is the necessary etiologic agent of a lymph vascular tumor, the Kaposi sarcoma, but it is also implicated in the pathogenesis of rare B cell lymphoproliferative disorders, mainly occurring in the setting of immunosuppression. The aim of this review is to provide an updated description of the different strategies used by these two herpesviruses to influence B cell fate decisions. Both EBV and HHV-8 have evolved specific mechanisms in order to: (1) interact with the B cell developmental machinery; (2) allow infected B cells to escape from the control of the immune system; (3) affect the B cell cycle checkpoints; (4) mimic and influence B cellular proliferation and differentiation pathways. Understanding the mechanisms of herpesvirus induced B cell lymphoproliferation will provide the basis for novel treatment approaches in patients with EBV and HHV-8 related lymphomas.

2007 - Cytarabine-related lung infiltrates on high resolution computerized tomography: a possible complication with benign outcome in leukemic patients. [Articolo su rivista]
Forghieri, Fabio; Luppi, Mario; Morselli, M; Potenza, Leonardo
abstract

Potentially fatal lung toxicity occurs in 12-20% of leukemic patients treated with cytarabine especially at intermediate to high doses, usually presenting as noncardiogenic pulmonary edema (NCPE). Anecdotally the association between cytarabine and the onset of bronchiolitis obliterans organizing pneumonia (BOOP) has been reported. We describe here three cases of patients affected by acute myeloid leukemia (AML) treated with chemotherapeutic regimens including high dose cytarabine, who developed early onset of fever, mild dyspnea, moderate hypoxemia on arterial blood gas analysis and lung infiltrates documented by high-resolution computerized tomography (HRCT), with a more indolent behaviour and a benign clinical outcome, compared with similar cases previously reported in the literature. Our cases widen the spectrum of clinical features of cytarabine-related toxicity in leukemic patients.

2007 - Diagnosis of invasive aspergillosis by tracking Aspergillus-specific T cells in hematologic patients with pulmonary infiltrates [Articolo su rivista]
Potenza, Leonardo; Barozzi, Patrizia; Vallerini, Daniela; Bosco, R; Quadrelli, Chiara; Morselli, M; Forghieri, Fabio; Volzone, F; Codeluppi, M; Rossi, G; Tazzioli, Giovanni; Venturelli, C; Torelli, Giuseppe; Luppi, Mario; Mediani, Laura
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2007 - Epstein-Barr virusassociated pneumonia in an adult patient with severe aplastic anaemia: resolutionafter the transient withdrawal of cyclosporine. [Articolo su rivista]
Potenza, Leonardo; Barozzi, Patrizia; Codeluppi, M; Morselli, M; Forghieri, Fabio; Volzone, F; Riva, Giovanni; Pietrosemoli, P; Pecorari, M; Leonardi, G; Torelli, Giuseppe; Luppi, Mario
abstract

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2007 - Fatal hemophagocytic syndrome related to active human herpesvirus-8/Kaposi sarcoma-associated herpesvirus infection in human immunodeficiency virus-negative, non-transplant patients without related malignancies [Articolo su rivista]
Re, A; Facchetti, F; Borlenghi, E; Cattaneo, C; Capucci, Ma; Ungari, M; Barozzi, Patrizia; Vallerini, Daniela; Potenza, Leonardo; Torelli, Giuseppe; Rossi, G; Luppi, Mario
abstract

Hemophagocytic syndrome (HS) may occur as a consequence of herpes viral infections. Human herpesvirus 8 (HHV-8)/Kaposi sarcoma-associated herpesvirus has so far been recognized as a trigger of HS only in immunosuppressed subjects or in patients with Kaposi sarcoma and/or HHV-8-related lymphoproliferative diseases. We report two Italian human immunodeficiency virus (HIV)-negative elderly men who developed an HS with a rapidly fatal course, following treatment with corticosteroids for autoimmune hemolytic anemia. An overwhelming active infection with HHV-8 was unequivocally documented by molecular and immunohistochemical methods, in the absence of HHV-8-related tumors. The occurrence of HHV-8-associated HS, although rare, may be considered, even out of the HIV or the transplantation settings, at least in areas endemic for HHV-8 infection.

2007 - Helicobacter pylori infection andchronic immune thrombocytopenic purpura: long-term results of bacteriumeradication and association with bacterium virulence profiles [Articolo su rivista]
Emilia, Giovanni; Luppi, Mario; Zucchini, Patrizia; Morselli, M; Potenza, Leonardo; Forghieri, Fabio; Volzone, F; Jovic, Gordana; Leonardi, G; Donelli, A; Torelli, Giuseppe
abstract

Eradication of Helicobacter pylori may lead to improvement of chronic immune thrombocytopenic purpura (ITP), although its efficacy over time is uncertain. We report the results of H pylori screening and eradication in 75 consecutive adult patients with ITP. We also used molecular methods to investigate lymphocyte clonality and H pylori genotypes in the gastric biopsies from 10 H pylori-positive patients with ITP and 19 H pylori-positive patients without ITP with chronic gastritis. Active H pylori infection was documented in 38 (51%) patients and successfully eradicated in 34 (89%) patients. After a median follow-up of 60 months, a persistent platelet response in 23 (68%) of patients with eradicated infection was observed; 1 relapse occurred. No differences in mucosal B- or T-cell clonalities were observed between patients with ITP and control participants. Of note, the frequency of the H pylori cagA gene (P = .02) and the frequency of concomitant H pylori cagA, vacAs1, and iceA genes (triple-positive strains; P = .015) resulted statistically higher in patients with ITP than in control participants. All asymptomatic H pylori-positive patients with ITP were suffering from chronic gastritis. Our data suggest a sustained platelet recovery in a proportion of patients with ITP by H pylori eradication alone. Overrepresentation of specific H pylori genotypes in ITP suggests a possible role for bacterium-related factors in the disease pathogenesis.

2007 - May the correlation between Kit-D816 mutation and AML1-ETO level change the use of prognostic factors in t(8;21) AML? [Articolo su rivista]
Potenza, Leonardo; Luppi, Mario; Riva, Giovanni; Zucchini, Patrizia; Morselli, M; Volzone, F; Forghieri, Fabio; Torelli, Giuseppe; Ottaviani, E; Martinelli, G.
abstract

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2006 - Diagnosis of occult tuberculosis in hematological malignancy by enumeration of antigen-specific T cells. [Articolo su rivista]
Richeldi, Luca; Luppi, Mario; Losi, Monica; Luppi, Fabrizio; Potenza, Leonardo; Roversi, P; Cerri, Stefania; Millington, Ka; Ewer, K; Fabbri, Leonardo; Torelli, Giuseppe; Lalvani, A.
abstract

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2006 - Human herpesvirus 6 latency characterized by high viral load: Chromosomal integration in many, but not all, cells [Articolo su rivista]
Luppi, Mario; Barozzi, Patrizia; Bosco, Raffaella; Vallerini, Daniela; Potenza, Leonardo; Forghieri, Fabio; Torelli, Giuseppe
abstract

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2006 - Isolated extramedullary relapse after autologous bone marrow transplantation for acute myeloid leukemia: Case report and review of the literature [Articolo su rivista]
Potenza, Leonardo; Luppi, Mario; Riva, Giovanni; M., Morselli; Ferrari, Alberto; Imovilli, Annalisa; F., Giacobbi; Temperani, Paola; A., Donelli; Narni, Franco; Torelli, Giuseppe
abstract

Isolated extramedullary relapse (IEMR) is a pattern of acute myeloid leukemia (AML) relapse post-allogeneic bone marrow transplantation (alloBMT). Less is known about IEMR post-autologous BMT (autoBMT) and about factors associated with IEMR. We report a case of a woman with M4 AML who experienced IEMR post-autoBMT and review the related literature. Seventy-two alloBMT and 3 autoBMT patients, including ours, were identified. The review suggests that an M2 or M4 French-American-British (FAB) phenotype, intermediate cytogenetic risk group, and chromosome 8 abnormalities are more frequently associated with the occurrence of IEMR. IEMR occurs earlier in autoBMT than in alloBMT. Combined treatment with radiation and high-dose chemotherapy may be effective. When we searched the European Bone Marrow Transplant Registry (EBMTR) database, we found the incidence of IEMR to be statistically greater in alloBMT than in autoBMT (11% vs. 6%; P = 0.02), but no correlations have been found with the conditioning transplant regimen used. A closer follow-up, including body and central nervous system scan, should be considered in patients who are undergoing BMT presenting with several IEMR-associated factors.

2006 - KSHV/HHV-8 infection of tubular epithelial cells in transplantation kidney [Articolo su rivista]
Barozzi, Patrizia; R., Bosco; Vallerini, Daniela; Potenza, Leonardo; Torelli, Giuseppe; Luppi, Mario; F., Facchetti; Guaraldi, Giovanni; T. F., Schulz
abstract

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2006 - Ocular involvement as first sign of isolated CNS relapse in diffuse large B-cell lymphoma [Articolo su rivista]
A., Ferrari; Luppi, Mario; A., Lazzerini; Potenza, Leonardo; Cavallini, Gian Maria; Torelli, Giuseppe
abstract

A 52-year-old man was diagnosed with stage IVB non-Hodgkin lymphoma of diffuse large B-cell lymphoma subtype that involved the bone marrow and liver. Analysis of serum samples showed a raised concentration of lactate dehydrogenase, suggesting a high–intermediate risk of non-Hodgkin lymphoma according to the international prognostic index, but no HIV-1. The patient received six cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus rituximab, and achieved complete remission. 6 months after diagnosis and 2 months after complete remission was achieved, the patient was admitted to hospital because of loss of vision. In the early phase of the examination, a fluorescein angiogram of the right eye (figure A) showed two large hyperfluorescent infiltrates with granularity (arrows) with small regions of retinal pigment epithelial detachments (arrowheads). In the late phase of the study, the left eye (figure B) showed a diffuse retinal pigment epithelial detachment that remained densely hypofluorescent (arrows), suggesting presence of lymphoma. However, bone-marrow biopsy and a CT scan of the neck, chest, and abdomen showed no relapse of lymphoma. 6 days later, the patient became somnolent and agitated, and developed confusion and lethargy. A CT scan (not shown) and an MRI of the brain (figure C) showed multifocal intraparenchymal lesions. Histological and immunohistochemical analysis of a stereotactic biopsy sample of one of the frontal lesions showed presence of B-lymphocyte antigen CD20-positive diffuse large B-cell lymphoma, and no presence of Epstein-Barr virus. The patient was given high-dose methotrexate followed by whole-brain radiotherapy. The patient died 1 month after CNS relapse because of disease progression.

2005 - Cytomegalovirus and ClostridiumDifficile co-infection in severe ulcero-hemorrhagic colitis during inductionchemotherapy for acute lymphoblastic leukemia [Articolo su rivista]
Riva, Giovanni; Luppi, Mario; Potenza, Leonardo; Morselli, M; Ferrari, A; Saviola, Alessia; Volzone, F; Imovilli, Annalisa; Merighi, A; Maiorana, Antonino; Torelli, Giuseppe
abstract

Here we describe the first case of a biopsyprovenCytomegalovirus ulcero-hemorrhagic colitis,associated with Clostridium Difficile co-infection,occurring during standard induction chemotherapyfor common B cell acute lymphoblastic leukemia.We discuss the case and focalize clinical managementand diagnostic issues arising from it.

2005 - Efficacy of imatinib mesylate as maintenance therapy in adults with acute lymphoblastic leukemia in first complete remission [Articolo su rivista]
Potenza, Leonardo; Luppi, Mario; Riva, Giovanni; Marasca, Roberto; Martinelli, Silvia; Torelli, Giuseppe
abstract

Seven Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) patients in first complete remission received maintenance therapy with imatinib alone. Two-year progression-free survival was 75%. Quantitative polymerase-chain-reaction (qPCR) monitoring of BCR-ABL showed that: (i) persisting molecular complete response (CR) was associated with long-lasting CR; (ii) molecular relapse did not invariably mean hematologic relapse; (iii) only the wide and rapid increment of BCR-ABL values was predictive of leukemia relapse.

2005 - Herpes simplex virus pneumonia during standard induction chemotherapy for acute leukemia: case report and review of literature. [Articolo su rivista]
Ferrari, A.; Luppi, Mario; Potenza, Leonardo; Riva, Giovanni; Morselli, M.; Imovilli, A.; Volzone, F.; Rossi, G.; Codeluppi, M.; Guaraldi, Giovanni; Torelli, Giuseppe
abstract

Reactivation of latent HSV is the most common viral infection in patients during the profound neutropenia that occurs during remission induction in patients with lymphoma and acute leukemia and during the conditioning phase of bone marrow transplantation. We report here the occurrence of HSV-1 pneumonia in a patient with B-cell common ALL.

2005 - Pneumonia in acute leukaemia:blossoming culprits [Articolo su rivista]
Potenza, Leonardo; Riva, Giovanni; Luppi, Mario; Torelli, Giuseppe
abstract

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2005 - Suppressive effect of human herpesvirus-8/Kaposi sarcoma-associated herpesvirus on in vitro colony formation of hematopoietic progenitor cells [Articolo su rivista]
Luppi, Mario; Trovato, R; Barozzi, Patrizia; Gibellini, F; Potenza, Leonardo; Riva, Giovanni; Torelli, Giuseppe
abstract

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2005 - Treatment of herpesvirus associated primary effusion lymphoma with intracavity cidofovir [Articolo su rivista]
Luppi, Mario; Trovato, R; Barozzi, Patrizia; Vallisa, D; Rossi, Giorgio; Re, A; Ravazzini, L; Potenza, Leonardo; Riva, Giovanni; Morselli, M; Longo, G; Cavanna, L; Roncaglia, R; Torelli, Giuseppe
abstract

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2004 - A t(11;20)(p15;q11) may identify a subset of nontherapy-related acute myelocytic leukemia [Articolo su rivista]
Potenza, Leonardo; B., Sinigaglia; Luppi, Mario; M., Morselli; A., Saviola; A., Ferrari; Riva, Giovanni; Zucchini, Patrizia; F., Giacobbi; G., Emilia; Temperani, Paola; Torelli, Giuseppe
abstract

A t(11;20)(p15;q11) is a rare but recurrent chromosomal aberration, reported in one case of polycythemia vera and a few cases of de novo acute myelocytic leukemia (AML) and therapy-related myelodysplastic syndrome (t-MDS). In t-MDS cases, the translocation resulted in the NUP98/TOP1 fusion transcript. The NUP98 gene has been suggested as the target for therapy-related malignancies. The reciprocal TOP1/NUP98 chimera, however, has not yet been encountered. We report a further case of de novo AML, subtype M2 in the French-American-British (FAB) classification, in which the reverse-transcriptase polymerase chain reaction (RT-PCR) revealed the NUP98/TOP1 chimera and also, for the first time, its reciprocal TOP1/NUP98. The literature review disclosed that, among six cases of de novo AML with t(11;20), the NUP98 gene was shown to be involved in one case and the NUP98/TOP1 chimera was detected in another. The translocation seems to be frequently associated with the FAB M2 subtype, younger age, hyperleukocytosis, and poor prognosis; thus, this translocation may identify a subset of not-therapy-related AML patients with shared clinical features.

2004 - Cardiac involvement in malignancies. Case 2. Right ventricular lesion as presenting feature of acute promyelocytic leukemia [Articolo su rivista]
Potenza, Leonardo; Luppi, Mario; Morselli, M; Riva, Giovanni; Saviola, A; Ferrari, Alberto; De Santis, M; Rossi, Rosario; Torelli, Giuseppe
abstract

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2004 - Is it now the time to update treatment protocols for lymphomas with new anti-virus systems? [Articolo su rivista]
Luppi, Mario; Barozzi, Patrizia; Potenza, Leonardo; Riva, Giovanni; Morselli, M; Torelli, Giuseppe
abstract

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2004 - Myocardial ischemia in a patient with acute lymphoblastic leukemia during L-asparaginase therapy [Articolo su rivista]
Saviola, A; Luppi, Mario; Potenza, Leonardo; Morselli, M; Bresciani, P; Ferrari, Alberto; Riva, Giovanni; Torelli, Giuseppe
abstract

Haemostatic abnormalities may occur in 1-2% of patients treated with L-asparaginase. Here, we present the second case of a myocardial infarction, developing in a patient with acute lymphoblastic leukemia (ALL), in the course of L-asparaginase treatment. In our patient and in the only one reported case from the literature, a recent exposure to vincristine and daunorubicin was also reported, but induction chemotherapy program was completed as scheduled, with the only withdrawal of L-asparaginase. Myocardial infarction should be included in the list of thrombotic complications possibly associated with L-asparaginase treatment, or with a combination of L-asparaginase and vinca alkaloids/anthracycline.

2004 - Thrombotic complications associated with thalidomide in multiple myeloma: an old problem with new questions and quandaries in decision-making [Articolo su rivista]
Potenza, Leonardo; Luppi, Mario; Morselli, M; Saviola, A; Ferrari, Alberto; Riva, Giovanni; Longo, G; Marietta, M; Torelli, Giuseppe
abstract

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2003 - Immune thrombocytopenic purpura and Helicobacter pylori infection [Articolo su rivista]
M., Morselli; Potenza, Leonardo; Luppi, Mario; Torelli, Giuseppe; G., Emilia
abstract

No abstract available

2003 - Late occurrence of hepatic veno-occlusive disease following gemtuzumab ozogamicin: successful treatment with defibrotide [Articolo su rivista]
Saviola, A; Luppi, Mario; Potenza, Leonardo; Morselli, M; Ferrari, Alberto; Riva, Giovanni; Torelli, Giuseppe
abstract

No abstract available

2003 - Leukaemic pulmonary infiltrates in adult acute myeloid leukaemia: a high-resolution computerized tomography study [Articolo su rivista]
Potenza, Leonardo; Luppi, Mario; Morselli, M; Tonelli, S; D'Apollo, N; Facchini, L; Torricelli, Pietro; Tazzioli, Giovanni; Saviola, A; Bresciani, P; Longo, G; Torelli, Giuseppe
abstract

Leukaemic infiltration of the lungs may occur in acute myeloid leukaemia (AML). Pulmonary infiltrates are usually microscopic and invariably associated with hyperleucocytosis. Four AML patients with respiratory symptoms and low leucocyte counts underwent standard chest radiography, bronchoscopy with bronchoalveolar lavage and high-resolution computerized tomography (HRCT) of the lungs. HRCT scans showed pulmonary infiltrates with alveolar, interstitial, mixed and peribronchial/perivascular patterns in all patients, including one with negative standard radiographic findings. Infectious agents were excluded. Histology of the lung biopsy/autopsy specimens showed leukaemic infiltrates. Pulmonary leukaemia may be the cause of pulmonary infiltrates, even in non-hyperleucocytosic AML patients with low blast counts.

2002 - 'Gloves and socks' papular purpuric syndrome following primary infection with parvovirus B19: a link between dermatologists and haematologists [Articolo su rivista]
Tonelli, S; Luppi, Mario; Morselli, M; Facchini, L; Potenza, Leonardo; Torelli, Giuseppe
abstract

No abstract available

2002 - Helicobacter pylori infection and idiopathic thrombocytopenic purpura [Articolo su rivista]
Emilia, G; Luppi, Mario; Morselli, M; Potenza, Leonardo; D'Apollo, N; Torelli, Giuseppe
abstract

No abstract available

2002 - Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura. [Articolo su rivista]
Emilia, G; Morselli, M; Luppi, Mario; Longo, G; Marasca, Roberto; Gandini, G; Ferrara, L; D'Apollo, N; Potenza, Leonardo; Bertesi, M; Torelli, Giuseppe
abstract

Treatment of severe, chronic idiopathic thrombocytopenic purpura (ITP) refractory to most usual therapies Is a difficult challenge. Little information exists on the clinical use of cyclosporin A (CyA) in the treatment of ITP. This report describes long-term treatment with CyA (median, 40 months) and follow-up (median, 36.8 months) in 12 adult patients with resistant ITR CyA used in relatively low doses (2.5-3 mg/kg of body weight per day) led to a clinical Improvement In 10 patients (83.3%). Five had a complete response (41.1%),4 a complete response to maintenance therapy (33.3%), and one a partial response (8.3%). Two patients had no response. Most patients with a response (60%) had a long-term remission (mean, 28.6 months) after discontinuation of CyA. One patient had a relapse of ITP 4 years after CyA therapy was stopped. Side effects were moderate and transient, even In patients dependent on continued CyA treatment. CyA seems to represent reasonable salvage treatment in severe, potentially life-threatening, refractory ITR

2002 - Mixed warm and cold autoimmune hemolytic anemia: complete recovery after 2 courses of rituximab treatment [Articolo su rivista]
M., Morselli; Luppi, Mario; Potenza, Leonardo; L., Facchini; S., Tonelli; D., Dini; G., Leonardi; A., Donelli; Narni, Franco; Torelli, Giuseppe
abstract

No abstract available

2001 - Unusual sites of malignancy: case 1. Primary non-Hodgkin's lymphoma of the hand in a patient with hepatitis C infection. [Articolo su rivista]
Longo, G; Potenza, Leonardo; D'Apollo, N; Ferrara, L; Gandini, G; Bertesi, M; Torelli, Giuseppe; Emilia, G.
abstract

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1999 - Anticoagulant pseudothrombocytopenia with platelet satellitism [Articolo su rivista]
Morselli, M; Longo, G; Bonacorsi, G; Potenza, Leonardo; Emilia, G; Torelli, Giuseppe
abstract

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