76 results on '"Alfredo Molteni"'
Search Results
2. PB2670: EQOL-MDS TRIAL: PATIENT-REPORTED OUTCOMES IN PATIENTS WITH LOWER RISK MYELODYSPLASTIC SYNDROMES WITH SEVERE THROMBOCYTOPENIA.
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Esther Oliva, Giuseppe Iannì, Marta Riva, Pasquale Niscola, Valeria Santini, Massimo Breccia, Valentina Gaidano, Antonella Poloni, Andrea Patriarca, Elena Crisà, Isabella Capodanno, Prassede Salutari, Gianluigi Reda, Grazia Sanpaolo, Dario Ferrero, Attilio Guarini, Giovanni Tripepi, Andrea Castelli, Bruno Fattizzo, Germana Beltrami, Monica Bocchia, Alfredo Molteni, Pierre Fenaux, Ulrich Germing, Alessandra Ricco, Giuseppe A. Palumbo, Stefana Impera, Nicola DI Renzo, Francesco Buccisano, Aspasia Stamatoullas, Anna Marina Liberati, Anna Candoni, Ilaria Maria Delfino, Patrizia Cufari, Lorenzo Rizzo, and Roberto Latagliata
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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3. Adapting the Fitness Criteria for Non-Intensive Treatments in Older Patients with Acute Myeloid Leukemia to the Use of Venetoclax-Hypomethylating Agents Combination—Practical Considerations from the Real-Life Experience of the Hematologists of the Rete Ematologica Lombarda
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Giuseppe Rossi, Erika Borlenghi, Patrizia Zappasodi, Federico Lussana, Massimo Bernardi, Claudia Basilico, Alfredo Molteni, Ivana Lotesoriere, Mauro Turrini, Marco Frigeni, Monica Fumagalli, Paola Cozzi, Federica Gigli, Chiara Cattaneo, Nicola Stefano Fracchiolla, Marta Riva, Gianluca Martini, Valentina Mancini, Roberto Cairoli, and Elisabetta Todisco
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fitness ,elderly ,acute myeloid leukemia ,treatment ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
A retrospective survey was conducted in hematologic centres of the Rete Ematologica Lombarda (REL) on 529 older AML patients seen between 2020–2022. Compared to 2008–2016, the use of intensive chemotherapy (ICT) decreased from 40% to 18.1% and of hypomethylating agents (HMAs) from 19.5% to 13%, whereas the combination of Venetoclax/HMA, initially not available, increased from 0% to 36.7%. Objective treatment-specific fitness criteria proposed by SIE/SIES/GITMO in 2013 allow an appropriate choice between ICT and HMAs by balancing their efficacy and toxicity. Venetoclax/HMA, registered for patients unfit to ICT, has a unique toxicity profile because of prolonged granulocytopenia and increased infectious risk. Aiming at defining specific fitness criteria for the safe use of Venetoclax/HMA, a preliminary investigation was conducted among expert REL hematologists, asking for modifications of SIE/SIES/GITMO criteria they used to select candidates for Venetoclax/HMA. While opinions among experts varied, a general consensus emerged on restricting SIE/SIES/GITMO criteria for ICT-unfit patients to an age limit of 80–85, cardiac function > 40%, and absence of recurrent lung infections, bronchiectasis, or exacerbating COPD. Also, the presence of an adequate caregiver was considered mandatory. Such expert opinions may be clinically useful and may be considered when treatment-specific fitness criteria are updated to include Venetoclax/HMA.
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- 2024
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4. Danazol Treatment for Thrombocytopenia in Myelodysplastic Syndromes: Can an 'Old-fashioned' Drug be Effective?
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Marta Riva, Alessandro Bosi, Lorenzo Rizzo, Federico Mazzon, Silvia Ferrari, Federico Lussana, Lorenza Borin, Andrea Castelli, Roberto Cairoli, Wilma Barcellini, Alfredo Molteni, and Bruno Fattizzo
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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5. Canakinumab as treatment for COVID-19-related pneumonia: A prospective case-control study
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Daniele Generali, Giancarlo Bosio, Fabio Malberti, Antonio Cuzzoli, Sophie Testa, Laura Romanini, Antonio Fioravanti, Alessandro Morandini, Luca Pianta, Guglielmo Giannotti, Erika Maria Viola, Matteo Giorgi-Pierfranceschi, Marina Foramitti, Rosa Angela Tira, Ilaria Zangrandi, Giulia Chiodelli, Andrea Machiavelli, Maria Rosa Cappelletti, Alessia Giossi, Valeria De Giuli, Chiara Costanzi, Chiara Campana, Ottavia Bernocchi, Marianna Sirico, Alessia Zoncada, Alfredo Molteni, Sergio Venturini, Fabiola Giudici, Maurizio Scaltriti, and Angelo Pan
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COVID-19 ,Pneumonia ,SARS-CoV-2 ,Canakinumab ,Infectious and parasitic diseases ,RC109-216 - Abstract
Objectives: Canakinumab is an IL-1β antibody that neutralises the activity of IL-1β. This study examined the efficacy and safety of canakinumab in patients with moderate COVID-19-related pneumonia. Design: This study aimed to evaluate the reduction in duration of hospitalisation with adequate oxygen status. Forty-eight patients with moderate COVID-19-related pneumonia were asked to participate in the prospective case-control study: 33 patients (cases) signed informed consent and received canakinumab (Cohort 1) and 15 patients (Controls) refused to receive the experimental drug and received institutional standard of care (Cohort 2). Results: Hospital discharge within 21 days was seen in 63% of patients in Cohort 1 vs. 0% in Cohort 2 (median 14 vs. 26 days, respectively; p < 0.001). There was significant clinical improvement in ventilation regimes following administration of canakinumab compared with Cohort 2 (Stuart-Maxwell test for paired data, p < 0.001). Patients treated with canakinumab experienced a significant increase in PaO2:FiO2 (p < 0.001) and reduction in lung damage by CT (p = 0.01), along with significant decreases in immune/inflammation markers that were not observed in Cohort 2. Only mild side-effects were seen in patients treated with canakinumab; survival at 60 days was 90.0% (95% CI 71.9–96.7) in patients treated with canakinumab and 73.3% (95% CI 43.6–89.1) for Cohort 2. Conclusions: Treatment with canakinumab in patients with COVID-19-related pneumonia rapidly restored normal oxygen status, decreased the need for invasive mechanical ventilation, and was associated with earlier hospital discharge and favourable prognosis versus standard of care.
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- 2021
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6. Second primary malignancies in ruxolitinib-treated myelofibrosis: real-world evidence from 219 consecutive patients
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Margherita Maffioli, Toni Giorgino, Barbara Mora, Alessandra Iurlo, Elena Elli, Maria Chiara Finazzi, Marianna Caramella, Elisa Rumi, Maria Cristina Carraro, Nicola Polverelli, Mariella D'Adda, Simona Malato, Marianna Rossi, Alfredo Molteni, Alessandro Vismara, Cinzia Sissa, Francesco Spina, Michela Anghilieri, Daniele Cattaneo, Rossella Renso, Marta Bellini, Maria Luisa Pioltelli, Chiara Cavalloni, Daniela Barraco, Raffaella Accetta, Lorenza Bertù, Matteo Giovanni Della Porta, and Francesco Passamonti
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Specialties of internal medicine ,RC581-951 - Published
- 2019
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7. Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer: The OLTRE Window of Opportunity Trial
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Francesco Schettini, Silvia Paola Corona, Fabiola Giudici, Carla Strina, Marianna Sirico, Ottavia Bernocchi, Manuela Milani, Nicoletta Ziglioli, Sergio Aguggini, Carlo Azzini, Giuseppina Barbieri, Valeria Cervoni, Maria Rosa Cappelletti, Alfredo Molteni, Maria Chiara Lazzari, Giuseppina Ferrero, Marco Ungari, Elena Marasco, Alice Bruson, Luciano Xumerle, Elisa Zago, Davide Cerra, Marco Loddo, Gareth H. Williams, Ida Paris, Giovanni Scambia, and Daniele Generali
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triple negative breast cancer ,window of opportunity clinical trial ,neoadjuvant ,BRCA ,olaparib (Lynparza™) ,TILs ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
IntroductionOlaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes BRCA1/2 (gBRCA-mut). The OLTRE window-of-opportunity trial preliminarily investigated potential pathologic, radiometabolic and immune biomarkers of early-response to olaparib in gBRCA-wild-type (wt) TNBC and, as proof-of-concept in gBRCA-mut HER2-negative BC.MethodsPatients received olaparib for 3 weeks (3w) before standard neoadjuvant chemotherapy and underwent multiple FDG18-PET/CT scan (basal, after olaparib), clinical assessments (basal, every 3w), tumor biopsies and blood samplings (baseline, after olaparib). Clinical and radiometabolic responses were evaluated according to RECIST1.1 and PERCIST criteria.Results27 patients with gBRCA-wt TNBC and 8 with gBRCA-mut BC (6 TNBC, 2 HR+/HER2-negative) were enrolled. Three (11.1%) patients showed mutations in non-BRCA1/2 DDR genes and 4 (14.8%) in other genes. 3w olaparib induced 16/35 and 15/27 partial clinical and radiometabolic responses, including in 40.7% and 50.0% gBRCA-wt patients. gBRCA-mut tumors presented numerically higher tumor-infiltrating lymphocytes (TILs) levels and PD-L1 positive tumors. Clinical responders experienced a reduction in T-regs/T-eff ratio (p=0.05), B and NK lymphocytes (p=0.003 both), with an average increase in T-helpers rate (p
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- 2021
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8. SARS-CoV-2 in Myelodysplastic Syndromes: A Snapshot From Early Italian Experience
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Sandra Mossuto, Enrico Attardi, Francesco Alesiani, Emanuele Angelucci, Enrico Balleari, Massimo Bernardi, Gianni Binotto, Costanza Bosi, Anna Calvisi, Isabella Capodanno, Antonella Carbone, Andrea Castelli, Marco Cerrano, Rosanna Ciancia, Daniela Cilloni, Marino Clavio, Cristina Clissa, Elena Crisà, Monica Crugnola, Matteo G. Della Porta, Nicola Di Renzo, Ambra Di Veroli, Roberto Fattizzo, Carmen Fava, Susanna Fenu, Ida L. Ferrara, Luana Fianchi, Carla Filì, Carlo Finelli, Valentina Giai, Francesco Frattini, Valentina Gaidano, Gianluca Guaragna, Svitlana Gumenyuk, Roberto Latagliata, Stefano Mancini, Emanuela Messa, Alfredo Molteni, Pellegrino Musto, Pasquale Niscola, Esther Oliva, Giuseppe A. Palumbo, Annamaria Pelizzari, Federica Pilo, Antonella Poloni, Marta Riva, Flavia Rivellini, Chiara Sarlo, Mariarita Sciumé, Roberto Secchi, Carmine Selleri, Agostino Tafuri, and Valeria Santini
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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9. JAK Inhibition with Ruxolitinib in Patients with COVID-19 and Severe Pneumonia: Multicenter Clinical Experience from a Compassionate Use Program in Italy
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Alessandro Maria Vannucchi, Andrea Mortara, Andrea D’Alessio, Mara Morelli, Alberto Tedeschi, Moreno Benedetto Festuccia, Antonella D’Arminio Monforte, Enrico Capochiani, Carmine Selleri, Federico Simonetti, Annalisa Saracino, Davide Rapezzi, Maria Rita Badagliacca, Katia Falasca, Alfredo Molteni, Roberto Palazzolo, Giuliano Schettino, Monica Bocchia, Mauro Turrini, Paolo A. Ascierto, Mike Zuurman, Carole Paley, Paola Coco, and Giuseppe Saglio
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COVID-19 ,pneumonia ,ruxolitinib ,SARS-CoV-2 ,hyperactive inflammatory response ,Medicine - Abstract
Jak inhibitors are potent anti-inflammatory drugs that have the potential to dampen the hyperactive inflammatory response associated with severe COVID-19. We reviewed the clinical outcomes of 218 patients with COVID-19 hospitalized for severe pneumonia and treated with ruxolitinib through a compassionate use program. Data on the duration of treatment; outcomes at 4, 7, 14, and 28 days; oxygen support requirements; clinical status; and laboratory parameters were retrospectively collected. Overall, according to the physician evaluation, 66.5% of patients showed improvement at follow-up; of these, 83.5% showed improvement by day 7. Oxygen support status also showed improvement, and by day 7, 21.6% of patients were on ambient air, compared with 1.4% at baseline, which increased to 48.2% by day 28. Significant decreases in C-reactive protein and increases in the lymphocyte total count were already observed by day 4, which seemed to correlate with a positive outcome. At the end of the observation period, 87.2% of patients were alive. No unexpected safety findings were observed, and grade 3/4 adverse events were reported in 6.9% of patients.
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- 2021
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10. PROGNOSTIC IMPACT OF IMMUNOHISTOCHEMICAL P53 EXPRESSION IN BONE MARROW BIOPSY IN HIGHER RISK MDS: A PILOT STUDY
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Alfredo Molteni, Emanuele Ravano, Marta Riva, Michele Nichelatti, Laura Bandiera, Lara Crucitti, Mauro Truini, and Roberto Cairoli
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MDS ,prognosis ,p53 expression ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background and objectives: Mutations of the TP53 gene have an unfavorable prognosis in Myelodysplastic Syndromes (MDS). The product of the TP53gene is the p53 protein. Most of TP53mutations entail the accumulation of the protein in the nucleus of tumor cells. The immunohistochemical (IHC) staining for p53 can be a surrogate suggesting a mutational status and, if overexpressed, seems to be of prognostic value by itself. The best prognostic cut-off value of overexpression is controversial. The aim of this pilot study is to investigate about the correct value from a homogenous group of patients with higher IPSS-R risk MDS. Methods: In sixty consecutive patients diagnosed with MDS and categorized as IPSS-R risk “intermediate”, “high” and “very high”, the bone marrow biopsies performed at the diagnosis were retrospectively re-examined for IHC p53 expression. The result of p53 expression was subsequently related to survival. Results: A worst overall survival was observed both in patients whose IHC p53 expression was ≥5% and ≥ 10% compared to the patients with a p53 expression respectively below 5% (p= 0.0063) or 10% (p=0.0038). Conclusions: The ICH p53 expression in bone marrow biopsy in higher risk MDS was confirmed to have prognostic value. These results indicate more than 10% expression as the best cut off value.
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- 2019
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11. Efficacy and Safety of Luspatercept in Adult Patients with Transfusion-Dependent Anemia Due to Very Low, Low and Intermediate Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts, Who Had an Unsatisfactory Response to or Are Ineligible for Erythropoietin-Based Therapy: A Retrospective Multicenter Study By Fondazione Italiana Sindromi Mielodisplastiche (FiSiM ETS)
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Luca Lanino, Prassede Salutari, Alessandra Perego, Bruno Fattizzo, Marta Riva, Marta Ubezio, Pellegrino Musto, Daniela Cilloni, Esther Natalie Oliva, Maria Teresa Voso, Anna Maria Pelizzari, Antonella Poloni, Isabella Capodanno, Chiara Elena, Claudio Fozza, Fabrizio Pane, Massimo Breccia, Marco De Gobbi, Francesco Di Bassiano, Daniela Barraco, Elena Crisà, Dario Ferrero, Chiara Frairia, Antonella Vaccarino, Davide Griguolo, Stefania Paolini, Martina Quintini, Mariarosaria Sessa, Mauro Turrini, Monica Bocchia, Nicola Di Renzo, Elisa Diral, Cristina Foli, Alfredo Molteni, Ubaldo Occhini, Giulia Rivoli, Carmine Selleri, Roberto Bono, Anna Calvisi, Andrea Castelli, Eros Di Bona, Ambra Di Veroli, Luana Fianchi, Sara Galimberti, Daniele Grimaldi, Monia Marchetti, Marianna Norata, Alessandro Rambaldi, Ilaria Tanasi, Patrizia Tosi, Ilaria Naldi, Valeria Santini, and Matteo G. Della Porta
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
12. Association of Hypometilating Agents (HMA) + Venetoclax (VEN) in the Treatment of Myeloproliferative Neoplasms in Blastic Phase (MPN-BP) and Acute Leukemias Evolved from Myelodysplastic Syndromes (AML-MDS) Already Treated with Azacytidine
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Roberto Latagliata, Gianluca Cristiano, Dorela Lama, Susanna Fenu, Lorenzo Rizzo, Benedetta Cambò, Simone Zoletto, Francesca Spirito, Fabrizio Cavalca, Daniele Cattaneo, Natalia Cenfra, Giulia De Luca, Beatrice Esposito Vangone, Ambra Di Veroli, Raffaele Palmieri, Mario Annunziata, Olga Mulas, Elisabetta Abruzzese, Alfredo Molteni, Monica Piedimonte, Ida Carmosino, Prassede Salutari, Annalisa Biagi, Monica Bocchia, Michelina Santopietro, Gianni Binotto, Alessandra Iurlo, Monica Crugnola, Marta Riva, Anna Lina Piccioni, Elena Maria Elli, Antonio Curti, and Antonella Poloni
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
13. Combined renal proximal tubulopathy and crystal storing histiocytosis in a patient with κ light chain multiple myeloma
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Laura Manotti, Fabio Malberti, Antonio Lavazza, Monica Trombatore, Marco Ungari, Simona Fisogni, Paolo Ghiringhelli, Giuseppina Ferrero, Alfredo Molteni, Gianluca Marchi, Elena Varotti, Marino Daniel Gusolfino, Giulia Tanzi, and Ramona Bertoni
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Kidney ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Case Report ,medicine.disease ,Cryoglobulinemia ,Pathology and Forensic Medicine ,Nephropathy ,Histiocytosis ,medicine.anatomical_structure ,medicine ,Renal biopsy ,Bone marrow ,business ,Multiple myeloma ,Monoclonal Immunoglobulin Deposition Disease - Abstract
Multiple myeloma accounts for 10-15% of all hematologic malignancies, and 20% of deaths related to cancers of the blood and bone marrow. Diagnosis is defined by the presence of a serum monoclonal spike (M-spike) of more than 3 g/dL or more than 10% clonal plasma cells in the bone marrow and at least one myeloma-defining event, such as hypercalcemia, anemia, bone lesions, or renal impairment. The kidney is a major target organ, and renal impairment is frequently the first manifestation of the disease. Renal damage occurs in up to 40% of patients and 10-20% will require dialysis. Monoclonal immunoglobulin light chains are the major causes of renal complications in multiple myeloma. Glomerular disease, with the deposition of monoclonal immunoglobulins or their components, includes monoclonal immunoglobulin deposition disease, AL or AH amyloidosis, type I cryoglobulinemia, proliferative glomerulonephritis with monoclonal IgG deposits, immunotactoid glomerulopathy, and fibrillary glomerulonephritis. In addition, tubulointerstitial diseases with the deposition of monoclonal immunoglobulins or their components, are constituted by light chain cast nephropathy, light chain proximal tubulopathy, and crystal-storing histiocytosis. We report the case of a 66-year-old woman who presented with albumin-predominant moderate proteinuria and renal failure. Serum and urine immunofixation electrophoresis showed monoclonal κ light chain in both. Renal biopsy confirmed κ-restricted crystal-storing renal disease involving proximal tubular epithelial cells and crystal storing histiocytosis. Multiple myeloma with crystal storing histiocytosis was discovered in bone marrow biopsy. Thus, we present an unusual case of a myeloma patient presenting light chain proximal tubulopathy and crystal-storing histiocytosis both in the kidney and in the bone marrow.
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- 2021
14. Efficacy and Safety of Danazol in Patients with Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms: A Multicenter Observational Study
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Alessandro Bosi, Bruno Fattizzo, Lorenzo Rizzo, Silvia Ferrari, Federico Lussana, Lorenza Maria Borin, Andrea Castelli, Paola Bianchi, Wilma Barcellini, Roberto Cairoli, Alfredo Molteni, and Marta Riva
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
15. Effects of Whole Pelvic Radiotherapy on the Distribution of Lymphocyte Subpopulations in Prostate Cancer Patients
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Giandomenico Roviello, Valerio Nardone, Alberto Bonetta, Pierpaolo Correale, Alfredo Molteni, Maria C. Lazzari, Daniele Generali, Roviello, G., Nardone, V., Bonetta, A., Correale, P., Molteni, A., Lazzari, M. C., and Generali, D.
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Male ,change ,lymphocyte ,radiotherapy ,subpopulations ,Cancer Research ,Prostatic Neoplasms ,Lymphocyte Subsets ,Pelvis ,Oncology ,Humans ,Prospective Studies ,Neoplasm Grading - Abstract
Introduction: In the current study, we have investigated the effects of the different modalities of treatment (volume of radiotherapy [RT], previous surgery) as well as the Gleason score of prostate cancer (PC) on the lymphocyte composition of PC patients undergoing RT. Methods: This is a monoinstitutional study that prospectively included PC patients that underwent RT from January 2016 until December 2017. To compare the different evaluations, the Wilcoxon signed-rank test was used among 2 times (Timepoint 0 to Timepoint 1). Percentage variation was calculated for all the lymphocyte subpopulation and was correlated with clinical parameters (previous surgery, Gleason score, and pelvic irradiation) with the χ2test. The statistical analysis was repeated also on the stratified dataset according to the above parameters (previous surgery, Gleason score, and whole pelvic radiotherapy [WPRT]). Results: One hundred and eleven patients were included in the present analysis. All the lymphocyte subpopulations resulted significantly lower after RT. The modifications of several lymphocyte subpopulations correlated with previous surgery, Gleason score, and WPRT, although stratified analysis demonstrated that WPRT showed the greatest correlation. Conclusion: Our results could be used to design a prospective trial in order to study the use of WPRT on the lymphocyte subpopulations.
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- 2022
16. Evolutionary Portrait of Adult Core-Binding Factor Leukemia Patients Treated with a Continuation Therapy with Midostaurin: Preliminary Results
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Roberto Cairoli, Arianna Gatti, Giovanni Grillo, Monica Fumagalli, Mauro Krampera, Patrizia Zappasodi, Erika Borlenghi, Elisabetta Todisco, Marta Ubezio, Massimo Bernardi, Alfredo Molteni, Claudia Basilico, Mauro Turrini, Rosa Greco, Valentina Mancini, Marta Riva, Beatrice De Marco, Marta Rachele Stefanucci, Bruno Brando, Silvio Marco Veronese, Alessandro Beghini, Cairoli, R, Gatti, A, Grillo, G, Fumagalli, M, Krampera, M, Zappasodi, P, Borlenghi, E, Todisco, E, Ubezio, M, Bernardi, M, Molteni, A, Basilico, C, Turrini, M, Greco, R, Mancini, V, Riva, M, De Marco, B, Stefanucci, M, Brando, B, Veronese, S, and Beghini, A
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MED/15 - MALATTIE DEL SANGUE ,Immunology ,Cell Biology ,Hematology ,CBFL, Midostaurin ,Biochemistry - Published
- 2022
17. JAK Inhibition with Ruxolitinib in Patients with COVID-19 and Severe Pneumonia: Multicenter Clinical Experience from a Compassionate Use Program in Italy
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Carole Paley, Maria Rita Badagliacca, Paolo A. Ascierto, Andrea D’Alessio, Alberto Tedeschi, Moreno Festuccia, Andrea Mortara, Mauro Turrini, Enrico Capochiani, Annalisa Saracino, Federico Simonetti, Alessandro M. Vannucchi, Alfredo Molteni, Giuseppe Saglio, Paola Coco, Roberto Palazzolo, Davide Rapezzi, Katia Falasca, Antonella d'Arminio Monforte, Mara Morelli, Carmine Selleri, Mike Zuurman, Monica Bocchia, and Giuliano Schettino
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Ruxolitinib ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,ruxolitinib ,Inflammatory response ,Lymphocyte ,macromolecular substances ,Article ,Internal medicine ,medicine ,pneumonia ,In patient ,Adverse effect ,hyperactive inflammatory response ,business.industry ,SARS-CoV-2 ,Compassionate Use ,COVID-19 ,General Medicine ,medicine.disease ,Pneumonia ,medicine.anatomical_structure ,Medicine ,business ,COVID-19, SARS-CoV-2, hyperactive inflammatory response, pneumonia, ruxolitinib ,medicine.drug - Abstract
Jak inhibitors are potent anti-inflammatory drugs that have the potential to dampen the hyperactive inflammatory response associated with severe COVID-19. We reviewed the clinical outcomes of 218 patients with COVID-19 hospitalized for severe pneumonia and treated with ruxolitinib through a compassionate use program. Data on the duration of treatment, outcomes at 4, 7, 14, and 28 days, oxygen support requirements, clinical status, and laboratory parameters were retrospectively collected. Overall, according to the physician evaluation, 66.5% of patients showed improvement at follow-up, of these, 83.5% showed improvement by day 7. Oxygen support status also showed improvement, and by day 7, 21.6% of patients were on ambient air, compared with 1.4% at baseline, which increased to 48.2% by day 28. Significant decreases in C-reactive protein and increases in the lymphocyte total count were already observed by day 4, which seemed to correlate with a positive outcome. At the end of the observation period, 87.2% of patients were alive. No unexpected safety findings were observed, and grade 3/4 adverse events were reported in 6.9% of patients.
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- 2021
18. Real‐world experience with decitabine as a first‐line treatment in 306 elderly acute myeloid leukaemia patients unfit for intensive chemotherapy
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Eros Di Bona, Margherita Sciumé, Monica Bocchia, Gianpaolo Nadali, Monica Fumagalli, Monica Crugnola, Carlotta Galeone, Marzia Defina, Alfredo Molteni, Daniela Lambertenghi Deliliers, Silvia Imbergamo, Emanuela Caizzi, Giuseppina Greco, Nicola Stefano Fracchiolla, Roberto Latagliata, Anna Sicuranza, Claudia Basilico, Carla Filì, Vincenzo Sammartano, Giuseppe Rossi, Francesco Rotondo, Mariagrazia Michieli, Enrico Capochiani, Claudio Pelucchi, Giulia Alunni, Barbara Scappini, Massimo Bernardi, Marta Riva, Francesco Mazziotta, Chiara Cattaneo, Marianna Rossi, Giulia Fontanelli, Erika Borlenghi, Anna Candoni, Michele Gottardi, Catia Bigazzi, Ugo Consoli, Renato Fanin, Federico Simonetti, Elisabetta Todisco, Michela Rondoni, and Anna Ermacora
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Male ,Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,Decitabine ,Kaplan-Meier Estimate ,Infections ,unfit patients ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,first-line therapy ,Cause of Death ,Internal medicine ,medicine ,Humans ,Multicenter Studies as Topic ,acute myeloid leukaemia ,Adverse effect ,Aged ,Proportional Hazards Models ,Cause of death ,Aged, 80 and over ,Proportional hazards model ,business.industry ,Hazard ratio ,Hematology ,General Medicine ,decitabine ,Prognosis ,Confidence interval ,Clinical trial ,Leukemia, Myeloid, Acute ,Observational Studies as Topic ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Despite widespread use of decitabine to treat acute myeloid leukaemia (AML), data on its effectiveness and safety in the real-world setting are scanty. Thus, to analyze the performance of decitabine in clinical practice, we pooled together patient-level data of three multicentric observational studies conducted since 2013 throughout Italy, including 306 elderly AML patients (median age 75 years), unfit for intensive chemotherapy, treated with first-line decitabine therapy at the registered schedule of 20 mg/m2 /iv daily for 5 days every 4 weeks. Overall response rate (ORR), overall survival (OS) curves, and multivariate hazard ratios (HRs) of all-cause mortality were computed. Overall, 1940 cycles of therapy were administered (median, 5 cycles/patient). A total of 148 subjects were responders and, therefore, ORR was 48.4%. Seventy-one patients (23.2%) had complete remission, 32 (10.5%) had partial remission, and 45 (14.7%) had haematologic improvement. Median OS was 11.6 months for patients with favourable-intermediate cytogenetic risk and 7.9 months for those with adverse cytogenetic risk. Median relapse-free survival after CR was 10.9 months (95% confidence interval [CI]: 8.7-16.0). In multivariate analysis, mortality was higher in patients with adverse cytogenetic risk (HR=1.58; 95% CI: 1.13-2.21) and increased continuously with white blood cell (WBC) count (HR=1.12; 95% CI: 1.06-1.18). A total of 183 infectious adverse events occurred in 136 patients mainly (>90%) within the first five cycles of therapy. This pooled analysis of clinical care studies confirmed, outside of clinical trials, the effectiveness of decitabine as first-line therapy for AML in elderly patients unfit for intensive chemotherapy. An adverse cytogenetic profile and a higher WBC count at diagnosis were, in this real life setting, unfavourable predictors of survival.
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- 2019
19. Nilotinib-induced bone marrow CD34+/lin-Ph+ cells early clearance in newly diagnosed CP-Chronic Myeloid Leukemia: Final report of the PhilosoPhi34 study
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Michela Anghilieri, Marianna Caramella, Alessandra Trojani, Gabriella De Canal, Salvatore Artale, Alessandra Iurlo, Francesca Lunghi, Maria Luisa Latargia, Michele Nichelatti, Barbara Di Camillo, Alessandra Perego, Chiara Elena, Ester Pungolino, Alfredo Molteni, Francesco Spina, Giacomo Baruzzo, Mariella D'Adda, Maria Cristina Carraro, Mauro Turrini, Roberto Cairoli, Lorenza Borin, Pungolino, E, D'Adda, M, De Canal, G, Trojani, A, Perego, A, Elena, C, Lunghi, F, Turrini, M, Borin, L, Iurlo, A, Latargia, M, Carraro, M, Spina, F, Artale, S, Anghilieri, M, Molteni, A, Caramella, M, Baruzzo, G, Nichelatti, M, Di Camillo, B, and Cairoli, R
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Male ,Oncology ,CD34 ,Cell Cycle Proteins ,Biomarkers, Pharmacological ,NF-KappaB Inhibitor alpha ,MED/15 - MALATTIE DEL SANGUE ,Bone Marrow ,Recurrence ,Granulocyte Colony-Stimulating Factor ,Philadelphia Chromosome ,Prospective Studies ,NFKBIA ,Aged, 80 and over ,Gene Expression Regulation, Leukemic ,Myeloid leukemia ,Hematology ,General Medicine ,Middle Aged ,Intercellular Adhesion Molecule-1 ,GEP ,medicine.anatomical_structure ,Neoplastic Stem Cells ,Female ,Stem cell ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Chronic Myeloid Leukemia ,Antineoplastic Agents ,stem cells ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,medicine ,Humans ,Protein Kinase Inhibitors ,nilotinib ,Aged ,business.industry ,Gene Expression Profiling ,Imatinib ,Janus Kinase 2 ,Discontinuation ,stem cell ,Gene expression profiling ,Pyrimidines ,Nilotinib ,Case-Control Studies ,ATP-Binding Cassette Transporters ,Bone marrow ,business - Abstract
Chronic Myeloid Leukemia is a clonal disorder characterized by the presence of the Ph-chromosome and the BCR-ABL tyrosine-kinase (TK). Target-therapy with Imatinib has greatly improved its outcome. Deeper and faster responses are reported with the second-generation TKI Nilotinib. Sustained responses may enable TKI discontinuation. However, even in a complete molecular response, some patients experience disease recurrence possibly due to persistence of quiescent leukemic CD34+/lin−Ph+ stem cells (LSCs). Degree and mechanisms of LSCs clearance during TKI treatment are not clearly established. The PhilosoPhi34 study was designed to verify the in-vivo activity and timecourse of first-line Nilotinib therapy on BM CD34+/lin−Ph+ cells clearance. Eighty-seven CP-CML patients were enrolled. BM cells were collected and tested for Ph+ residual cells, at diagnosis, 3, 6 and 12 months of treatment. FISH analysis of unstimulated CD34+/lin− cells in CCyR patients were positive in 8/65 (12.3%), 5/71 (7%), 0/69 (0%) evaluable tests, respectively. Per-Protocol analysis response rates were as follows: CCyR 95% at 12 months, MR4.5 31% and 46% at 12 and 36 months, respectively. An exploratory Gene Expression Profiling (GEP) study of CD34+/lin− cells was performed on 30 patients at diagnosis and after, on 79 patients at diagnosis vs 12 months of nilotinib treatment vs 10 healthy subjects. Data demonstrated some genes significantly different expressed: NFKBIA, many cell cycle genes, ABC transporters, JAK-STAT signaling pathway (JAK2). In addition, a correlation between different expression of some genes (JAK2, OLFM4, ICAM1, NFKBIA) among patients at diagnosis and their achievement of an early and deeper MR was observed.
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- 2021
20. Canakinumab as treatment for COVID-19-related pneumonia: A prospective case-control study
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Chiara Costanzi, Daniele Generali, Ilaria Zangrandi, Valeria De Giuli, Fabio Malberti, Maria Rosa Cappelletti, Giancarlo Bosio, Andrea Machiavelli, Marianna Sirico, Antonio Fioravanti, Guglielmo Giannotti, Angelo Pan, Sophie Testa, Ottavia Bernocchi, Fabiola Giudici, Alessia Giossi, Erika Maria Viola, Alfredo Molteni, Marina Foramitti, Alessandro Morandini, Antonio Cuzzoli, Matteo Giorgi-Pierfranceschi, Maurizio Scaltriti, Sergio Venturini, Giulia Chiodelli, Chiara Campana, Alessia Zoncada, Luca Pianta, Laura Romanini, Rosa Angela Tira, Generali, D., Bosio, G., Malberti, F., Cuzzoli, A., Testa, S., Romanini, L., Fioravanti, A., Morandini, A., Pianta, L., Giannotti, G., Viola, E. M., Giorgi-Pierfranceschi, M., Foramitti, M., Tira, R. A., Zangrandi, I., Chiodelli, G., Machiavelli, A., Cappelletti, M. R., Giossi, A., De Giuli, V., Costanzi, C., Campana, C., Bernocchi, O., Sirico, M., Zoncada, A., Molteni, A., Venturini, S., Giudici, F., Scaltriti, M., and Pan, A.
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0301 basic medicine ,Male ,medicine.medical_treatment ,Cohort Studies ,0302 clinical medicine ,Monoclonal ,80 and over ,030212 general & internal medicine ,Viral ,Prospective Studies ,Prospective cohort study ,Humanized ,Aged, 80 and over ,General Medicine ,Middle Aged ,Hospitalization ,Infectious Diseases ,medicine.anatomical_structure ,Treatment Outcome ,Settore SECS-S/01 - STATISTICA ,Cohort ,Female ,Case-Control Studie ,medicine.drug ,Cohort study ,Human ,Microbiology (medical) ,Adult ,medicine.medical_specialty ,Canakinumab ,030106 microbiology ,Pneumonia, Viral ,Antibodies, Monoclonal, Humanized ,Article ,Antibodies ,lcsh:Infectious and parasitic diseases ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,lcsh:RC109-216 ,Aged ,Mechanical ventilation ,Lung ,business.industry ,SARS-CoV-2 ,Case-control study ,COVID-19 ,Pneumonia ,medicine.disease ,Prospective Studie ,Case-Control Studies ,Cohort Studie ,business - Abstract
Highlights • Canakinumab is an IL-1β antibody that neutralizes the activity of IL-1β. • The effects of canakinumab in patients with COVID-19-related pneumonia were studied. • 33 patients received canakinumab and 15 received institutional standard of care. • Treatment with canakinumab rapidly restored normal oxygen status. • Canakinumab was also associated with favorable prognosis versus SoC., Objectives Canakinumab is an IL-1β antibody that neutralizes the activity of IL-1β. We studied the efficacy and safety of canakinumab in patients with moderate COVID-19-related pneumonia. Design The aim of our study was to evaluate the reduction in duration of hospitalization with adequate oxygen status. Forty-eight patients with moderate COVID-19-related pneumonia were asked to participate in the prospective case-control study; 33 patients (Cases) signed informed consent and received canakinumab (Cohort 1); 15 patients (Controls) refused to receive the experimental drug and received institutional standard of care (SoC), (Cohort 2). Results Hospital discharge within 21 days was seen in 63% of patients in Cohort 1 vs. 0% in Cohort 2 (median 14 vs 26 days, respectively; p
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- 2021
21. SARS-CoV-2 in Myelodysplastic Syndromes: A Snapshot From Early Italian Experience
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Federica Pilo, A. Pelizzari, Daniela Cilloni, Massimo Bernardi, Giuseppe A. Palumbo, Carlo Finelli, Alfredo Molteni, Carla Filì, Pellegrino Musto, Marino Clavio, Agostino Tafuri, Francesco Alesiani, Cristina Clissa, Nicola Di Renzo, Valeria Santini, Antonella Poloni, Stefano Mancini, Mariarita Sciumè, Valentina Giai, Enrico Balleari, Chiara Sarlo, Enrico Attardi, Monica Crugnola, Gianluca Guaragna, Anna Calvisi, Marco Cerrano, Sandra Mossuto, Roberto Secchi, Matteo G. Della Porta, Carmen Fava, Gianni Binotto, Esther Oliva, Roberto Fattizzo, Isabella Capodanno, Marta Riva, Costanza Bosi, Carmine Selleri, Flavia Rivellini, Roberto Latagliata, Rosanna Ciancia, Emanuele Angelucci, Svitlana Gumenyuk, Pasquale Niscola, Ambra Di Veroli, Luana Fianchi, Andrea Castelli, Francesco Frattini, Elena Crisà, Emanuela Messa, Susanna Fenu, Ida Lucia Ferrara, Antonella Carbone, and Valentina Gaidano
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Sars-cov2, myelodysplastic syndromes ,2019-20 coronavirus outbreak ,Letter ,Coronavirus disease 2019 (COVID-19) ,business.industry ,lcsh:RC633-647.5 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Myelodysplastic syndromes ,Hematology ,myelodysplastic ,lcsh:Diseases of the blood and blood-forming organs ,lymphopenia ,medicine.disease ,Virology ,infections ,Medicine ,Snapshot (computer storage) ,business - Published
- 2020
22. Immune system and angiogenesis-related potential surrogate biomarkers of response to everolimus-based treatment in hormone receptor-positive breast cancer: an exploratory study
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Anna Ianza, Tiziana Triulzi, Eva Ciruelos, Manuela Milani, Alfredo Molteni, Fabiola Giudici, Maria Rosaria Cappelletti, Silvia Paola Corona, Francesco Schettini, Carla Strina, Navid Sobhani, Guy Jerusalem, Sherine Loi, Stephen B. Fox, Daniele Generali, Ottavia Bernocchi, Maria Chiara Lazzari, Marianna Sirico, Schettini, Francesco, Sobhani, Navid, Ianza, Anna, Triulzi, Tiziana, Molteni, Alfredo, Lazzari, Maria Chiara, Strina, Carla, Milani, Manuela, Corona, Silvia Paola, Sirico, Marianna, Bernocchi, Ottavia, Giudici, Fabiola, Cappelletti, Maria Rosaria, Ciruelos, Eva, Jerusalem, Guy, Loi, Sherine, Fox, Stephen B., and Generali, Daniele
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Receptor, ErbB-2 ,Angiogenesis ,Breast Neoplasms ,Hormone receptors ,Hormone receptor ,Immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Immune system ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,Everolimus ,mTOR ,Biomarker ,Humans ,Retrospective Studies ,business.industry ,Endothelial Cells ,medicine.disease ,Clinical Trial ,Metastatic breast cancer ,Hormones ,Everolimu ,030104 developmental biology ,Immune System ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,Female ,business ,CD8 ,medicine.drug - Abstract
Purpose mTOR inhibitor everolimus is used for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (mBC). No reliable predictive biomarker of response is available. Following evidences from other solid tumors, we aimed to assess the association between treatment-associated immune system features and everolimus activity. Methods We retrospectively explored a correlation with the therapeutic activity of everolimus and tumor-associated immune pathways with ingenuity pathway analysis (IPA), neutrophil-to-lymphocyte ratio (NLR), circulating lymphocytes, and endothelial cells (CECs) in 3 different HR+ mBC studies, including the BALLET phase IIIb study. Results The circulating levels of CD3+/CD8+, CD3+/CD4+, and overall T lymphocytes were higher in responders versus non-responders at baseline (p = 0.017, p p = 0.034) and after treatment (p = 0.01, p = 0.003, p = 0.023). Reduced CECs, a tumor neoangiogenesis marker, were observed in responders after treatment (p 4.4) (p = 0.01). IPA showed that the majority of immunity-related genes were found upregulated in responders compared to non-responders before treatment, but not after. Conclusions Lymphocytes subpopulations, CECs and NLR could be interesting biomarkers predictive of response to everolimus-based regimens, potentially useful in daily clinical practice to select/monitor everolimus-based treatment in mBC. Further studies to confirm such hypotheses are warranted.
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- 2020
23. Reply to 'CLL and COVID-19 at the Hospital Clinic of Barcelona: an interim report' Analysis of six hematological centers in Lombardy
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Lucia Farina, Lydia Scarfò, Alessandra Tedeschi, Gianluigi Reda, Chiara Borella, Paolo Ghia, Alessandro Noto, Ramona Cassin, Giulia Zamprogna, Marco Montillo, Alfredo Molteni, Reda, Gianluigi, Noto, Alessandro, Cassin, Ramona, Zamprogna, Giulia, Borella, Chiara, Scarfò, Lydia, Farina, Lucia, Molteni, Alfredo, Ghia, Paolo, Tedeschi, Alessandra, and Montillo, Marco
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Chronic lymphocytic leukaemia ,Cancer Research ,medicine.medical_specialty ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Epidemiology ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,Betacoronavirus ,Internal medicine ,Correspondence ,Pandemic ,medicine ,Humans ,Pandemics ,Interim report ,Hematology ,biology ,SARS-CoV-2 ,business.industry ,COVID-19 ,biology.organism_classification ,Leukemia, Lymphocytic, Chronic, B-Cell ,Virology ,Oncology ,Coronavirus Infections ,business - Published
- 2020
24. Author response for 'REAL‐WORD EXPERIENCE WITH DECITABINE AS A FIRST‐LINE TREATMENT IN 306 ELDERLY ACUTE MYELOID LEUKAEMIA PATIENTS UNFIT FOR INTENSIVE CHEMOTHERAPY'
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Michela Rondoni, Elisabetta Todisco, Daniela Lambertenghi Deliliers, Catia Bigazzi, Barbara Scappini, Michele Gottardi, Massimo Bernardi, Francesco Mazziotta, Maria Grazia Michieli, Giuseppe Rossi, Marianna Rossi, Marta Riva, Gianpaolo Nadali, Eros Di Bona, Anna Candoni, Emanuela Caizzi, Renato Fanin, Monica Fumagalli, Margherita Sciumé, Alfredo Molteni, Claudia Basilico, Monica Bocchia, Carla Filì, Giulia Fontanelli, Nicola Stefano Fracchiolla, Ugo Consoli, Vincenzo Sammartano, Erika Borlenghi, Francesco Rotondo, Roberto Latagliata, Giulia Alunni, Carlotta Galeone, Silvia Imbergamo, Chiara Cattaneo, Claudio Pelucchi, Enrico Capochiani, Anna Ermacora, Marzia Defina, Giuseppina Greco, Federico Simonetti, Monica Crugnola, and Anna Sicuranza
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First line treatment ,Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Medicine ,Decitabine ,Intensive chemotherapy ,Real word ,Myeloid leukaemia ,business ,medicine.drug - Published
- 2019
25. Somatic mutations as markers of outcome after azacitidine and allogeneic stem cell transplantation in higher-risk myelodysplastic syndromes
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Elisa Cerqui, Maria Teresa Voso, Carlo Finelli, Elisa Linnea Lindfors Rossi, Marianna Criscuolo, Simona Sica, Alfredo Molteni, Tiziana Ottone, Emiliano Fabiani, Giulia Falconi, Anna Candoni, Francesco Lo-Coco, Alfonso Piciocchi, Matteo Parma, Luana Fianchi, Stella Santarone, and Giuseppe Leone
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Adult ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Somatic cell ,Azacitidine ,MEDLINE ,Brief Communication ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Young adult ,Aged ,business.industry ,Myelodysplastic syndromes ,Hematopoietic Stem Cell Transplantation ,markers of outcome after azacitidine ,Hematology ,Middle Aged ,medicine.disease ,Transplantation ,030104 developmental biology ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Mutation ,Female ,Stem cell ,business ,Settore MED/15 - Malattie del Sangue ,medicine.drug - Published
- 2019
26. Mutational profile and haematological response to iron chelation in myelodysplastic syndromes (MDS)
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Pasquale Niscola, Enrico Balleari, Francesco Buccisano, Maria Teresa Voso, Francesco Lo Coco, Alfredo Molteni, Giulia Falconi, Chiara Calabrese, Serena Lavorgna, Flavia Salvi, Marianna Criscuolo, Luana Fianchi, Luca Maurillo, Emiliano Fabiani, Carlo Finelli, Susanna Fenu, and Daniela Cilloni
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medicine.medical_specialty ,Hematology ,Haematological response ,business.industry ,Myelodysplastic syndromes ,medicine.disease ,Gastroenterology ,Iron chelation ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,NGS ,medicine ,MDS ,iron overload ,mutation analysis ,business ,Settore MED/15 - Malattie del Sangue ,030215 immunology - Published
- 2019
27. Second primary malignancies in ruxolitinib-treated myelofibrosis: Real-world evidence from 219 consecutive patients
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Elena Maria Elli, Toni Giorgino, Lorenza Bertù, Elisa Rumi, Chiara Cavalloni, Marianna Caramella, Alessandro Vismara, Daniela Barraco, Margherita Maffioli, Maria Chiara Finazzi, Mariella D'Adda, Francesco Spina, Daniele Cattaneo, Francesco Passamonti, Nicola Polverelli, Simona Malato, Maria Cristina Carraro, Alfredo Molteni, Barbara Mora, Alessandra Iurlo, Maria Luisa Pioltelli, Marianna Rossi, Rossella Renso, Raffaella Accetta, Matteo G. Della Porta, Michela Anghilieri, Marta Bellini, and Cinzia Sissa
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Ruxolitinib ,Population ,Aggressive lymphoma ,myelofibrosis ,Young Adult ,Mutation Rate ,Internal medicine ,Neoplasms ,Nitriles ,medicine ,80 and over ,Humans ,Janus Kinase Inhibitors ,Cumulative incidence ,Aged ,Aged, 80 and over ,Biomarkers ,Duration of Therapy ,Female ,Italy ,Middle Aged ,Mutation ,Neoplasms, Second Primary ,Primary Myelofibrosis ,Pyrazoles ,Myelofibrosis ,education ,education.field_of_study ,Essential thrombocythemia ,business.industry ,hematology ,Gandotinib ,medicine.disease ,Stimulus Report ,Second Primary ,Pyrimidines ,International Prognostic Scoring System ,business ,medicine.drug - Abstract
Myeloproliferative neoplasms (MPNs) are clonal disorders that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Patients with MPNs have a higher risk than the general population of developing a lymphoid neoplasm.1 It is still unclear whether this holds true for nonhematological second primary malignancies (SPMs).2-4 However, among 20 250 MPN patients included in the Surveillance, Epidemiology, and End Results (SEER) Program database, the 10-year cumulative incidence of SPMs was 12.7%, significantly higher than that expected in the general US population.5 Ruxolitinib (RUX) is an oral JAK inhibitor (JAKi) approved for International Prognostic Scoring System (IPSS)/Dynamic IPSS (DIPSS) intermediate- and high-risk myelofibrosis (MF)6,7 and for inadequately controlled PV. More than 2600 RUX-treated MF patients have been prospectively observed for at least 2 years within the 2 pivotal COMFORT trials8,9 and the expanded-access JUMP trial.10,11 Safety data from these trials underline a possibly increased incidence of nonmelanoma skin cancers (NMSCs), but no significant increase of lymphoproliferative neoplasms, similarly to what occurs in PV.12,13 Recently, Porpaczy et al alerted, however, on the possible 16-fold increased risk of developing aggressive lymphomas in MPN patients treated with JAKis, especially in the presence of a preexisting B-cell clone.14 The publication included a total of 1555 MPN patients, 126 of whom were treated with a JAKi (ruxolitinib, gandotinib, fedratinib, momelotinib), obtained assembling 2 broad academic data sets. In the well-described Viennese cohort, 3 of 31 MF patients treated with JAKi developed lymphomas. Median time from JAKi initiation to lymphoma diagnosis was 25 months. Subsequent analyses of other large academic data sets did, however, not confirm an increased risk of aggressive lymphoma development under JAKis in MPNs15,16 and in post-PV and post-ET MF (secondary MF [SMF]).17 These contradictory results were derived either from clinical trials with strict eligibility criteria, possibly at the expense of uncertainty about the generalizability of results, or from highly selected data sets of patients evaluated at referral centers, thus highlighting the need for real-world data (RWD). We consequently set out to assess the occurrence of SPMs, including lymphoproliferative neoplasms, in RUX-treated MF patients on the basis of RWD provided by the health authority of the Lombardy Region, integrated with institutional data.
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- 2019
28. Long Term Effects of Eltrombopag Treatment Versus Placebo for Low-Risk Myelodysplastic Syndromes with Thrombocytopenia (EQoL-MDS): Interim Results of a Single-Blind, Randomised, Controlled, Phase 2 Superiority Trial
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Francesco Buccisano, Ulrich Germing, Antonella Poloni, Elena Crisà, Bruno Martino, Enrico Balleari, Alfredo Molteni, Valeria Santini, Anna Marina Liberati, Pierre Fenaux, Caterina Alati, Giorgina Specchia, Stefana Impera, Dario Ferrero, Roberto Latagliata, Marta Riva, Monica Bocchia, Pasquale Niscola, Esther Oliva, Maria Teresa Voso, Giuseppe A. Palumbo, Isabella Capodanno, Gianluigi Reda, Maria Grazia D'Errigo, Stefano Mancini, Anna Candoni, Patrizia Cufari, Prassede Salutari, Grazia Sanpaolo, Gina Zini, and Valentina Giai
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medicine.medical_specialty ,Randomization ,Surrogate endpoint ,business.industry ,Myelodysplastic syndromes ,Immunology ,Eltrombopag ,Cell Biology ,Hematology ,medicine.disease ,Placebo ,Biochemistry ,chemistry.chemical_compound ,Superiority Trial ,chemistry ,Interim ,Internal medicine ,medicine ,business ,Adverse effect ,health care economics and organizations - Abstract
Background: In myelodysplastic syndromes (MDS), thrombocytopenia is associated with mortality and treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, be effective in improving outcomes in lower-risk MDS with severe thrombocytopenia within a multicentre clinical trial (EQoL-MDS). Initial interim results of short-term efficacy and safety have been published (Oliva et al. Lancet Hem 2017) in the first 90 subjects. We present interim results of the second phase for long-term results in the initial 90 of 174 subjects. Methods: In a single-blind, randomised, controlled, phase 2 trial of adult patients with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk MDS and severe thrombocytopenia. Adult patients with a stable platelet (PLT) count Results: The first 90 subjects were enrolled between 2011 and 2016. Characteristics of patients have been previously published (Lancet Hem 2017). PLT responses occurred in 28 (47.5%) of 59 patients in the eltrombopag group versus 1 (3.2%) of 31 patients in the placebo group (odds ratio 27.1 [95% CI 3.5-211.9], p=0.002) in median time 14 days (95% CI 7-40 days). Severe bleeding (WHO bleeding score ≥2) occurred in 19 patients, with a significantly higher incidence in the placebo (11 [35.3%] of 31 patients) than in the eltrombopag arm (8 [13.6%] of 59 patients; p=0.015). Sixty-eight grade 3-4 adverse events occurred in 30 of 59 (50.8%) eltrombopag patients versus 10 events in 6 of 31 placebo cases (19.4%;χ2=8,4, p=0.004, stopping rule not reached). The outcomes acute myeloid leukemia (AML) evolution, progression and death occurred in 5 (8.5%), 4 (6.8%), and 5 (8.5%), respectively of 59 eltrombopag cases versus 2 (6.5%), 3 (9.7%), 2 (6.5%), respectively of 31 placebo cases (P ranging from 0.69 to 1.00). Median LFS, combined outcome (AML, disease progression and death) and OS were not reached in the whole group. Differences in LFS, combined outcome and OS at 2 and 5 years by study arms were adjusted for baseline bone marrow blasts since the proportion of patients with >2% blasts (i.e. the median value of the whole study cohort) tended to be higher (P=0.06) in Eltrombopag (59.3%) than in placebo treated (38.7%) patients and resulted to be a strong predictor of study outcomes at both 2 and 5 years (P Conclusion. Eltrombopag is well-tolerated in patients with lower-risk MDS and severe thrombocytopenia and is clinically effective in raising PLT count and reducing bleeding events. QoL improves with response to treatment. The assessment of long-term safety and efficacy of eltrombopag and its effect on survival (phase 2 part of study) is still ongoing. Disclosures Oliva: Novartis: Consultancy, Speakers Bureau; Apellis: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Alati:Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Giai:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Balleari:Celgene: Membership on an entity's Board of Directors or advisory committees. Ferrero:Novartis: Honoraria. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Fenaux:Aprea: Research Funding; Jazz: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding. Palumbo:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Hospira: Honoraria. Liberati:Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Molteni:Celgene: Membership on an entity's Board of Directors or advisory committees. Buccisano:Astellas: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bocchia:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Candoni:Merck SD: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Martino:Bristol myers squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Latagliata:Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. OffLabel Disclosure: Eltrombopag is indicated for: 1. the treatment of patients aged 1 year and above with primary immunethrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory to other treatments; 2. in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy; 3. in adult patients with acquired severe aplastic anaemia who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for hematopoietic stem cell transplantation
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- 2019
29. Real-Rd - Real Life Italian Experience with Lenalidomide and Low-Dose Dexamethasone (Rd) As First Line Treatment of Newly-Diagnosed Multiple Myeloma Patients Not Eligible to Stem Cell Transplantation: Outcomes and Tolerability
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Concetta Conticello, Paola Bertazzoni, Valerio Leotta, Federico Vozella, Angelo Belotti, Guido Montanaro, Monica Galli, Loredana Pettine, Sara Aquino, Adelina Sementa, Ugo Consoli, Velia Bongarzoni, Alessandra Lombardo, Salvatore Palmieri, Annalisa Citro, Alessandro Inzoli, Alessandra Pompa, Elisabetta Antonioli, Valeria Ferla, Agostina Siniscalchi, Laura Paris, Lucia Tognazzi, Diana Giannarelli, Francesca Gaia Rossi, Silvia Mangiacavalli, Gabriele Buda, Alessandra Romano, Alfredo Molteni, Francesca Cavallaro, Daniele Derudas, Iolanda Vincelli, Massimo Gentile, Angela Bonalumi, Sara Pezzatti, Renato Zambello, Luca Baldini, Vittorio Del Fabro, Niccolò Frungillo, Francesca Fioritoni, Magda Marcatti, and Federica Elia
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Oncology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Neutropenia ,medicine.disease ,Biochemistry ,Granulocyte colony-stimulating factor ,Tolerability ,Internal medicine ,medicine ,business ,Dexamethasone ,Fibrinolytic agent ,Multiple myeloma ,Lenalidomide ,medicine.drug - Abstract
Introduction Lenalidomide (Len) and low-dose Dexamethasone (dex) (Rd) in continuous is a new standard of care for elderly newly-diagnosed multiple myeloma (NDMM) patients (pts), as established by FIRST trial (Facon et al, Blood 2018). Methods and results This is a retrospective, multicentric study conducted in Italy with the aim of evaluating efficacy and tolerability of Rd in a real-life population. Thirty-seven centers were involved and data of 429 pts are available. Pts were considered eligible for the study when completing at least 2 cycles of Rd regimen. Table 1 summarizes the characteristics of pts at time of MM diagnosis. Median age was 78 years (range 57-92), 36.6% had an ECOG PS≥2, creatinine clearance (ClCr) was After a median follow-up of 11 months, most pts are still on treatment (60,4%), the median number of administered cycles was 7 (range 2-33). Overall response rate (ORR, ≥PR) was 74.5% with 34.1% of pts obtaining at least a VGPR. Clinical Benefit Rate (CBR, including minimal responses) was 83.3%. Responses were rapid with median time to first and to best response respectively of 1.8 (range 1-8) and 5 (1-26) months. Median OS and PFS were not reached with a 1-y and 2-y OS of 84.8 and 73.8% and a 1-y and 2-y PFS of 78.6 and 65%. Median EFS was 19.8 months. In univariate analysis, factors significatively impairing ORR were frailty (fit/unfit/frail 91.2/77/55.9%, p2 81.7/61.6%, p upper level of normal (ULN) (65.8 vs 77%, p=0.034). 1-y PFS is significantly shorter in pts with lower ECOG (0-1 vs 2, 66.5 vs 84.8%, pULN (66.4 vs 83.2%, p=0.02), lower ClCr (50 57.2/81.3/80.1%, P=0.01), presence of t(14;16) (42.9 vs 80.4% p=0.01) and amp(1q) (63.5 vs 85.6%, p=0.01); factor impairing OS are ECOG (0-1/>2 93.4 vs 69.4%, pULN (75.1 vs 97.1, p=0004), impaired ClCr (50 64/83.7/88.2%, p2 74.2 vs 47.3%, p In multivariate analysis ORR is significantly correlated with ECOG>2 (p=0.05), LDH >ULN (p=0.005) and presence of amp1q (p=0.006); PFS was significantly affected by R-ISS III (p=0.04), LDH >ULN (P=0.01) and ClCr2 still impact on OS (p Dose reduction of Len or dex was required respectively in 20.7% and 22.1% and 39.2% needed cycle delay for adverse events (AEs). Grade 3-4 (G3-4) AEs occurred in 52% of pts with 30.9 and 36.6% having at least a hematological or extra-hematological G3-4 AE. In particular, 17.9 and 16.6% of pts had severe neutropenia and anemia while the most common non-hematological AEs were infections (25.8%, G3-4 12.2%), mainly involving respiratory tract (71.2%). Gastroenteric and cutaneous AEs were quite common (22.1 and 19.2%), mainly diarrhea and itching, but in the vast majority were mild. G3-4 asthenia was present in 22.8% of pts. Although 99% of pts was given antithrombotic prophylaxis, 8.5% had a thromboembolic event, a third of severe entity. G-CSF and EPO analogs were required in 27.4 and 26% of pts. Conclusion Real-life data confirm efficacy and tolerability of Rd in elderly NDMM pts. Performance status by ECOG and IMWG frailty score and severe renal impairment but not age itself act as limiting factors affecting outcome. These data must be confirmed by longer follow-up. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Mangiacavalli:Janssen cilag: Consultancy; celgene: Consultancy; Amgen: Consultancy. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Molteni:Celgene: Membership on an entity's Board of Directors or advisory committees. Aquino:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Del Fabro:Janssen: Consultancy. Galli:Leadiant (Sigma-Tau): Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria.
- Published
- 2019
30. Infection control in patients with myelodysplastic syndromes who are candidates for active treatment: Expert panel consensus-based recommendations
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Alfredo Molteni, Corrado Girmenia, Giuseppe A. Palumbo, Prassede Salutari, Roberto Latagliata, Maria Teresa Voso, Valeria Santini, Antonella Poloni, Anna Candoni, Esther Oliva, Pellegrino Musto, and Mario Delia
- Subjects
medicine.medical_specialty ,Consensus ,Infections ,Myelodysplastic syndrome ,Prophylaxis ,Vaccination ,Clinical Trials as Topic ,Disease Management ,Expert Testimony ,Humans ,Infection ,Myelodysplastic Syndromes ,Risk Assessment ,Risk Factors ,Infection Control ,Epidemiology ,Medicine ,Infection control ,Disease management (health) ,Intensive care medicine ,Hematology ,Oncology ,Lenalidomide ,business.industry ,Risk of infection ,Myelodysplastic syndromes ,medicine.disease ,Supportive psychotherapy ,business ,Risk assessment ,Settore MED/15 - Malattie del Sangue ,medicine.drug - Abstract
The improvement in supportive care and the introduction of new therapeutic agents, including lenalidomide and hypomethylating agents, in myelodysplastic syndromes have improved patients' outcomes; however, at the same time, the frequency and epidemiology of infections have changed. Therefore, the great strides in the indications and use of new treatment strategies for myelodysplastic syndromes need a parallel progress in the best approach to prophylaxis and supportive therapy for infections. Based on the recognition that the above issues represent an unmet clinical need in myelodysplastic syndromes, an Italian expert panel performed a review of the literature and composed a framework of the best recommendations for optimal infection control in patient candidates to receive active treatment for myelodysplastic syndromes. In this consensus document we report the outcomes of that review and of the consensus meetings held during 2017. The issues tackled in the project dealt with: information to be collected from candidates for active treatment for myelodysplastic syndromes; how to monitor the risk of infection; antimicrobial prophylaxis; the role of iron chelation and antiviral/antibacterial vaccinations. For each of these issues, practice recommendations are provided.
- Published
- 2018
31. Bone Marrow Fibrosis and Early Hematological Response as Predictors of Poor Outcome in Azacitidine Treated High Risk-Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia
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Ramona Cassin, Agostino Cortelezzi, Alfredo Molteni, Marta Riva, Martina Pennisi, Bruno Fattizzo, Roberto Cairoli, Diana Giannarelli, Gianluigi Reda, Alessandra Freyrie, Reda, G, Riva, M, Fattizzo, B, Cassin, R, Giannarelli, D, Pennisi, M, Freyrie, A, Cairoli, R, Molteni, A, and Cortelezzi, A
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Adult ,Male ,medicine.medical_specialty ,Myeloid ,Myelodysplasia ,Azacitidine ,Chronic myelomonocytic leukemia ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Myelofibrosis ,Bone marrow fibrosi ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Myeloid, Acute ,Treatment Outcome ,medicine.anatomical_structure ,Primary Myelofibrosis ,International Prognostic Scoring System ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Female ,Bone marrow ,business ,Bone marrow cellularity ,Febrile neutropenia ,030215 immunology ,medicine.drug - Abstract
Azacitidine (AZA) treatment is effective treatment for patients with myeloid disorders, and factors predictive of treatment outcome are under investigation. Little is known about the effect of bone marrow fibrosis on response to AZA therapy. We, retrospectively, evaluated clinical predictors of overall survival (OS) and overall response rate (ORR) for patients treated with AZA in a real-life cohort. We evaluated 94 consecutive patients treated with AZA outside of clinical trials (75mg/m2/day for 7 days every 28 days; 5 + 2 + 2 schedule), from June 2009 to February 2016. Ninety-three patients were evaluated for response. After a median of 6 cycles, ORR-complete response (CR; including marrow CR) + partial response (PR) + hematological improvement (HI)-was 41.9% (CR = 18.3%; PR = 11.8%; HI = 11.8%). Stable disease was observed in 21.5%, and failure in 36.5%. Pre-AZA bone marrow blast percentage, International Prognostic Scoring System (IPSS) or IPSS-R category, and time from diagnosis to AZA had no effect on response. Median OS from start of therapy was 18.5 months, and was significantly related to higher IPSS category (P = .01), poor cytogenetics according to the IPSS (P = .01), poor and very poor cytogenetics according to the IPSS-R (P = .02), and lower ORR (P = .006). Patients with MF-0 pre-AZA demonstrated significantly higher ORR, (CR + PR + HI) and stable disease, and lower failure rates than those with any grade of fibrosis. Indeed, cases with pre-AZA fibrosis > MF-1 had shorter OS (P = .005). Achievement of HI before 4 cycles of treatment negatively impacted OS (P = .009).
- Published
- 2018
32. PS1462 SECOND PRIMARY MALIGNANCIES IN MYELOFIBROSIS PATIENTS TREATED WITH RUXOLITINIB: REAL WORLD EVIDENCE FROM 215 CONSECUTIVELY TREATED PATIENTS IN LOMBARDY
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C. Sissa, Elena Maria Elli, Francesco Passamonti, Maria Chiara Finazzi, Elisa Rumi, Barbara Mora, Mariella D'Adda, A. Vismara, M.G. Della Porta, Alfredo Molteni, Toni Giorgino, Margherita Maffioli, Daniela Barraco, Marianna Caramella, Francesco Spina, Nicola Polverelli, Michela Anghilieri, Simona Malato, Maria Cristina Carraro, Alessandra Iurlo, and Marianna Rossi
- Subjects
Oncology ,Ruxolitinib ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Hematology ,Second primary cancer ,Myelofibrosis ,medicine.disease ,business ,Real world evidence ,medicine.drug - Published
- 2019
33. Prognostic relevance of the flow cytometric count of medullar blasts in myelodysplastic syndromes
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Roberto Cairoli, Rosa Greco, Silvano Rossini, Valentina Speziale, Marta Riva, Michele Nichelatti, Enrica Morra, Barbara Scarpati, Alfredo Molteni, Emanuele Ravano, Clara Cesana, Molteni, A, Riva, M, Cesana, C, Speziale, V, Nichelatti, M, Scarpati, B, Greco, R, Ravano, E, Cairoli, R, Rossini, S, and Morra, E
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Pathology ,Immature cells ,CD33 ,CD34 ,Bone Marrow Cells ,Cell Count ,Blast Count ,Immunophenotyping ,Bone Marrow ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Retrospective analysis ,Humans ,In patient ,Medullar blasts count ,Aged ,Aged, 80 and over ,biology ,CD117 ,business.industry ,Myelodysplastic syndromes ,Bone Marrow Examination ,Hematology ,General Medicine ,Middle Aged ,Flow Cytometry ,Prognosis ,medicine.disease ,Myelodysplastic Syndromes ,biology.protein ,Female ,business ,Myelodysplastic syndrome ,Prognostic assessment ,Biomarkers - Abstract
Objective The medullar blast count is a milestone in the prognostic assessment in myelodysplastic syndromes (MDS). The optical microscopy (OM) may sometimes be inaccurate in this disease. The aim of this work is to test the flow immunocytometric (FCM) determinations of medullar immature cells (CD45±) and the expression, among them, of CD33, CD34, and CD117 markers, for their prognostic relevance. Methods In a retrospective analysis of 98 patients affected by MDS, the IPSS was re-calculated by means of the FCM determination of blasts. Survival of patients at low or intermediate-1 IPSS risk was compared with the survival of patients at intermediate-2 or high IPSS risk. In the 64 cases with OM blast count lower than 5%, the survival of patients with the FCM count of medullar blasts ≤2% was compared with that of patients with FCM count >2%. Results Each single marker had a prognostic weight comparable to the optical blast count. The FCM blast count was particularly efficient in distinguishing the risk of having up to 2% or more than 2% of blasts in patients without OM excess of blasts. Conclusion This method is interesting as prognostic tool, especially in patients without excess of blast.
- Published
- 2014
34. Decision analysis of allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome stratified according to the revised International Prognostic Scoring System
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Alfredo Molteni, Stefano Guidi, Marta Ubezio, Pellegrino Musto, Emilio Paolo Alessandrino, Francesco Onida, Pietro Pioltelli, Luca Malcovati, Mario Cazzola, Bernardino Allione, Giovanni Grillo, Marianna Rossi, Francesca Bonifazi, M. T. Van Lint, Armando Santoro, Andrea Bacigalupo, Alessandro Rambaldi, Valeria Santini, Emanuele Angelucci, A. P. Iori, Cristiana Pascutto, Alberto Bosi, Simona Sica, Chiara Milanesi, Elena Oldani, Elisabetta Todisco, Raffaella Cerretti, Christopher Jackson, Virginia Valeria Ferretti, Massimo Bernardi, M.G. Della Porta, Lorenza Borin, and Maria Teresa Voso
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Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Natural history of disease ,Article ,Decision Support Techniques ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Intensive care medicine ,business.industry ,Myelodysplastic syndromes ,Hematopoietic Stem Cell Transplantation ,Hematology ,allogeneic hematopoietic stem cell transplantation myelodysplastic syndrome revised international prognostic scoring system ,Middle Aged ,medicine.disease ,Prognosis ,Quality-adjusted life year ,Transplantation ,International Prognostic Scoring System ,030220 oncology & carcinogenesis ,Life expectancy ,Female ,Quality-Adjusted Life Years ,business ,Risk assessment ,Settore MED/15 - Malattie del Sangue ,030215 immunology - Abstract
Allogeneic hematopoietic stem cell transplantation (allo-SCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Crucial questions in clinical decision-making include the definition of optimal timing of the procedure and the benefit of cytoreduction before transplant in high-risk patients. We carried out a decision analysis on 1728 MDS who received supportive care, transplantation or hypomethylating agents (HMAs). Risk assessment was based on the revised International Prognostic Scoring System (IPSS-R). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of different treatment policies on survival. Life expectancy increased when transplantation was delayed from the initial stages to intermediate IPSS-R risk (gain-of-life expectancy 5.3, 4.7 and 2.8 years for patients aged ⩽55, 60 and 65 years, respectively), and then decreased for higher risks. Modeling decision analysis on IPSS-R versus original IPSS changed transplantation policy in 29% of patients, resulting in a 2-year gain in life expectancy. In advanced stages, HMAs given before transplant is associated with a 2-year gain-of-life expectancy, especially in older patients. These results provide a preliminary evidence to maximize the effectiveness of allo-SCT in MDS.
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- 2017
35. A PROPOSAL OF MULTI-DIMENSIONAL EVALUATION OF ELDERLY PATIENTS AFFECTED BY MDS: THE 'NO-CHAIN' ALGORITHM
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Roberto Cairoli, Marta Riva, Alfredo Molteni, Emanuele Ravano, Riva, M, Ravano, E, Cairoli, R, and Molteni, A
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Cancer Research ,medicine.medical_specialty ,Physical medicine and rehabilitation ,Theoretical computer science ,Chain (algebraic topology) ,Oncology ,Computer science ,medicine ,Multi dimensional ,Hematology - Published
- 2017
36. Health-related quality of life in transfusion-dependent patients with myelodysplastic syndromes: a prospective study to assess the impact of iron chelation therapy
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Carlo Finelli, Giovanni Quarta, Daniela Cilloni, Franco Mandelli, Antonio Volpe, Lorenza Borin, Susanna Fenu, Valeria Santini, Anna Angela Di Tucci, Emanuele Angelucci, Fabio Efficace, Grazia Sanpaolo, Alfredo Molteni, Giorgio La Nasa, Francesco Cottone, Flavia Salvi, Giulia Quaresmini, Flavia Rivellini, Giuliana Alimena, and Maria Teresa Voso
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Adult ,Male ,medicine.medical_specialty ,genetic structures ,Chelation Therapy ,Myelodysplastic Syndromes ,Quality of life ,Symptom Burden ,Transfusions ,Medicine (miscellaneous) ,Iron Chelating Agents ,Benzoates ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Chelation therapy ,Prospective cohort study ,Aged ,Aged, 80 and over ,Health related quality of life ,Chelation Therapy, Myelodysplastic Syndromes, Quality of life, Symptom Burden, Transfusions ,Oncology (nursing) ,business.industry ,Myelodysplastic syndromes ,Deferasirox ,Transfusion Reaction ,General Medicine ,Iron chelation therapy ,Middle Aged ,Triazoles ,medicine.disease ,humanities ,Medical–Surgical Nursing ,Treatment Outcome ,030220 oncology & carcinogenesis ,Transfusion dependence ,Quality of Life ,Physical therapy ,Female ,business ,Settore MED/15 - Malattie del Sangue ,030215 immunology ,medicine.drug - Abstract
The primary objective of this study was to evaluate the health-related quality of life (HRQOL) in lower-risk, transfusion-dependent patients with myelodysplastic syndromes (MDS) treated with deferasirox. A secondary objective was to investigate the relationship between HRQOL, serum ferritin levels and transfusion dependency.This was a prospective multicentre study enrolling 159 patients, of whom 152 received at least one dose of deferasirox. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) at baseline and then at 3, 6, 9 and 12 months. Primary analysis was performed estimating mean HRQOL scores over time by a linear mixed model on selected scales.The median age of treated patients was 72 years (range 24-87 years). No statistically significant changes over time were found in mean scores for global health status/quality of life (p=0.564), physical functioning (p=0.409) and fatigue (p=0.471) scales. Also, no significant changes were found for constipation (p=0.292), diarrhoea (p=0.815) and nausea and vomiting (p=0.643). Serum ferritin levels were not associated with HRQOL outcomes. A higher patient-reported baseline pain severity was an independent predictive factor of an earlier achievement of transfusion independence with a HR of 1.032 (99% CI 1.004 to 1.060; p=0.003).HRQOL of transfusion-dependent patients with MDS receiving deferasirox therapy remains stable over time. HRQOL assessment might also provide important predictive information on treatment outcomes.NCT00469560.
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- 2014
37. Invasive fungal infections in lymphoproliferative disorders: a monocentric retrospective experience
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Alberto Volonterio, Michele Nichelatti, Pierluigi Lombardi, Anna Maria Nosari, Cristina Gabutti, Enrica Morra, Eleonora Vismara, Antonino Greco, Marta Riva, Alfredo Molteni, Laura Marbello, and Maria Luisa Pioltelli
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Male ,Cancer Research ,medicine.medical_specialty ,Antifungal Agents ,Lymphoproliferative disorders ,Neutropenia ,Biology ,Aspergillosis ,Blood serum ,Antineoplastic Combined Chemotherapy Protocols ,Epidemiology ,medicine ,Humans ,Mortality ,Aged ,Retrospective Studies ,Aspergillus ,Incidence ,Incidence (epidemiology) ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,biology.organism_classification ,Dermatology ,Fungal antigen ,Lymphoproliferative Disorders ,Treatment Outcome ,Mycoses ,Oncology ,Immunology ,Female - Abstract
Invasive fungal infections (IFIs) seem to be a relevant cause of morbidity and mortality in patients with chronic lymphoproliferative disorders. We studied retrospectively the epidemiology, clinical manifestations and outcome of invasive fungal infections in 42 patients with lymphoproliferative diseases, treated between January 2004 and February 2012 for probable or proven IFI. In our entire population (1355 patients) of chronic lymphoproliferative malignancies, the incidence of probable/proven IFI was 3% (molds 2.3%, yeasts 0.5%, mixed infections 0.2%). Eight patients developed a yeast infection documented by blood cultures in seven cases and by the microscopic observation of Candida spp. in the vitreum after vitrectomy in one case. Among molds we diagnosed three proven infections by histologic evidence of Aspergillus spp. (n = 2) and Mucor (n = 1) in the lung and 28 probable mycoses. Three mixed infections from both molds and yeasts were also observed. Twenty-two cases showed positivity of galactomannan antigen in the serum (n = 16), in bronchoalveolar lavage (BAL) fluid (n = 4) or in both (n = 2). Cultures were positive in 11 cases. The overall rate of response to therapy was 64%. Fungal-attributable mortality rate was 17%, with a significant difference between molds and yeasts (16% vs. 25%, p = 0.03). At univariate analysis, the only risk factors related to mortality were severe and prolonged neutropenia (p = 0.003) and age (p = 0.03). Among molds, the rapid start of antifungals was probably partially responsible, together with new drugs, for the reduction of mortality, despite the severe immunosuppression of these patients.
- Published
- 2014
38. P53 and CD34 Immunohistochemical Expression on Bone Marrow Biopsy As Predictive Marker of Response to Erythropoietin in Low Risk Myelodysplastic Syndrome
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Agostino Cortelezzi, Alfredo Molteni, Gianluigi Reda, Umberto Gianelli, Ramona Cassin, Marta Riva, Laura Bandiera, Emanuela Bonoldi, Marco Barella, Alessandro Del Gobbo, and Francesca Boggio
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Oncology ,medicine.medical_specialty ,Univariate analysis ,Predictive marker ,Myeloid ,business.industry ,Anemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Median follow-up ,International Prognostic Scoring System ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Bone marrow ,business ,Myelofibrosis - Abstract
Introduction: Erythropoietin stimulating agents (ESAs) are first-line therapy for International Prognostic Scoring System (IPSS)-low risk myelodysplastic syndrome (MDS) when symptomatic anaemia (Hb Attempts have been made to build prognostic scores (integrating transfusion need, erythropoietin level, R-IPSS and ferritin) able to predict response to ESAs (6-7). No data concerning the predictive value of morphological and immunohistochemical analysis on bone marrow biopsy in low risk MDS patients are emerged till now. Methods: We retrospectively examined 96 IPSS low/int-1 MDS patients treated with ESAs in order to evaluate the morphological and immunohistochemical features of the bone marrow biopsies performed at baseline. All the patients had hemoglobin (Hb) ≤10 g/dL and serum EPO A detailed analysis of the morphological features (including quantitative and qualitative changes in the erythroid, myeloid and megakariopoyetic lineages) was performed, together with an immunohistochemical evaluation of p53 expression and CD34-positive blasts percentage. Results: Sixty-eight percent of the patients were classified as responder while 32% as non-responder. The morphologic profiles of the responder and non-responder did not differ significantly. A significant correlation was found between the response to the therapy and a percentage of CD34-positive blasts > 3% (univariate analysis: p= .0211). Moreover p53 expression in less than 1% of the nucleated cells correlated with the treatment response (univariate analysis: p = .0086). These results were also confirmed on multivariate analysis (p= .002). Fifty-eight percent of patients maintained response to ESAs for the entire duration of the follow up while 42% lost the response (median follow up: 35 months). More than 3% CD34-positive blasts was associated with a higher probability to lose the response to ESAs (p = .00003). Kaplan-Meier method was than applied to estimate the response duration. Patients with more than 3% CD34-positive blasts showed earlier loss of response in comparison with those with a lower percentage of blasts (p value= .0003; HR=3.9, IC 95% 1.8154-8.6238). Finally, the expression of p53 in more than ≥ 1% of the nucleated cells correlated with the loss of response before 24 mounts (p value= 0.029). Conclusions: Our study identifies 2 well-known parameters that could be useful to better predict outcome of ESAs therapy in low risk MDS patients. Therefore role of bone marrow biopsy together with its diagnostic contribution in the clinical evaluation of MDS patients (cellularity, morphologic dysplasia, percentage of CD34-positive blasts, grading of bone marrow fibrosis) could be helpful as a predictive tool in ESAs candidate patients. Further studies based on larger series of patients are needed to confirm these preliminary results. Disclosures Reda: Gilead: Consultancy; ABBVIE: Consultancy; Janssen and Cilag: Consultancy; Celgene: Consultancy. Riva:Jannsen and Cilag: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Molteni:Janssen and Cilag: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Celgene: Consultancy; AMGEN: Consultancy. Cortelezzi:abbvie: Consultancy; novartis: Consultancy; roche: Consultancy; janssen: Consultancy.
- Published
- 2018
39. Danazol Treatment for Thrombocytopenia in Lower-Risk Myelodysplastic Syndromes: A Pilot Real Life Experience
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Emanuele Ravano, Roberto Cairoli, Marta Riva, Alfredo Molteni, Lara Crucitti, Michele Nichelatti, Cristina Fiamenghi, Gianluigi Reda, Riva, M, Crucitti, L, Ravano, E, Nichelatti, M, Reda, G, Fiamenghi, C, Cairoli, R, and Molteni, A
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Response rate (survey) ,Danazol ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Immunology ,Eltrombopag ,Repeated measures design ,Cell Biology ,Hematology ,medicine.disease ,Lower risk ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Hypocellularity ,chemistry ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Adverse effect ,business ,030215 immunology ,medicine.drug - Abstract
Background: Severe thrombocytopenia is an uncommon event in patients (pts) with lower-risk MDS, but it may significantly affect the prognosis. No specific pharmacological approaches other than hypometilating agents (not licensed in Europe in lower-risk MDS), able to improve platelet count in this setting, are currently available. Trials testing efficacy and safety of Eltrombopag are ongoing (Oliva 2017). Few data were reported about danazol, an attenuated androgen, that seems to have also some effectiveness in this still unmet need (Wattel 1994; Chan 2002). Aims: To assess the efficacy and safety of danazol in improving the platelet count in low risk MDS pts with severe thrombocytopenia. Methods: We retrospectively reviewed 35 thrombocytopenic MDS pts treated with danazol. The initial and maximal dose was 600 mg/day for all pts, modulated according to response and toxicity. The response was evaluated according to IWG response criteria (Cheson 2006). The outcome was strictly observed every 3 months (mo) up to the 12th mo, and the platelets average number in each observation moment was described. The time to response, the response rate and the enduring of response were also recorded. Results: Of the 35 pts, according to 2016 WHO classification, 4 pts were MDS-ULD; 19 were MDS-MLD (3 of them with medullar hypocellularity), 7 were MDS-EB1 and 5 were affected by MDS/MPN. At baseline the platelet count was lower than 20x10^3/mL in 11 pts, the median was 23x10^3/mL . At starting time of danazol therapy the IPSS-R cytogenetic class of risk was very low in 2 cases, low in 28 cases, intermediate in 3 cases and very high in 1 case. Cytogenetic was not available in one patient. In the 30 MDS pts, the IPSS-R was "very low" in 1 patient, "low" in 16, "intermediate" in 7, "high" in 4 and "very high" in 1. In 1 case it was not evaluable due to the lack of cytogenetics. Two pts were not included in the analysis because they were treated for less than 3 mo (in 1 case danazol was withdraw to permit the beginning of another therapy and in 1 case due to death for other neoplastic disease). The response rate was 63,6% (21 responders on 33 evaluable). Median time to response was 3.5 mo (range 0.3 - 12.4 mo); the average response time was 5.09 mo. In the first year of treatment, the platelet count (evaluated at baseline, 3, 6, 9 and 12 mo) changed in a significant way (F test after repeated measures ANOVA: p < 0.001 as shown in Figure 1). Pairwise comparisons of platelet count according to Bonferroni showed a significant difference for baseline vs. 3 mo (p = 0.0013), baseline vs 6 mo (p = 0.0255), baseline vs 9 mo (p = 0.0047) and baseline vs 12 mo (p = 0.0014); however, no significant differences (p ≥ 0.05) in counts were seen for all the further pairwise comparisons at 3, 6, 9 and 12 mo. The median and average duration of the response for the entire population were respectively 12,5 and 32,5 mo. Only 6 of the 21 responders (28%) lost the response (the median and average duration of response were respectively 5.8 and 12.9 mo). Within the 21 responders, the median progression free survival was not reached after 24 mo. The probability to maintain the response after 50 mo was assessed at 58.2% (C.I. 24.1% to 81.4% - Figure 2). The overall survival showed a significant difference (logrank test: p = 0.0064) between responders and non-responders (Figure 3). Adverse events recorded were as follows: moderate (grade 1 and 2) increase in transaminases in 4 cases (with reduction of danazol to 400 mg/day); 1 case of severe but reversible liver toxicity (grade 3) (with subsequently drug suspension); severe (grade 3) but reversible renal failure in 1 case (the drug was stopped); moderate (grade 1 and 2) increasing of serum creatinine in 6 case (with reduction of danazol to 400 mg/day in 2 of these); reversible cutaneous rash in 3 cases; amenorrhea in 1 case (the only fertile woman in the series); weight loss and loss of appetite in 1 case, weight gain in 1 case. Conclusion: Even if the mechanism of action of danazol in pts with MDS is unclear, this series confirms its efficacy to improve platelet count in the most of MDS pts with severe thrombocytopenia. The response was often clinically significant. It may not be immediate but seems to be reachable after 3-6 mo of treatment. A responsive patient has a good probability to maintain a long-lasting response. The toxicity profile of this drug is acceptable. Waiting for more effective options, danazol may be a good therapeutic option for these pts. Disclosures Riva: Jannsen and Cilag: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Reda:Celgene: Consultancy; Janssen and Cilag: Consultancy; Gilead: Consultancy; ABBVIE: Consultancy. Molteni:AMGEN: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Celgene: Consultancy; Janssen and Cilag: Consultancy.
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- 2018
40. Verifying Hellström-Lindberg score as predictive tool for response to erythropoietin therapy according to the 'International Working Group' criteria, in anemic patients affected by myelodysplastic syndrome: a monocentric experience
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Annamaria Nosari, Rosa Greco, Alfredo Molteni, Enrica Morra, Michele Nichelatti, Marta Riva, Emanuele Ravano, and Laura Marbello
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Adult ,Male ,medicine.medical_specialty ,Scoring system ,Databases, Factual ,Risk Factors ,Internal medicine ,Humans ,Medicine ,In patient ,Erythropoietin ,Aged ,Aged, 80 and over ,Response rate (survey) ,Hematology ,business.industry ,Myelodysplastic syndromes ,Anemia ,Middle Aged ,International working group ,Prognosis ,medicine.disease ,Treatment Outcome ,ROC Curve ,Myelodysplastic Syndromes ,Erythropoietin therapy ,Physical therapy ,Female ,business ,medicine.drug - Abstract
The Hellström-Lindberg score (HLS) (1997) is designed to predict erythroid response to erythropoietin treatment in myelodysplastic patients. In order to test the validity of this scoring system, 58 patients affected by myelodysplastic syndrome, treated with a "standard dose" approach between 2001 and 2010, were analyzed. The response to erythropoietin treatment was evaluated in accordance with the "international working group" (IWG) criteria. Among the patients only two were scored "poor," 12 "intermediate," and 44 "good" (15 of whom were scored "3" and 29 "4"). Although the system was verified as a predictive tool for response to erythropoietin therapy, we noted that of patients scored as "good," those with a numerical score of "4" responded more frequently than did those scored "3", as evaluated under both the 2006- and 2000-IWG ("major response") criteria. The modest response rate in patients scoring "3" did not show a difference in response rate in comparison to the "intermediate" group. The present data suggest that only patients scoring "4" on the scale may show an adequate response to the standard dose erythropoietin therapy, while frontline high-dose therapy should be offered to other patients. A further analysis considering endogenous erythropoietin as a possible determinant of response revealed the optimal cut-off value of 80 mIU/mL, instead of the value of 100 mIU/mL utilized by the HLS.
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- 2013
41. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial
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Aspasia Stamatoullas, Maria Grazia D'Errigo, Anna Marina Liberati, Stefano Mancini, Monica Bocchia, Irene Santacaterina, Prassede Salutari, Esther N. Oliva, Patrizia Cufari, Enrico Balleari, Valeria Santini, Grazia Sanpaolo, Stefana Impera, Pierre Fenaux, Maria Antonietta Aloe Spiriti, Paola Carluccio, Gina Zini, Maria Teresa Voso, Irene Bova, Paolo Avanzini, Flavia Salvi, Austin G. Kulasekararaj, Pasquale Niscola, Giuseppe A. Palumbo, Agostino Cortelezzi, Antonella Poloni, Caterina Alati, Fortunato Morabito, Alfredo Molteni, Roberto Latagliata, Francesco Buccisano, and Ulrich Germing
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Male ,medicine.medical_specialty ,Population ,Eltrombopag ,Placebo ,Aged ,Aged, 80 and over ,Benzoates ,Disease Progression ,Female ,Humans ,Hydrazines ,Middle Aged ,Myelodysplastic Syndromes ,Platelet Count ,Pyrazoles ,Receptors, Thrombopoietin ,Single-Blind Method ,Thrombocytopenia ,Treatment Outcome ,Hematology ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Receptors ,80 and over ,medicine ,education ,education.field_of_study ,Intention-to-treat analysis ,business.industry ,Interim analysis ,Surgery ,Platelet transfusion ,Thrombopoietin ,chemistry ,International Prognostic Scoring System ,030220 oncology & carcinogenesis ,myelodysplasia, eltrombopag , thrombocytopenia ,business ,Settore MED/15 - Malattie del Sangue ,030215 immunology - Abstract
Summary Background In myelodysplastic syndromes, thrombocytopenia is associated with mortality, but treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, might be effective in improving thrombocytopenia in lower-risk myelodysplastic syndromes and severe thrombocytopenia. Methods EQoL-MDS was a single-blind, randomised, controlled, phase 2 superiority trial of adult patients with low-risk or International Prognostic Scoring System intermediate-1-risk myelodysplastic syndromes and severe thrombocytopenia. Patients with a stable platelet count of lower than 30 × 10 9 platelets per L, aged at least 18 years, with refractoriness, ineligibility to receive treatment with alternative medications, or relapse while receiving treatment with alternative medications were included in this trial. Patients were randomly assigned (2:1) to receive eltrombopag (50 mg to 300 mg) or placebo for at least 24 weeks and until disease progression and were masked to treatment allocation. Here, we report the results in the intention-to-treat population of the first phase of the trial, for which the primary endpoints were the proportion of patients achieving a platelet response within 24 weeks and safety. The interim analysis presented here was protocol-specified and used a two-sided significance level of 0·001 and a p value at or below this limit for both primary endpoints to indicate the need for early trial termination. Duration of platelet transfusion independence, duration of response, overall survival, leukaemia-free survival, and pharmacokinetics will be reported at the end of the phase 2 portion of the trial. This trial is registered with EudraCT, number 2010-022890-33. Findings Between June 13, 2011, and June 17, 2016, we enrolled 90 participants for the first phase of the trial. The median follow-up time to assess platelet responses was 11 weeks (IQR 4–24). Platelet responses occurred in 28 (47%) of 59 patients in the eltrombopag group versus one (3%) of 31 patients in the placebo group (odds ratio 27·1 [95% CI 3·5–211·9], p=0·0017). During the follow-up, 21 patients had at least one severe bleeding event (WHO bleeding score ≥2). There were a higher number of bleeders in the placebo (13 [42%] of 31 patients) than in the eltrombopag arm (eight [14%] of 59 patients; p=0·0025). 52 grade 3–4 adverse events occurred in 27 (46%) of 59 patients in the eltrombopag group versus nine events in five (16%) of 31 patients in the placebo group (χ 2 =7·8, p=0·0053, stopping rule not reached). The outcome acute myeloid leukaemia evolution or disease progression occurred in seven (12%) of 59 patients in the eltrombopag group versus five (16%) of 31 patients in the placebo group (χ 2 =0·06, p=0·81). Interpretation Eltrombopag is well-tolerated in patients with lower-risk myelodysplastic syndromes and severe thrombocytopenia and is clinically effective in raising platelet counts and reducing bleeding events. The assessment of long-term safety and efficacy of eltrombopag and its effect on survival (phase 2 part of study) is still ongoing. Funding Associazione QOL-ONE.
- Published
- 2016
42. Clofarabine-based chemotherapy as a bridge to transplant in the setting of refractory or relapsed acute myeloid leukemia, after at least one previous unsuccessful salvage treatment containing fludarabine: a single institution experience
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Roberto Cairoli, Marta Riva, Emanuele Ravano, Rosa Greco, Alfredo Molteni, Valentina Mancini, Giovanni Grillo, Laura Marbello, Elisa Zucchetti, Molteni, A, Riva, M, Ravano, E, Marbello, L, Mancini, V, Grillo, G, Zucchetti, E, Greco, R, and Cairoli, R
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Adult ,Male ,medicine.medical_specialty ,Relapsed/refractory AML ,Adolescent ,medicine.medical_treatment ,Salvage therapy ,Hematopoietic stem cell transplantation ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,medicine ,Clofarabine ,Humans ,Etoposide ,Aged ,Retrospective Studies ,Salvage Therapy ,Mitoxantrone ,Chemotherapy ,business.industry ,Adenine Nucleotides ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Allografts ,Surgery ,Fludarabine ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,Cytarabine ,Female ,Arabinonucleosides ,business ,Vidarabine ,030215 immunology ,medicine.drug - Abstract
For refractory or relapsed acute myeloid leukemia patients, allogeneic hematopoietic stem cell transplantation is the only curative treatment option, but the disease must be in remission before this can be attempted. “Salvage” therapy regimens containing high-dose cytarabine plus fludarabine or cladribine with or without anthracyclines or plus mitoxantrone and etoposide fail in 30–50% of cases. We report the outcome of 14 patients treated with a clofarabine-based treatment administered after at least one failed fludarabine-based “salvage” attempt in a “real life” (outside a clinical trial) context. No death related to the clofarabine-based treatment was observed. Four of the 14 patients (29%) reached complete remission and one (7%) achieved a reduction of marrow blasts to fewer than 10%. Three of these five patients were successfully transplanted and have shown a long-term survival. The small number of this group of patients does not permit the identification of clinical features clearly related to a favorable outcome, but we note that all the three long-term survivals were FLT3 wild type. Clofarabine-based “salvage therapy” in patients with very poor expectancy is feasible even after a fludarabine-based salvage attempt, albeit with success only in a small percentage of cases (3/14 = 21%).
- Published
- 2016
43. The influence of disease and comorbidity risk assessments on the survival of MDS and oligoblastic AML patients treated with 5-azacitidine: A retrospective analysis in ten centers of the 'Rete Ematologica Lombarda'
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Alessandra Freyrie, Emanuele Ravano, Enrica Morra, Roberto Cairoli, Jacopo Mariotti, Marta Ubezio, Rosa Greco, Matteo G. Della Porta, Domenica Caramazza, Massimo Bernardi, Marta Riva, Simona Guarco, Alfredo Molteni, Lorenza Borin, Giulia Quaresmini, Michele Nichelatti, Federica Gigli, Anna Maria Pelizzari, Molteni, A, Riva, M, Borin, L, Bernardi, M, Pelizzari, A, Freyrie, A, Della Porta, M, Nichelatti, M, Ravano, E, Quaresmini, G, Mariotti, J, Caramazza, D, Ubezio, M, Guarco, S, Gigli, F, Greco, R, Cairoli, R, and Morra, E
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Antimetabolites, Antineoplastic ,Azacitidine ,Disease ,Comorbidity ,Kaplan-Meier Estimate ,Prognostic indice ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Young adult ,Psychiatry ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Retrospective cohort study ,5-Azacytidine ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Myeloid, Acute ,Oncology ,ROC Curve ,International Prognostic Scoring System ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,High risk myelodysplastic syndrome ,Oligoblastic acute myeloid leukemia ,Female ,business ,Risk assessment ,030215 immunology ,medicine.drug - Abstract
5-Azacytidine is an effective therapy in high risk MDS and oligoblastic AML. This "real life" analysis was made on 185 patients treated with 5-azacytidine in 10 centers afferent to REL ("Rete Ematologica Lombarda"), a network in Lombardia region. The aim was to assess the influence of disease and comorbidity risk assessments on the survival. The results confirm the utility of 5-azacitidine in prolonging OS regardless of advanced age and the presence of comorbidities. They also encourage an early treatment since patients with IPSS-R High risk MDS have better outcome with respect to Very High risk ones. According to the IPSS cytogenetic risk, there was no difference in the outcome between Intermediate and High risk patients. Nevertheless, a poorer cytogenetic risk, according to the IPSS-R cytogenetic stratification, negatively influenced the outcome.
- Published
- 2016
44. Feasibility of Allogeneic Stem Cell Transplantation After Azacitidine in Patients with High Risk Myelodysplastic Syndromes or Low-Blast Count Acute Myeloid Leukemias: the Experience of the BMT-AZA Multicenter Prospective Study
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Maria Teresa Voso, Francesco Spina, Elisa Cerqui, Carlo Finelli, Alfonso Piciocchi, Agostino Cortelezzi, Stella Santarone, Anna Candoni, Marianna Criscuolo, Giuseppe Leone, Simona Sica, Alfredo Molteni, Flavia Salvi, Luana Fianchi, Antonella Poloni, Matteo Parma, Alessandro Rambaldi, Nicola Cascavilla, Emilio Paolo Alessandrino, Andrea Bacigalupo, and Arianna Masciulli
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Azacitidine ,Hematology ,Blast Count ,medicine.disease ,Transplantation ,Internal medicine ,medicine ,In patient ,Stem cell ,Prospective cohort study ,business ,Acute myeloid leukemias ,medicine.drug - Published
- 2016
45. Three copies of isochromosome 8q in Ph+ B-cell acute lymphoblastic leukemia
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Barbara Scarpati, Alfredo Molteni, Clara Cesana, Giovanni Grillo, Maria Angela Mura, Fausto Fedeli, Silvia Soriani, Alessandra Tedeschi, Cristina Campidelli, Anna Leszl, Gabriella De Canal, and Renata Farioli
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Cancer Research ,Oncology ,business.industry ,Isochromosome ,Cancer research ,Medicine ,Hematology ,B-cell acute lymphoblastic leukemia ,business - Published
- 2011
46. Deferasirox for Transfusion-Dependent Patients with Myelodysplastic Syndromes: Safety, Efficacy, and Beyond (GIMEMA MDS0306 Trial)
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Lorenza Borin, Flavia Rivellini, Sante Tura, Giancarlo Latte, Emanuele Angelucci, Marco Vignetti, Grazia Sanpaolo, Carlo Finelli, Giovanni Quarta, Susanna Fenu, Paola Fazi, Flavia Salvi, Giulia Quaresmini, Antonio Volpe, Daniela Cilloni, Daniele Vallisa, Valeria Santini, Sergio Storti, Giovanni Caocci, Anna Angela Di Tucci, Maria Teresa Voso, Giuliana Alimena, Alfredo Molteni, and Alfonso Piciocchi
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Male ,Serum Ferritin ,Benzoates ,law.invention ,Randomized controlled trial ,law ,Risk Factors ,80 and over ,Medicine ,Chelation therapy ,Deferasirox ,Iron chelation ,Iron overload ,Myelodysplastic syndromes ,Safety ,Serum ferritin ,Adult ,Aged ,Aged, 80 and over ,Female ,Ferritins ,Humans ,Iron Chelating Agents ,Iron Overload ,Middle Aged ,Myelodysplastic Syndromes ,Treatment Outcome ,Triazoles ,Young Adult ,Blood Transfusion ,Hematology ,Medicine (all) ,Cumulative incidence ,General Medicine ,International Prognostic Scoring System ,deferasirox ,medicine.drug ,chelation therapy ,iron chelation ,iron overload ,myelodysplastic syndromes ,safety ,serum ferritin ,myelodysplastic syndromes (MDS), iron chelation ,medicine.medical_specialty ,Deferasirox (DFX) ,Multicenter trial ,Internal medicine ,Adverse effect ,business.industry ,Transfusion Reaction ,medicine.disease ,Settore MED/15 ,Chelation Therapy ,Iron Chelation ,Surgery ,Clinical trial ,Settore MED/15 - MALATTIE DEL SANGUE ,business - Abstract
Background In the absence of randomized, controlled trial data to support iron chelation therapy in transfusion-dependent patients with myelodysplastic syndromes (MDS), continued evidence from large prospective clinical trials evaluating the efficacy and safety of iron chelation therapy in this patient population is warranted. Methods The safety and efficacy of deferasirox was examined in a prospective, open-label, single-arm, multicenter trial of transfusion-dependent patients with International Prognostic Scoring System low- or intermediate-1-risk MDS and evidence of transfusion-related iron overload. The effects of deferasirox therapy on hematological response and disease progression were also examined. Results Of 159 participants enrolled from 37 Italian centers, 152 received ≥1 dose of deferasirox (initiated at 10–20 mg/kg/day and titrated as appropriate), and 68 completed the study. Of 84 patients who discontinued deferasirox therapy, 22 died during the trial, and 28 withdrew due to an adverse event (AE). Fourteen treatment-related grade 3 AEs occurred in 11 patients, whereas no grade 4 or 5 drug-related AEs were reported. Significant risks for dropout were a higher serum ferritin level at baseline, a higher MDS-Specific Comorbidity Index, and a shorter diagnosis–enrollment interval. Median serum ferritin level fell from 1966 ng/mL to 1475 ng/mL (P
- Published
- 2014
47. A Proposal for a Novel Approach to Fitness in the Elderly Patients: The 'NO-Chain' Algorithm
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Roberto Cairoli, Marta Riva, and Alfredo Molteni
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Activities of daily living ,Mini–Mental State Examination ,Performance status ,medicine.diagnostic_test ,business.industry ,Immunology ,Context (language use) ,Cognition ,Cell Biology ,Hematology ,Disease ,Biochemistry ,Transplantation ,Pharmacotherapy ,Medicine ,business ,Algorithm - Abstract
A proper assessment of elderly patients is a relevant clinical problem in the onco-hematological setting. In this context, age and extra-hematological morbidity are of primary importance, but performance status and overall functionality related to geriatric age, as physical abilities, cognitive aspects and ability to self-management are not negligible. Thus, a defined multi-dimensional assessment is needed to differentiate between fit, unfit and frail older adults (Klepin ASH Education Program 2014). We propose a tool to evaluate the tolerance to more or less intensive treatments in over 60 years aged patients, and to estimate the impact on the outcome. Our algorithm is based on 4 main variables universally recognized: age, performance status, comorbidities and geriatric aspects (functional, physical and cognitive). 1- As regards age, two cut-off values were considered: 70-years limit because it represents the threshold below which the allogeneic bone marrow transplantation may still run; and the 85-year limit because it denotes the edge beyond which chemotherapy (also non-intensive) should not be administered. 2- About performance status, it was chosen the ECOG (Eastern Cooperative Oncology Group) scale more or equal to 3 as the limit beyond which chemotherapy should be avoided. 3- Considering co-morbidities, the SIE, SIES GITMO group consensus-based definition of inability to intensive and non-intensive chemotherapy in acute myeloid leukemia (Ferrara et al. Leukemia 2013) was chosen to identify both patients candidate to intensive or candidate to only non-intensive chemotherapy. 4- Approaching the geriatric assessment, two levels of impairment were considered: the most important level of seriousness occurs when the Activities of Daily Living (ADL) functional scale is not overtaken; the lowest level of seriousness is verified if at least one among the functional Instrumental Activities of Daily Living (IADL) scale or the physical Short Physical Performace Battery (SPPB) scale or the cognitive Mini Mental State Examination (MMSE) scale are not overcome. The stratification of patients works with some steps that must be excluded in order to get over the various levels of fitness (Figure 1). We call this approach the NO-chain algorithm. It foresees that: - Patient with at least one of the following features are considered frail: 85 or more years of age; at least 3 of ECOG; assessed functional impairment with the ADL scale - Not-frail patient with at least one of the following features are considered unfit: age over 70 years; at least one of criteria, according to the SIE, SIES GITMO consensus-based definition of inability to intensive chemotherapy in acute myeloid leukemia; at least one among functional impairment assessed by IADL scale - All patients who get through all these steps are considered fit and potentially eligible for allogeneic stem cell transplantation. Although the used cut-off levels might need amelioration in the practice, the basic principle of this algorithm is the definition of fitness actually correlated to the patient's condition in itself, regardless of the hematological disease. The algorithm was originally developed for elderly patients with acute myeloid leukemia (AML), but subsequently applied to patients with myelodysplastic syndrome (MDS) and to the other hematological malignancies. The application is undoubtedly different, depending on the disease the patient is affected by and its classification. For instance: an AML frail patients, regardless of biological risk, can be candidate only to supportive care; a low-risk MDS frail patients may still be candidate to pharmacological therapy as erythropoiesis stimulating agents or iron chelation therapy. The validation of this algorithm has to be carried out within each hematologic malignancy and must take into account the specific application. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
- Published
- 2016
48. The Immunohistochemical Expression of p53 in Bone Marrow Biopsy Has Unfavorable Prognostic Impact in Higher Risk Myelodysplastic Syndromes If It Is at Least 10%
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Michele Nichelatti, Marta Riva, Laura Bandiera, Alfredo Molteni, Emanuele Ravano, Silvia Cantoni, Mauro Truini, and Roberto Cairoli
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Pathology ,medicine.medical_specialty ,Framingham Risk Score ,business.industry ,Proportional hazards model ,Myelodysplastic syndromes ,Immunology ,Hazard ratio ,De novo Myelodysplastic Syndrome ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Log-rank test ,symbols.namesake ,Positive predicative value ,Internal medicine ,medicine ,symbols ,business ,Fisher's exact test - Abstract
Background The p53 protein is an onco-suppressor protein encoded by the TP53 gene, which is mutated in 5-10% of cases of de novo myelodysplastic syndromes (MDS). In 75% of cases TP53 mutations lead to store the p53 protein within the nucleus of the neoplastic cells. TP53 mutations were shown to have an unfavorable prognostic impact in patients with MDS. The immunohistochemical (IHC) expression of p53 in bone marrow (BM) biopsy has in itself negative impact on prognosis in low risk MDS, especially in MDS with isolated del(5q) category. However, the p53 cut-off value related to prognosis has not been established with accuracy, ranging between 1 and 5% in different reports. Moreover, no data are available on the possible prognostic impact of p53 BM expression and cut-off levels in patients with higher risk MDS. Aim To evaluate the prognostic value of IHC expression of p53in BM biopsies from patients with intermediate, high and very high R-IPSS risk MDS Methods BM biopsies performed at diagnosis in patients with intermediate, high and very high R-IPSS risk MDS with a follow up of at least three years were revised and screened for IHC p53 expression. Percentage of p53 expression was evaluated by two independent pathologists (L.B.; M.T.), and related to patient survival. Only cells with strong p53 staining were counted as positive. The statistical evaluations were carried out with the logistic analysis and the influence of p53 expression on survival was analyzed by Cox regression. A ROC analysis was carried out using theYouden method to analyze the optimal cut-off value influencing the survival. The verification was performed with the positive and negative predictive values (respectively PPV and NPV), the sensibility and the specificity with their respective 95% confidence intervals (95%CI). Survivorships were estimated with the Kaplan-Meier product limit method, followed by the logrank test, and by the Cox proportional-hazard regression. The association among categorical variables was evaluated by Fisher exact test. Results A total of 60 BM biopsies performed at MDS diagnosis were screened for p53 expression. Themedian age of these 60 patients was 67 years (range 19 - 82). Diagnoses, according to WHO, were RCMD in 26/60 (43.3%) cases; RAEB1 in 21/60 (35%) cases; RAEB2 in 13/60 (21.7%) cases. The IPSS-R was intermediate in 43 (71.7%) cases; high in 9 (15%) cases and very high in 8 (13.3%) cases. Cytogenetic risk according to the IPSS-R stratification was: very low in 1(1.6%) case; low in 30 (50%) cases; intermediate in 10 (16.7%) cases; high in 12 (20%) cases; very high in 7 (11.7%) cases. Median overall survival was 41 months. The p53 expression was: < 1% in 39 cases (65.0%), 1% in 5 cases (8.3%), 2% in 6 cases (10.0%), 3% in 2 cases (3.3%), 5% in 3 cases (5.0%),at least 10% in 5 cases (8.3%). Upon analysis, a significant association between percentage of p53 expression and patient survival was found (p=0.013; Hazard Ratio 1.067; 95%CI: 1.014 - 1.124). A cut-off value of 10% p53 expression was associated with outcome (specificity 100%; sensibility 13.5%;PPV 100%; NPV 41.8%). Specifically, as shown in figure 1, a significantly better overall survival was observed in the 55 (91.7%) patients whose BM p53 expression was < 10% compared to the 5 (8.3 %) patients with a BM p53 expression at least 10% (p=0.0038). No association was found between either BM blast countor BM grade of fibrosis and p53 expression.A significant association between the cytogenetic risk according to R-IPSS stratification and the expression of p53was instead found: any single unitary arbitrary increase in the cytogenetic risk score rises by 1600% the odds of a BM p53 expression at least 10% (p=0.015). Conclusion In our study population we confirm the unfavorable prognostic significance of BM p53 expression in higher risk MDS patients. Contrary to the reported cut-off values of p53 expression in low risk MDS, in our cohort of higher risk MDS the levels related to prognosis were greater (10% compared with 1 to 5% according to different reports). A tentative explanation for this difference may be that factors other than p53 expression strongly impact on survival in patients with higher risk MDS. Thus the negative prognostic value of p53 only emerges at higher levels of expression. The association between p53 expression and the IPSS-R cytogenetic risk score, if confirmed on a larger cohort, should be evaluated in specific biologic investigations. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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- 2016
49. Impact of Bone Marrow Fibrosis and Early Response on Outcome after Azacitidine Therapy in 94 Patients with Myelodisplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia
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Agostino Cortelezzi, Roberto Cairoli, Alfredo Molteni, Gianluigi Reda, Martina Pennisi, Alessandra Freyrie, Ramona Cassin, Marta Riva, Bruno Fattizzo, and Diana Giannarelli
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Oncology ,medicine.medical_specialty ,business.industry ,Basic Local Alignment Search Tool ,Immunology ,Azacitidine ,Chronic myelomonocytic leukemia ,Myeloid leukemia ,Bone marrow fibrosis ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Partial response ,Internal medicine ,medicine ,business ,Myelofibrosis ,medicine.drug - Abstract
Azacitidine (AZA) is effective in high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia type 2 (CMML-2) and low blast count acute myeloid leukemia (AML) patients not suitable for more intensive treatment. Factors that may influence response to AZA are still under investigation. Bone marrow fibrosis is a potentially negative prognostic marker on overall survival (OS), but its clinical significance in this setting of patients remains to be clarified. We evaluated clinical predictors of OS and overall response rate (ORR; complete/partial response CR/PR; stable/progressive disease SD/PD) to AZA in a real life cohort. We studied 94 consecutive patients, treated at two Institutions from June 2009 till February 2016 with AZA subcutaneously (5+2+2 schedule) every 28 days, outside clinical trials. We analyzed data from routine laboratory analysis, bone marrow histology, morphology and cytogenetics at diagnosis. OS was measured from the starting of AZA treatment. Table 1 shows the clinical characteristics pre- and post-AZA: most patients (68%) were AREB1 or AREB2, 13% RCUD/RCMD or MDS NOS according to WHO 2008 classification, 17% AML, 2% CMML. At the onset of AZA therapy the majority of MDS cases (68%) showed an intermediate-2 risk, according to the International Prognostic Scoring System (IPSS) and high/very high risk (78%) according to IPSS-revised. Secondary and de novo cases, as well as cytogenetics risk groups, were equally represented; 50% of patients were transfusion dependant and moderate to severe neutropenia or thrombocytopenia were present in roughly 50/70% of cases respectively. As expected, bone marrow biopsies pre-AZA showed hypercellularity in most patients (65%). Remarkably, 47,5% of cases showed bone marrow fibrosis of ≥1 grade before AZA initiation. These findings were mostly unchanged at post-AZA evaluation. On the whole, 93 patients receiving > 4 cycles of therapy were available for response evaluation according to International Working Group 2006 criteria. After a median of 6 cycles (4-44), ORR was 41.9% (CR 18.3%, PR 11.8%, SD with hematologic improvement HI 11.8%), SD was 21.5%, PD 10.7% and 25.8% failed to achieve a response. Thirteen percent of patients reached at least partial cytogenetic response and 50% a HI. ORR was not influenced by monocytosis, neutropenia or IPSS cytogenetic risk category. Interestingly, pre-AZA marrow blast percentage, cytogenetic risk, time from diagnosis to AZA and the interval from 1st to 6th cycle had no impact on response. As regards marrow characteristics, patients with MF-0 pre-AZA displayed significantly lower PD rate and higher ORR, SD and HI than those with any grade of fibrosis (21.4% vs 51.4% and 78.6% vs 48,6%, respectively p=0.006, Fig1). This observation was also confirmed at marrow evaluation after AZA (22% versus 48% for PD and 78% versus 52% for ORR/SD/HI, p=0.05, Fig1). Regarding cellularity pre- and post-AZA, higher ORR,SD and HI and lower PD were observed for patients with normo/hypo compared to those with hyper-cellularity (Fig1) although not significantly. Forty-one percent of cases presented a hematologic toxicity (33% neutropenia and 18% thrombocytopenia of any grade) occurring after a median of 2 (1-18) AZA cycles. Moreover 28.6% of patients had an infection during AZA treatment, not related to neutropenia degree. Of note, toxicities did not affect median time from the 1st to the 6th AZA cycle (170,115-240 days), nor ORR. Median OS from the beginning of therapy was 18.5 months (12.7-24.4, 95% CI). IPSS high category [HR 2.24 (1.19-4.20) p=0.01], poor cytogenetics [2.19 (1.27-3.78) p=0.005], and lower ORR [0.46 (0.26-0.80) p=0.006] significantly affected OS. Unexpectedly, a response obtained after less than 4 cycles negatively impact OS [HR 0.86 (0.80-0.92) p Disclosures Reda: Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding.
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- 2016
50. Feasibililty of Azacitidine As Bridge to Allogeneic Stem Cell Transplantation in Patients with Higher-Risk MDS or Low-Blast Count AML: Results of the BMT-AZA Multicenter Prospective Study
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Luana Fianchi, Marianna Criscuolo, Agostino Cortelezzi, Alfredo Molteni, Paolo Bartolomeo, Anna Candoni, Mauro Montanari, Nicola Cascavilla, Alessandro Rambaldi, Giuseppe Leone, Elisa Cerqui, Simona Sica, Flavia Salvi, Emilio Paolo Alessandrino, Carlo Finelli, Matteo Parma, Francesco Spina, Alfonso Piciocchi, Arianna Masciulli, Maria Teresa Voso, and Flavia Rivellini
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Oncology ,medicine.medical_specialty ,Hematology ,business.industry ,Myelodysplastic syndromes ,Immunology ,Azacitidine ,Chronic myelomonocytic leukemia ,Context (language use) ,Cell Biology ,medicine.disease ,Biochemistry ,Surgery ,Transplantation ,Internal medicine ,medicine ,Prospective cohort study ,business ,Progressive disease ,medicine.drug - Abstract
Background Allogeneic SCT remains the only curative option in myelodysplastic syndromes (MDS). We prospectively evaluated in a multicenter phase 2 GITMO (Italian Bone Marrow Transplantation Group) trial, the feasibility of allogeneic stem cell transplantation (ASCT, primary protocol end-point) after induction treatment with azacitidine (Vidaza, Celgene). According to the protocol, patients had to perform at least 4 and up to 12 cycles of azacitidine as induction treatment before ASCT. Patients not eligible for ASCT could continue treatment until disease progression. Methods Between November 2010 and September 2014, 102 patients were enrolled by 20 Italian hematology centers. Nine patients never started treatment due to progressive disease (PD, n=2), refusal (n=3), or unknown causes (n=4). Of remaining 93 patients, 70 had with IPSS Int-2/High-risk MDS, 15 WHO-defined acute myeloid leukemia (AML) and 8 chronic myelomonocytic leukemia (CMML). There were 32 females and 61 males with median age 59 yrs (range 21-66.5 yrs). At treatment start, ECOG performance status was: 0 in 66 patients, 1 in 17 and 2 in 10 patients, while MDS HCT-index was: low (0) in 43 patients, intermediate (1-2) in 31 and high (>2) in 18 patients. All 93 patients started azacitidine s.c. at the standard dose of 75 mg/sqm/day, 7 days/month, at a median of 0.8 months (range 0-105 months) from initial MDS diagnosis. Results At response assessment after a median of 4.5 cycles (range 1-11), 25% of patients (n=19) achieved complete remission (CR), 3% marrow-CR (n=2), 14% partial remission (PR, n=11), 9% hematologic improvement (HI, n=7), 35% had stable disease (SD, n=27) and 14% PD (n=11). ASCT was performed in 48 patients (52%), after a median of 4.5 azacitidine cycles (range: 1-11). Data on ASCT are presently available for 45 patients, transplanted with bone marrow (n=10 pts) or peripheral blood stem cells (n=35 pts) from an HLA-identical donor (sibling in 11, and MUD in 34 cases). Forty-five patients did not receive ASCT due to: disease relapse or progression (n=16, 35%), adverse events (n=12, 27%), refusal (n=5, 11%), or other causes (n=12, 27%). At a median follow-up of 18.5 months (range 0.2-31.5), 43 patients are alive (25 received ASCT), and 50 patients died. Causes of death are reported in Table 1. Median overall survival (OS) for the whole patient cohort was 13.4 months (95% CI: 10.9-18.6, Figure 1). Disease status after azacitidine was predictive of significantly improved survival for patients in CR/PR/HI, compared to SD or PD (n=77 patients who completed at least 4 cycles, Figure 2). ASCT considered as time-dependent covariate was associated to a significantly longer survival (p=0.008, HR 0.4, 95% CI: 0.2-0.8). Stratification of MDS according to IPSS and karyotype was not associated to survival. Conclusions Our study shows that allogeneic transplantation following azacitidine is feasible in HR-MDS/CMML and AML, with about 50% of patients being able to undergo HSCT. These data favourably compare with previous studies in MDS on ASCT preceded by conventional chemotherapy. Disease status at the time of HSCT confirms its significant prognostic role for survival, also in the context of hypomethylating treatment, where stabilization of disease also represents a therapeutic target. Disease relapse or progression remain the major causes of death indicating the need for other strategies aimed at improving disease control in MDS. Figure 1. Overall survival (n=93 pts) Figure 1. Overall survival (n=93 pts) Figure 2. Survival according to disease status at response assessment after a median of 4.5 azacitidine cycles (n=77 evaluable pts) Figure 2. Survival according to disease status at response assessment after a median of 4.5 azacitidine cycles (n=77 evaluable pts) Disclosures Voso: Celgene: Honoraria, Research Funding. Off Label Use: Azacitidine used as induction treatment before allogeneic stem cell transplantation in MDS. Finelli:Janssen: Other: Speaker; Novartis: Other: Speaker; Celgene: Other: Speaker, Research Funding.
- Published
- 2015
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