81 results on '"Costanza Bosi"'
Search Results
2. P1028: MYELOFIBROSIS (MF) TREATED WITH RUXOLITINIB (RUX) MONOTHERAPY: PREDICTORS OF EARLY DISCONTINUATION AND DEATH ON TREATMENT. THE SHORT-TERM RUX PROGNOSTIC MODEL (STR-PM)
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Francesca Palandri, Giuseppe Auteri, Alessandra Iurlo, Elena Maria Elli, Simona Paglia, Massimiliano Bonifacio, Mario Tiribelli, Malgorzata Monica Trawinska, Nicola Polverelli, Giulia Benevolo, Alessia Tieghi, Florian Heidel, Fabrizio Cavalca, Giovanni Caocci, Eloise Beggiato, Gianni Binotto, Francesco Cavazzini, Maurizio Miglino, Costanza Bosi, Monica Crugnola, Monica Bocchia, Bruno Martino, Novella Pugliese, Marta Venturi, Camilla Mazzoni, Alessandro Isidori, Daniele Cattaneo, Mauro Krampera, Fabrizio Pane, Daniela Cilloni, Gianpietro Semenzato, Roberto M. Lemoni, Antonio Cuneo, Elisabetta Abruzzese, Nicola Vianelli, Michele Cavo, Giuseppe Palumbo, and Massimo Breccia
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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3. P1467: THE EMPLOYMENT OF DIRECT ORAL ANTICOAGULANTS IN PATIENTS AFFECTED BY Β-THALASSEMIA: A MULTICENTER ANALYSIS FROM THE EXTENSION-MYOCARDIAL IRON OVERLOAD IN THALASSEMIA NETWORK (E-MIOT)
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Simona Raso, Meloni Antonella, Anna Spasiano, Andrea Salvo, Maria Grazia Roberti, Valerio Cecinati, Angela Ciancio, Amalia Acquafredda, Ilaria Fotzi, Rosamaria Rosso, Marilena Serra, Costanza Bosi, Calogera Gerardi, Mariasanta Napolitano, Vincenzo Sucato, Rosario DI Maggio, Angela Vitrano, Filippo Cademartiri, and Aurelio Maggio
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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4. PB2611: EVANS SYNDROME: DISEASE AWARENESS AND CLINICAL MANAGEMENT IN A NATION-WIDE ITALIAN SURVEY
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Bruno Fattizzo, Valentina Carrai, Monica Crugnola, Erminia Baldacci, Marta Bellini, Costanza Bosi, Elisa Buzzatti, Domenica Caramazza, Giuseppe Carli, Monica Carpenedo, Cristina Clissa, Cristina Danesin, Maria Rosaria De Paolis, Juri Alessandro Giannotta, Vanessa Innao, Monia Marchetti, Uros Markovic, Alessandro Morotti, Mariasanta Napolitano, Andrea Patriarca, Loredana Pettine, Antonella Poloni, Elena Rivolti, Elena Rossi, Teresa Maria Santeremo, Cristina Santoro, Maria Elena Zannier, Francesco Zaja, Silvia Cantoni, Francesca Palandri, and Valerio De Stefano
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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5. Cancer Treatment Closer to the Patient Reduces Travel Burden, Time Toxicity, and Improves Patient Satisfaction, Results of 546 Consecutive Patients in a Northern Italian District
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Luigi Cavanna, Chiara Citterio, Patrizia Mordenti, Manuela Proietto, Costanza Bosi, and Stefano Vecchia
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travel burden ,cancer patients ,time toxicity ,rural patients ,Medicine (General) ,R5-920 - Abstract
Background and Objectives: The distance to cancer facilities may cause disparities by creating barriers to oncologic diagnosis and treatment, and travel burden may cause time and financial toxicity. Materials and Methods: To relieve travel burden, a program to deliver oncologic treatment closer to the patient was initiated in the district of Piacenza (Northern Italy) several years ago. The oncologic activities are performed by oncologists and by nurses who travel from the oncologic ward of the city hospital to territorial centres to provide cancer patient management. This model is called Territorial Oncology Care (TOC): patients are managed near their home, in three territorial hospitals and in a health centre, named “Casa della Salute” (CDS). A retrospective study was performed and the records of patients with cancer managed in the TOC program were analysed. The primary endpoints were the km and time saved, the secondary endpoints: reduction of caregiver need for transport and patient satisfaction. Results: 546 cancer patients managed in the TOC program from 2 January 2021 to 30 June 2022 were included in this study. Primary endpoints: median km to reach the city hospital: 26 (range 11–79 km) median time: 44 min (range 32–116); median km to reach the territorial clinicians in the TOC program: 7 (range 1–35 km), median time: 16 minutes (range 6–54), p < 0.001. Secondary endpoints: 64.8% of patients who needed a caregiver for the city hospital could travel alone in the TOC program and 99.63% of patients were satisfied. Conclusions: The results of this retrospective study highlight the possibility of treating cancer patients near their residence, reducing travel burden and saving time.
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- 2023
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6. A Prognostic Model to Predict Ruxolitinib Discontinuation and Death in Patients with Myelofibrosis
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Francesca Palandri, Giuseppe A. Palumbo, Massimiliano Bonifacio, Elena M. Elli, Mario Tiribelli, Giuseppe Auteri, Malgorzata M. Trawinska, Nicola Polverelli, Giulia Benevolo, Alessia Tieghi, Fabrizio Cavalca, Giovanni Caocci, Eloise Beggiato, Gianni Binotto, Francesco Cavazzini, Maurizio Miglino, Costanza Bosi, Monica Crugnola, Monica Bocchia, Bruno Martino, Novella Pugliese, Marta Venturi, Alessandro Isidori, Daniele Cattaneo, Mauro Krampera, Fabrizio Pane, Daniela Cilloni, Gianpietro Semenzato, Roberto M. Lemoli, Antonio Cuneo, Elisabetta Abruzzese, Filippo Branzanti, Nicola Vianelli, Michele Cavo, Florian Heidel, Alessandra Iurlo, and Massimo Breccia
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ruxolitinib ,myelofibrosis ,prognostic model ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Most patients with myelofibrosis (MF) discontinue ruxolitinib (JAK1/JAK2 inhibitor) in the first 5 years of therapy due to therapy failure. As the therapeutic possibilities of MF are expanding, it is critical to identify patients predisposed to early ruxolitinib monotherapy failure and worse outcomes. We investigated predictors of early ruxolitinib discontinuation and death on therapy in 889 patients included in the “RUX-MF” retrospective study. Overall, 172 patients were alive on ruxolitinib after ≥5 years (long-term ruxolitinib, LTR), 115 patients were alive but off ruxolitinib after ≥5 yrs (short-term RUX, STR), and 123 patients died while on ruxolitinib after p = 0.08). Overall survival (OS) was significantly longer in LTR pts (p = 0.002). In multivariate analysis, PLT < 100 × 109/L, Hb < 10 g/dL, primary MF, absence of spleen response at 3 months and ruxolitinib starting dose
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- 2023
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7. Ruxolitinib discontinuation syndrome: incidence, risk factors, and management in 251 patients with myelofibrosis
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Francesca Palandri, Giuseppe Alberto Palumbo, Elena Maria Elli, Nicola Polverelli, Giulia Benevolo, Bruno Martino, Elisabetta Abruzzese, Mario Tiribelli, Alessia Tieghi, Roberto Latagliata, Francesco Cavazzini, Micaela Bergamaschi, Gianni Binotto, Monica Crugnola, Alessandro Isidori, Giovanni Caocci, Florian Heidel, Novella Pugliese, Costanza Bosi, Daniela Bartoletti, Giuseppe Auteri, Daniele Cattaneo, Luigi Scaffidi, Malgorzata Monica Trawinska, Rossella Stella, Fiorella Ciantia, Fabrizio Pane, Antonio Cuneo, Mauro Krampera, Gianpietro Semenzato, Roberto Massimo Lemoli, Alessandra Iurlo, Nicola Vianelli, Michele Cavo, Massimo Breccia, and Massimiliano Bonifacio
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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8. Characteristics and outcomes of five patients with COVID‐19 and hematological malignancies
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Chiara Citterio, Antonio Lazzaro, Costanza Bosi, Maurice De Ponzio, and Luigi Cavanna
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hematology ,infectious diseases ,Medicine ,Medicine (General) ,R5-920 - Abstract
Abstract Patients with hematological cancer are at major risk of developing infectious complication. The prevention and treatment of COVID‐19 in these patients is challenging. This experience, with the limitation of a small number of patients, highlights that early treatment of COVID‐19 can overcome the infection, also in hematological patients.
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- 2021
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9. 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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10. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain
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Simona Soverini, Sabrina Colarossi, Alessandra Gnani, Fausto Castagnetti, Gianantonio Rosti, Costanza Bosi, Stefania Paolini, Michela Rondoni, Pier Paolo Piccaluga, Francesca Palandri, Panagiota Giannoulia, Giulia Marzocchi, Simona Luatti, Nicoletta Testoni, Ilaria Iacobucci, Daniela Cilloni, Giuseppe Saglio, Michele Baccarani, and Giovanni Martinelli
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelphia chromosome-positive (Ph+) leukemia has prompted the development of second-generation compounds active against several imatinib-insensitive mutant forms of Bcr-Abl, including dasatinib (BMS-354825; Bristol-Myers Squibb). In order to assess which pre-existent or emerging kinase domain mutations are associated with decreased clinical efficacy of desatinib, we analyzed BCR-ABL kinase sequences before and during treatment in 21 Ph+ patients who failed to respond to or relapsed during dasatinib therapy. In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317.
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- 2007
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11. Ruxolitinib in cytopenic myelofibrosis: Response, toxicity, drug discontinuation, and outcome
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Francesca Palandri, Massimo Breccia, Camilla Mazzoni, Giuseppe Auteri, Elena Maria Elli, Malgorzata M. Trawinska, Nicola Polverelli, Mario Tiribelli, Giulia Benevolo, Alessandra Iurlo, Alessia Tieghi, Florian H. Heidel, Giovanni Caocci, Eloise Beggiato, Gianni Binotto, Francesco Cavazzini, Maurizio Miglino, Costanza Bosi, Monica Crugnola, Monica Bocchia, Bruno Martino, Novella Pugliese, Mattia Biondo, Marta Venturi, Luigi Scaffidi, Alessandro Isidori, Daniele Cattaneo, Mauro Krampera, Fabrizio Pane, Daniela Cilloni, Gianpietro Semenzato, Roberto M. Lemoli, Antonio Cuneo, Elisabetta Abruzzese, Daniela Bartoletti, Simona Paglia, Nicola Vianelli, Michele Cavo, Massimiliano Bonifacio, and Giuseppe A. Palumbo
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Cancer Research ,Oncology ,ruxolitinib ,cytopenia ,myelofibrosis ,myelodepletive phenotype ,myeloproliferative neoplasms - Published
- 2023
12. Peripheral blasts are associated with responses to ruxolitinib and outcomes in patients with chronic‐phase myelofibrosis
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Francesca Palandri, Daniela Bartoletti, Alessandra Iurlo, Massimiliano Bonifacio, Elisabetta Abruzzese, Giovanni Caocci, Elena M. Elli, Giuseppe Auteri, Mario Tiribelli, Nicola Polverelli, Maurizio Miglino, Florian H. Heidel, Alessia Tieghi, Giulia Benevolo, Eloise Beggiato, Carmen Fava, Francesco Cavazzini, Novella Pugliese, Gianni Binotto, Costanza Bosi, Bruno Martino, Monica Crugnola, Emanuela Ottaviani, Giorgia Micucci, Malgorzata M. Trawinska, Antonio Cuneo, Monica Bocchia, Mauro Krampera, Fabrizio Pane, Roberto M. Lemoli, Daniela Cilloni, Nicola Vianelli, Michele Cavo, Giuseppe A. Palumbo, and Massimo Breccia
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myelofibrosis ,outcome ,peripheral blasts ,response ,ruxolitinib ,Cancer Research ,Pyrimidines ,Treatment Outcome ,Oncology ,Primary Myelofibrosis ,Nitriles ,Humans ,Pyrazoles - Abstract
The presence of peripheral blasts (PB) is a negative prognostic factor in patients with primary and secondary myelofibrosis (MF) and PB ≥4% was associated with a particularly unfavorable prognosis. Ruxolitinib (RUX) is the JAK1/2 inhibitor most used for treatment of MF-related splenomegaly and symptoms. Its role has not been assessed in correlation with PB.In 794 chronic-phase MF patients treated with RUX, we evaluated the impact of baseline percentage of PB on response (spleen and symptoms responses) and outcome (RUX discontinuation-free, leukemia-free, and overall survival). Three subgroups were compared: PB-0 (no PB, 61.3%), PB-4 (PB 1%-4%, 33.5%), and PB-9 (PB 5%-9%, 5.2%).At 3 and 6 months, spleen responses were less frequently achieved by PB-4 (P = .001) and PB-9 (P = .004) compared to PB-0 patients. RUX discontinuation-free, leukemia-free, and overall survival were also worse for PB-4 and PB-9 patients (P = .001, P = .002, and P.001, respectively).Personalized approaches beyond RUX monotherapy may be useful in PB-4 and particularly in PB-9 patients.
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- 2022
13. Impact of comorbidities and body mass index in patients with myelofibrosis treated with ruxolitinib
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Daniele Cattaneo, Nicola Sgherza, Roberto Latagliata, Francesco Cavazzini, Renato Fanin, Antonio Cuneo, Giuseppe A. Palumbo, Alessia Tieghi, Nicola Vianelli, Gianpietro Semenzato, Gianni Binotto, Robin Foà, Matteo Molica, Mariella D'Adda, Roberto M. Lemoli, Francesca Palandri, Michele Cavo, Daniela Bartoletti, Alessandra Iurlo, Massimo Breccia, Elisabetta Abruzzese, Nicola Polverelli, Domenico Russo, Giuseppe Auteri, Mario Tiribelli, Florian H. Heidel, Lucia Catani, Costanza Bosi, Alessandro Isidori, Luigi Scaffidi, Franco Aversa, Micaela Bergamaschi, Massimiliano Bonifacio, Monica Crugnola, Massimo Breccia, Daniela Bartoletti, Massimiliano Bonifacio, Giuseppe A. Palumbo, Nicola Polverelli, Elisabetta Abruzzese, Micaela Bergamaschi, Alessia Tieghi, Mario Tiribelli, Alessandra Iurlo, Francesco Cavazzini, Nicola Sgherza, Gianni Binotto, Alessandro Isidori, Mariella D’Adda, Monica Crugnola, Costanza Bosi, Florian Heidel, Matteo Molica, Luigi Scaffidi, Daniele Cattaneo, Roberto Latagliata, Giuseppe Auteri, Roberto M. Lemoli, Renato Fanin, Domenico Russo, Franco Aversa, Antonio Cuneo, Gianpietro Semenzato, Lucia Catani, Michele Cavo, Nicola Vianelli, Robin Foà, and Francesca Palandri
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Male ,Ruxolitinib ,Time Factors ,Myelofibrosis ,BMI ,CCI ,Comorbidities ,Adult ,Age Factors ,Aged ,Aged, 80 and over ,Disease-Free Survival ,Female ,Humans ,Middle Aged ,Primary Myelofibrosis ,Pyrazoles ,Sex ,Sex Factors ,Survival Rate ,Body Mass Index ,Gastroenterology ,0302 clinical medicine ,80 and over ,Hematology ,Myelofibrosi ,General Medicine ,030220 oncology & carcinogenesis ,Cohort ,BMI, CCI, Comorbidities, Myelofibrosis, Ruxolitinib ,Comorbiditie ,Underweight ,medicine.symptom ,medicine.drug ,medicine.medical_specialty ,Anemia ,NO ,03 medical and health sciences ,Internal medicine ,Nitriles ,medicine ,Survival rate ,business.industry ,medicine.disease ,Pyrimidines ,business ,Body mass index ,030215 immunology - Abstract
Comorbidities defined by the Charlson comorbidity index (CCI) and body mass index (BMI) are significantly associated with outcome in patients who receive continuous treatment with tyrosine kinase inhibitors. We evaluated the impact of CCI and BMI on responses, drug-related toxicities, and outcome in a cohort of 402 patients with myelofibrosis (MF) treated with ruxolitinib in 23 European Hematology Centers. Comorbidities were evaluable in all 402 patients. A higher (≥ 3) CCI did not correlate with a lower spleen reduction at any time (p = 0.68) or symptoms' response (p = 0.11), but influenced the onset of anemia during the first 3months of treatment and later (p = 0.02 and p = 0.03, respectively) in patients without anemia baseline. BMI was evaluable in 380 patients and did not correlate with differences in spleen and symptoms response (p = 0.57 and p = 0.49, respectively). A higher CCI and a lower BMI correlated also with a reduced overall survival (p
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- 2018
14. Re: The first report on coronavirus disease 2019 vaccine refusal by patients with cancer in Italy: Early data from a single-institute survey
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Luigi Cavanna, Costanza Bosi, Evelina Cattadori, Chiara Citterio, and Serena Caprioli
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Cancer Research ,medicine.medical_specialty ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Cancer ,medicine.disease ,Vaccination ,Vaccination Refusal ,Oncology ,Internal medicine ,Vaccine refusal ,medicine ,business ,Letter to the Editor - Published
- 2021
15. Ruxolitinib rechallenge in resistant or intolerant patients with myelofibrosis: Frequency, therapeutic effects, and impact on outcome
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Costanza Bosi, Nicola Vianelli, Fabrizio Pane, Giovanni Caocci, Massimiliano Bonifacio, Mario Tiribelli, Michele Cavo, Malgorzata Monika Trawinska, Daniela Bartoletti, Mauro Krampera, Giuseppe Auteri, Giulia Benevolo, Bruno Martino, Daniele Cattaneo, Roberto M. Lemoli, Giuseppe A. Palumbo, Nicola Polverelli, Massimo Breccia, Luigi Scaffidi, Monica Crugnola, Elisabetta Abruzzese, Antonio Cuneo, Florian H. Heidel, Elena Maria Elli, Elena Masselli, Francesca Palandri, Roberto Latagliata, Francesco Cavazzini, Alessandra Iurlo, Novella Pugliese, Rossella Stella, Giorgia Micucci, Alessia Tieghi, Gianpietro Semenzato, Gianni Binotto, Palandri F., Tiribelli M., Breccia M., Bartoletti D., Elli E.M., Benevolo G., Martino B., Cavazzini F., Tieghi A., Iurlo A., Abruzzese E., Pugliese N., Binotto G., Caocci G., Auteri G., Cattaneo D., Trawinska M.M., Stella R., Scaffidi L., Polverelli N., Micucci G., Masselli E., Crugnola M., Bosi C., Heidel F.H., Latagliata R., Pane F., Cuneo A., Krampera M., Semenzato G., Lemoli R.M., Cavo M., Vianelli N., Bonifacio M., and Palumbo G.A.
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Cancer Research ,medicine.medical_specialty ,Disease status ,Ruxolitinib ,ruxolitinib ,rechallenge ,myelofibrosis ,NO ,03 medical and health sciences ,0302 clinical medicine ,myelofibrosi ,Internal medicine ,Nitriles ,Overall survival ,Medicine ,cancer ,Humans ,In patient ,030212 general & internal medicine ,Myelofibrosis ,Retrospective Studies ,outcome ,business.industry ,Therapeutic effect ,Retrospective cohort study ,medicine.disease ,Discontinuation ,Pyrimidines ,Treatment Outcome ,Oncology ,Primary Myelofibrosis ,030220 oncology & carcinogenesis ,Pyrazoles ,business ,medicine.drug - Abstract
BACKGROUND: After ruxolitinib discontinuation, the outcome of patients with myelofibrosis (MF) is poor with scarce therapeutic possibilities. METHODS: The authors performed a subanalysis of an observational, retrospective study (RUX-MF) that included 703 MF patients treated with ruxolitinib to investigate 1) the frequency and reasons for ruxolitinib rechallenge, 2) its therapeutic effects, and 3) its impact on overall survival. RESULTS: A total of 219 patients (31.2%) discontinued ruxolitinib for ≥14 days and survived for ≥30 days. In 60 patients (27.4%), ruxolitinib was rechallenged for ≥14 days (RUX-again patients), whereas 159 patients (72.6%) discontinued it permanently (RUX-stop patients). The baseline characteristics of the 2 cohorts were comparable, but discontinuation due to a lack/loss of spleen response was lower in RUX-again patients (P =.004). In comparison with the disease status at the first ruxolitinib stop, at its restart, there was a significant increase in patients with large splenomegaly (P 10 mg twice daily predicted better spleen (P =.05) and symptom improvements (P =.02), the reasons for/duration of ruxolitinib discontinuation and the use of other therapies before rechallenge were not associated with rechallenge efficacy. At 1 and 2 years, 33.3% and 48.3% of RUX-again patients, respectively, had permanently discontinued ruxolitinib. The median overall survival was 27.9 months, and it was significantly longer for RUX-again patients (P =.004). CONCLUSIONS: Ruxolitinib rechallenge was mainly used in intolerant patients; there were clinical improvements and a possible survival advantage in many cases, but there was a substantial rate of permanent discontinuation. Ruxolitinib rechallenge should be balanced against newer therapeutic possibilities.
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- 2021
16. Ruxolitinib discontinuation syndrome: incidence, risk factors, and management in 251 patients with myelofibrosis
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Bruno Martino, Daniele Cattaneo, Florian H. Heidel, Elisabetta Abruzzese, Gianni Binotto, Rossella Stella, Giulia Benevolo, Michele Cavo, Micaela Bergamaschi, Roberto Latagliata, Francesco Cavazzini, Novella Pugliese, Massimo Breccia, Alessandro Isidori, Gianpietro Semenzato, Daniela Bartoletti, Mauro Krampera, Malgorzata Monica Trawinska, Costanza Bosi, Giovanni Caocci, Fabrizio Pane, Alessia Tieghi, Francesca Palandri, Roberto M. Lemoli, Elena Maria Elli, Antonio Cuneo, Fiorella Ciantia, Alessandra Iurlo, Monica Crugnola, Giuseppe Auteri, Mario Tiribelli, Massimiliano Bonifacio, Nicola Vianelli, Luigi Scaffidi, Giuseppe A. Palumbo, Nicola Polverelli, Palandri F., Palumbo G.A., Elli E.M., Polverelli N., Benevolo G., Martino B., Abruzzese E., Tiribelli M., Tieghi A., Latagliata R., Cavazzini F., Bergamaschi M., Binotto G., Crugnola M., Isidori A., Caocci G., Heidel F., Pugliese N., Bosi C., Bartoletti D., Auteri G., Cattaneo D., Scaffidi L., Trawinska M.M., Stella R., Ciantia F., Pane F., Cuneo A., Krampera M., Semenzato G., Lemoli R.M., Iurlo A., Vianelli N., Cavo M., Breccia M., and Bonifacio M.
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Ruxolitinib ,medicine.medical_specialty ,Humans ,Janus Kinases ,Multivariate Analysis ,Primary Myelofibrosis ,Protein Kinase Inhibitors ,Pyrazoles ,Risk Factors ,Treatment Outcome ,medicine.medical_treatment ,Splenectomy ,lcsh:RC254-282 ,Nitriles ,Pyrimidines ,Ruxolitinib discontinuation syndrome, risk factors, myelofibrosis ,NO ,Myeloproliferative disease ,Internal medicine ,Correspondence ,medicine ,Risk factor ,Bone pain ,Myelofibrosis ,Respiratory distress ,business.industry ,Incidence (epidemiology) ,Hematology ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Discontinuation ,Oncology ,medicine.symptom ,business ,Haematological diseases ,medicine.drug - Abstract
No abstract available
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- 2020
17. Author response for 'RISK FACTORS FOR PROGRESSION TO BLAST PHASE AND OUTCOME IN 589 PATIENTS WITH MYELOFIBROSIS TREATED WITH RUXOLITINIB: REAL WORLD DATA'
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Alessia Tieghi, Alessandro Isidori, Mario Tiribelli, Giulia Benevolo, Bruno Martino, Florian H. Heidel, E Abruzzese, Roberto Latagliata, Gianpietro Semenzato, Giuseppe Auteri, Massimo Breccia, Elena Maria Elli, Michele Cavo, Mauro Krampera, Davide Griguolo, F. Cavazzini, Monica Crugnola, A. Iurlo, Daniela Bartoletti, Daniele Cattaneo, Francesca Palandri, Micaela Bergamaschi, Massimiliano Bonifacio, Dorian Forte, Giuseppe A. Palumbo, Roberto M. Lemoli, Nicola Polverelli, Nicola Vianelli, Antonio Cuneo, Francesco Di Raimondo, Malgorzata Monika Trawinska, Costanza Bosi, and Gianni Binotto
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Oncology ,medicine.medical_specialty ,Ruxolitinib ,business.industry ,Internal medicine ,medicine ,Myelofibrosis ,medicine.disease ,Blast Phase ,business ,Outcome (game theory) ,Real world data ,medicine.drug - Published
- 2020
18. Risk factors for progression to blast phase and outcome in 589 patients with myelofibrosis treated with ruxolitinib: Real-world data
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Massimo Breccia, Mauro Krampera, Alessandro Isidori, Monica Crugnola, Daniela Bartoletti, Elena Maria Elli, Alessia Tieghi, Massimiliano Bonifacio, Micaela Bergamaschi, Costanza Bosi, Roberto Latagliata, Roberto M. Lemoli, Francesco Cavazzini, Florian H. Heidel, Michele Cavo, Nicola Polverelli, Malgorzata Monika Trawinska, Francesca Palandri, Bruno Martino, Daniele Cattaneo, Giulia Benevolo, Giuseppe Auteri, Elisabetta Abruzzese, Gianni Binotto, Alessandra Iurlo, Nicola Vianelli, Antonio Cuneo, Francesco Di Raimondo, Dorian Forte, Davide Griguolo, Gianpietro Semenzato, Giuseppe A. Palumbo, Mario Tiribelli, Palandri F., Breccia M., Tiribelli M., Bonifacio M., Benevolo G., Iurlo A., Elli E.M., Binotto G., Tieghi A., Polverelli N., Martino B., Abruzzese E., Bergamaschi M., Heidel F.H., Cavazzini F., Crugnola M., Bosi C., Isidori A., Auteri G., Forte D., Latagliata R., Griguolo D., Cattaneo D., Trawinska M., Bartoletti D., Krampera M., Semenzato G., Lemoli R.M., Cuneo A., Di Raimondo F., Vianelli N., Cavo M., and Palumbo G.A.
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Male ,Cancer Research ,Ruxolitinib ,ruxolitinib ,Gastroenterology ,0302 clinical medicine ,myelofibrosi ,80 and over ,risk factors ,blast phase ,myelofibrosis ,outcome ,Adult ,Aged ,Aged, 80 and over ,Blast Crisis ,Disease Progression ,Female ,Follow-Up Studies ,Humans ,Janus Kinases ,Middle Aged ,Primary Myelofibrosis ,Prognosis ,Pyrazoles ,Retrospective Studies ,Survival Rate ,Young Adult ,Incidence (epidemiology) ,Hematology ,General Medicine ,risk factor ,Oncology ,030220 oncology & carcinogenesis ,blast phase, myelofibrosis, outcome, risk factors, ruxolitinib, Blast Crisis, Disease Progression ,medicine.drug ,medicine.medical_specialty ,Socio-culturale ,Alpha interferon ,03 medical and health sciences ,Internal medicine ,Nitriles ,medicine ,Risk factor ,Myelofibrosis ,Survival rate ,business.industry ,Induction chemotherapy ,Anagrelide ,medicine.disease ,Pyrimidines ,business ,030215 immunology - Abstract
The impact of ruxolitinib therapy on evolution to blast phase (BP) in patients with myelofibrosis (MF) is still uncertain. In 589 MF patients treated with ruxolitinib, we investigated incidence and risk factors for BP and we described outcome according to disease characteristics and treatment strategy. After a median follow-up from ruxolitinib start of 3 years (range 0.1-7.6), 65 (11%) patients transformed to BP during (93.8%) or after treatment. BP incidence rate was 3.7 per 100 patient-years, comparably in primary and secondary MF (PMF/SMF) but significantly lower in intermediate-1 risk patients (2.3 vs 5.6 per 100 patient-years in intermediate-2/high-risk patients, P
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- 2020
19. 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
20. Weight discordance and perinatal mortality in monoamniotic twin pregnancy: analysis of MONOMONO, NorSTAMP and STORK multiple-pregnancy cohorts
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Gabriele, Saccone, Asma, Khalil, Basky, Thilanagathan, Svetlana, Glinianaia, Vincenzo, Berghella, Francesco, D'Antonio, Mariavittoria, Locci, Tullio, Ghi, Tiziana, Frusca, Mariano, Lanna, Stefano, Faiola, Anna, Fichera, Federico, Prefumo, Giuseppe, Rizzo, Costanza, Bosi, Bruno, Arduino, Pietro, D'Alessandro, Maria, Borgo, Silvana, Arduino, Elisabetta, Cantanna, Giuliana, Simonazzi, Nicola, Rizzo, Giorgetta, Francesca, Viola, Seravalli, Miller, Jena L., Elena Rita Magro‐Malosso, Mariarosaria Di Tommaso, Andrea, Dall'Asta, Letizia, Galli, Nicola, Volpe, Silvia, Visentin, Erich, Cosmi, Laura, Sarno, Claudia, Caissutti, Lorenza, Driul, Hannah, Anastasio, DI MASCIO, Daniele, BENEDETTI PANICI, Pierluigi, Vena, Flaminia, Brunelli, Roberto, Andrea, Ciardulli, Corina, Schoen, Anju, Suhag, Zita Maria Gambacorti‐Passerini, Maria Angeles Anaya Baz, Giulia, Magoga, Enrico, Busato, Elisa, Filippi, María José Rodriguez Suárez, Francisco Gamez Alderete, Paula Alonso Ortuno, Amerigo, Vitagliano, Antonio, Mollo, Antonio, Raffone, Marianne, Vendola, Preethi, Navaneethan, Ruwan, Wimalasundera, Raffaele, Napolitano, Carmen Imma Aquino, Serena, D'Agostino, Cinzia, Gallo, Giuseppe Maria Maruotti, Maria Elena Flacco, Baschat, Ahmet A., Roberta, Venturella, Maurizio, Guida, Pasquale, Martinelli, Fulvio Zullo Therese Hannon, Sturgiss, Stephen N., Judith, Rankin, Nicola, Miller, Danielle, Martin, Arash, Bahamie, Amar, Bhide, Aris, Papageorghiou, Anne, Deans, Kim, Morgan, Michael, Egbor, Adetunji, Matiluko, Cheryl, Ellis, Hina, Gandhi, Rosol, Hamid, Renata, Hutt, Lesley, Roberts, Faz, Pakarian, Elisabeth, Peregrine, Saccone, G, Khalil, A, Thilaganathan, B, Glinianaia, Sv, Berghella, V, D'Antonio, F, Guida, M, et al., : MONOMONO, Norstamp, STORK research, Collaboratives, Papageorghiou, A, Saccone G1, Khalil A2,3, Thilaganathan B2,3, Glinianaia SV4, Berghella V5, D'Antonio F6, and MONOMONO, NorSTAMP and STORK research collaboratives. Zullo F, Locci M, Guida M, Anastasio H, Ghi T, Frusca T, Dall'Asta A, Galli L, Volpe N, Lanna M, Faiola S, Fichera A, Prefumo F, Rizzo G, Arduino S, Cantanna E, Simonazzi G, Seravalli V, Rita Magro-Malosso E, Di Tommaso M, L Miller J, A Baschat A, Vitagliano A, Visentin S, Cosmi E, Caissutti C, Driul L, Di Mascio D, Benedetti Panici P, Vena F, Brunelli R, Ciardulli A, Schoen C, Suhag A, Maria Gambacorti-Passerini Z, Angeles Anaya Baz M, Magoga G, Busato E, Filippi E, José Rodriguez Suárez M, Gamez Alderete F, Alonso Ortuno P, Vendola M, Navaneethan P, Wimalasundera R, Napolitano R, Mollo A, Imma Aquino C, D'Agostino S, Gallo C, Venturella R, Flacco M, Hannon T, N Sturgiss S, Rankin J, Miller N, Martin D, Bahamie A, Bhide A, Papageorghiou A, Deans A, Morgan K, Egbor M, Matiluko A, Ellis C, Gandhi H, Hamid R, Hutt R, Roberts L, Pakarian F, Peregrine E.
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chorionicity ,Predictive Value of Test ,Logistic regression ,Cohort Studies ,0302 clinical medicine ,Pregnancy ,Risk of mortality ,Birth Weight ,030212 general & internal medicine ,Fetal Monitoring ,Twin Pregnancy ,030219 obstetrics & reproductive medicine ,Fetal Growth Retardation ,Radiological and Ultrasound Technology ,Obstetrics ,Perinatal mortality ,cord entanglement ,Obstetrics and Gynecology ,Cesarean delivery ,healthcare ,Prenatal Care ,General Medicine ,twin pregnancy ,cesarean delivery ,cord accident ,health care ,monochorionic ,multiple gestation ,perinatal death ,respiratory distress syndrome ,Fetal Weight ,Female ,Human ,Adult ,medicine.medical_specialty ,Logistic Model ,Risk Assessment ,Multiple Gestation ,03 medical and health sciences ,Predictive Value of Tests ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Perinatal Mortality ,Fetus ,business.industry ,Infant, Newborn ,Odds ratio ,Twins, Monozygotic ,medicine.disease ,Logistic Models ,Reproductive Medicine ,ROC Curve ,Pregnancy, Twin ,Settore MED/40 - Ginecologia e Ostetricia ,Cohort Studie ,business - Abstract
Objectives:The primary objective was to quantify the risk of perinatal mortality in non‐anomalous monochorionic monoamniotic (MCMA) twin pregnancies complicated by birth‐weight (BW) discordance. The secondary objectives were to investigate the effect of inpatientvsoutpatient fetal monitoring on the risk of mortality in weight‐discordant MCMA twin pregnancies, and to explore the predictive accuracy of BW discordance for perinatal mortality. Methods:This analysis included data on 242 MCMA twin pregnancies (484 fetuses) from three major research collaboratives on twin pregnancy (MONOMONO, STORK and NorSTAMP). The primary outcomes were the risks of intrauterine (IUD), neonatal (NND) and perinatal (PND) death, according to weight discordance at birth from ≥ 10% to ≥ 30%. The secondary outcomes were the association of inpatientvsoutpatient fetal monitoring with the risk of mortality in weight‐discordant pregnancies, and the accuracy of BW discordance in predicting mortality. Logistic regression and receiver‐operating‐characteristics‐curve analyses were used to analyze the data. Results:The risk of IUD was significantly increased in MCMA twin pregnancies with BW discordance ≥ 10% (odds ratio (OR), 2.2; 95% CI, 1.1–4.4;P= 0.022) and increased up to an OR of 4.4 (95% CI, 1.3–14.4;P= 0.001) in those with BW discordance ≥ 30%. This association remained significant on multivariate logistic regression analysis for BW‐discordance cut‐offs ≥ 20%. However, weight discordance had low predictive accuracy for mortality, with areas under the receiver‐operating‐characteristics curve of 0.60 (95% CI, 0.46–0.73), 0.52 (95% CI, 0.33–0.72) and 0.57 (95% CI, 0.45–0.68) for IUD, NND and PND, respectively. There was no difference in the risk of overall IUD, single IUD, double IUD, NND or PND between pregnancies managed as an inpatient compared with those managed as an outpatient, for any BW‐discordance cut‐off. Conclusions:MCMA twin pregnancies with BW discordance are at increased risk of fetal death, signaling a need for increased levels of monitoring. Despite this, the predictive accuracy for mortality is low; thus, detection of BW discordance alone should not trigger intervention, such as iatrogenic delivery. The current data do not demonstrate an advantage of inpatient over outpatient management in these cases. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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- 2020
21. Second primary malignancy in myelofibrosis patients treated with ruxolitinib
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Elena Maria Elli, Florian H. Heidel, Uros Markovic, Fabrizio Pane, Gianpietro Semenzato, Daniela Bartoletti, Francesca Palandri, Giulia Benevolo, Mauro Krampera, Malgorzata Monika Trawinska, Micaela Bergamaschi, Mario Tiribelli, Giovanni Caocci, Lucia Catani, Elisabetta Abruzzese, Massimo Breccia, Rossella Stella, Antonio Cuneo, Fabio D'Amore, Alessandro Isidori, Costanza Bosi, Monica Crugnola, Lisa Gandolfi, Domenico Russo, Alessandra Iurlo, Nicola Polverelli, Roberto M. Lemoli, Michele Cavo, Gianni Binotto, Roberto Latagliata, Francesco Cavazzini, Bruno Martino, Daniele Cattaneo, Nicola Vianelli, Novella Pugliese, Luigi Scaffidi, Massimiliano Bonifacio, Mariella D'Adda, Alessia Tieghi, Giuseppe Auteri, Giuseppe A. Palumbo, Polverelli N., Elli E.M., Abruzzese E., Palumbo G.A., Benevolo G., Tiribelli M., Bonifacio M., Tieghi A., Caocci G., D'Adda M., Bergamaschi M., Binotto G., Heidel F.H., Cavazzini F., Crugnola M., Pugliese N., Bosi C., Isidori A., Bartoletti D., Auteri G., Latagliata R., Gandolfi L., Martino B., Scaffidi L., Cattaneo D., D'Amore F., Trawinska M.M., Stella R., Markovic U., Catani L., Pane F., Cuneo A., Krampera M., Semenzato G., Lemoli R.M., Vianelli N., Breccia M., Russo D., Cavo M., Iurlo A., and Palandri F.
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Male ,Ruxolitinib ,Skin Neoplasms ,Lymphoma ,ruxolitinib ,Aggressive lymphoma ,Gastroenterology ,Hydroxycarbamide ,0302 clinical medicine ,myelofibrosi ,Risk Factors ,Neoplasms ,80 and over ,Aged, 80 and over ,Thrombocytosis ,Incidence (epidemiology) ,Incidence ,Hazard ratio ,Neoplasms, Second Primary ,Hematology ,Arteries ,Middle Aged ,Second Primary ,JAK inhibitor ,030220 oncology & carcinogenesis ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Context (language use) ,myelofibrosis ,JAK inhibitors ,second cancer ,toxicity ,NO ,03 medical and health sciences ,Internal medicine ,Nitriles ,medicine ,Humans ,Janus Kinase Inhibitors ,Myelofibrosis ,Aged ,Retrospective Studies ,business.industry ,Thrombosis ,medicine.disease ,Case-Control Studies ,Follow-Up Studies ,Multivariate Analysis ,Primary Myelofibrosis ,Pyrazoles ,Pyrimidines ,business ,030215 immunology - Abstract
Ruxolitinib (RUX), the first JAK1/JAK2 inhibitor approved for myelofibrosis (MF) therapy, has recently been associated with the occurrence of second primary malignancies (SPMs), mainly lymphomas and non-melanoma skin cancers (NMSCs). We analyzed the incidence, risk factors and outcome of SPMs in 700 MF patients treated with RUX in a real-world context. Median follow-up from starting RUX was 2·9years. Overall, 80 (11·4%) patients developed 87 SPMs after RUX start. NMSCs were the most common SPMs (50·6% of the cases). Multivariate analysis demonstrated that male sex [hazard ratio (HR): 2·37, 95% confidence interval (95%CI): 1·22–4·60, P=0·01] and thrombocytosis>400×109/l at RUX start (HR:1·98, 95%CI: 1·10–4·60, P=0·02) were associated with increased risk for SPMs. Risk factors for NMSC alone were male sex (HR: 3·14, 95%CI: 1·24–7·92, P=0·02) and duration of hydroxycarbamide and RUX therapy>5years (HR: 3·20, 95%CI: 1·17–8·75, P=0·02 and HR: 2·93, 95%CI: 1·39–6·17, P=0·005 respectively). In SPMs excluding NMSCs, male sex (HR: 2·41, 95%CI: 1·11–5·25, P=0·03), platelet>400×109/l (HR: 3·30, 95%CI: 1·67–6·50, P=0·001) and previous arterial thromboses (HR: 3·47, 95%CI: 1·48–8·14, P=0·004) were shown to be associated with higher risk of SPMs. While it is reassuring that no aggressive lymphoma was documented, active skin surveillance is recommended in all patients and particularly after prolonged hydroxycaramide therapy; oncological screening should be triggered by thrombocytosis and arterial thrombosis, particularly in males.
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- 2020
22. Peripheral Blasts Are Associated with Response to Ruxolitinib and Outcome in Patients with Chronic-Phase Myelofibrosis
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Bruno Martino, Eloise Beggiato, Mario Tiribelli, Francesco Cavazzini, Novella Pugliese, Giovanni Caocci, Antonio Cuneo, Monica Crugnola, Emanuela Ottaviani, Massimo Breccia, Mauro Krampera, Daniela Bartoletti, Carmen Fava, Giorgia Micucci, Elisabetta Abruzzese, Michele Cavo, Gianni Binotto, Nicola Polverelli, Fabrizio Pane, Giulia Benevolo, Christian Di Pietro, Monica Bocchia, Massimiliano Bonifacio, Daniela Cilloni, Roberto M. Lemoli, Florian H. Heidel, Francesca Palandri, Giuseppe A. Palumbo, Malgorzata Monika Trawinska, Alessandra Iurlo, Elena Maria Elli, Alessia Tieghi, Giuseppe Auteri, Nicola Vianelli, Maurizio Miglino, and Costanza Bosi
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Oncology ,medicine.medical_specialty ,Ruxolitinib ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Outcome (game theory) ,Peripheral ,Internal medicine ,medicine ,In patient ,Myelofibrosis ,business ,medicine.drug - Abstract
Background: The presence of peripheral blasts (PB) is a negative prognostic factor in patients (pts) with primary and secondary myelofibrosis (PMF/SMF) and PB ≥4% was associated with a particularly unfavorable prognosis (Masarova L et al, Cancer 2020). Ruxolitinib (RUX) is the JAK1/2 inhibitor most used for treatment of MF-related splenomegaly and symptoms. Its role has not been assessed in correlation with PB. Aims: To evaluate the impact of PB percentage on RUX efficacy and prognosis Methods: After IRB approval, the "RUX-MF" retrospective study collected 804 RUX-treated chronic-phase (CP, defined as PB Comparisons of quantitative variables between the 3 groups were carried out by Kruskal-Wallis and Dunn's tests while association between categorical variables was tested by the χ2 test. Variables significantly associated to RUX stop/leukemic transformation (LT)/overall survival (OS) in univariate analysis (Log-rank test) were considered for multivariable analyses, carried out using the Cox regression model, with evaluation of the model's performance in terms of goodness of fit. Results: Pts were categorized according to PB at RUX start: PB-0 (no PB; n. 487, 61.3%), PB-5 (PB 1-5%; n. 283, 35.8%), and PB-9 (PB 6-9%; n. 24, 2.9%). Pts characteristics at RUX start were: median age 68.1y (24-89); males 58.1%; PMF 52.5%; JAK2, CALR and MPL mutated: 80.5%, 13.1% and 2% (4.4% triple negative), high DIPSS: 7.6%; PLT25 x10 9/l: 10.8%/16.4%; spleen length ≥10 cm: 47.8%, TSS ≥20: 60.6%; ≥1/≥2 high-risk mutation (HMR): 69/18 out of 167 evaluable (41.3%/10.8%); fibrosis grade ≥2: 77.9%; starting/cumulative RUX dose ≥15 mg BID: 61.4%/52.6%. Higher PB count was associated to high DIPSS risk (PB-0: 1.9%, PB-5: 16.2%, PB-9: 21.7%, p At 3 and 6 mos, 26.9% and 30.4% of evaluable pts achieved a SR, while 59.7% and 68.1% were in SyR, respectively. At 3 mos, SR (PB-0: 31.8%, PB-5: 20.6%, PB-9: 10%, p=0.001) and SyR (PB-0: 62.9%, PB-5: 55.5%, PB-9: 36.8%, p=0.02) were less frequently achieved by PB-5 and PB-9 pts compared to PB-0 pts. This association remained significant for SR at 6 mos (PB-0: 35%, PB-5: 23.9%, PB-9: 14.3%, p=0.006) and for both SR (p=0.003) and SyR (p=0.01) at any time. After a median RUX exposure of 1.5 y (0.1-8.9), 491 (61.8%) pts stopped RUX, 110 (13.9%) had a LT and 365 (46%) died. In univariate analysis, at 2y PB-9 pts had higher rates of RUX stop (73.9% vs 40.8% and 34.3% in PB-5 and PB-0 pts, log-rank p In multivariable analysis, PB-9 pts confirmed their association with: 1) RUX stop (HR 3.74, 95%CI 1.51-3.70, p20 (HR 1.66, 95%CI 1.05-2.61, p=0.03), and HMR≥2 (HR 2.69, 95%CI 1.26-4.47, p=0.007); 2) LT (HR 3.71, 95%CI 1.71-8.04, p Conclusions: CP-MF pts with PB>5% have a worse response to RUX and a worse outcome. Personalized approaches beyond RUX monotherapy may be useful in this context. Further clinical trials evaluating combination strategies and new drugs are required. Figure 1 Figure 1. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AOP: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy. Abruzzese: Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Iurlo: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau. Bonifacio: Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Cuneo: AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Pane: AbbVie; Amgen; Novartis: Other: Travel, accommodation, expenses; Novartis Pharma SAS;: Research Funding; AbbVie; Amgen; Novartis, GSK , Incyte: Consultancy; AbbVie; Amgen; Novartis, GSK, Incyte: Speakers Bureau. Lemoli: Celgene: Other: Support for attending meetings and/or travel; Jazz, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Daiichi Sankyo, Servier: Honoraria, Speakers Bureau. Cavo: Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Abbvie: Honoraria.
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- 2021
23. Durability of spleen response affects the outcome of ruxolitinib-treated patients with myelofibrosis: Results from a multicentre study on 284 patients
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Giuseppe Auteri, Nicola Sgherza, Mario Tiribelli, Lucia Catani, Daniela Bartoletti, Costanza Bosi, Roberto Latagliata, Francesco Cavazzini, Michele Cavo, Franco Aversa, Bruno Martino, Massimiliano Bonifacio, Antonio Cuneo, Gianni Binotto, Giuseppe A. Palumbo, Massimo Breccia, Adalberto Ibatici, Nicola Vianelli, Alessandro Isidori, Monica Crugnola, Gianpietro Semenzato, Alessia Tieghi, Micaela Bergamaschi, Maura Nicolosi, Francesca Palandri, Alessandra Iurlo, Nicola Polverelli, Elisabetta Abruzzese, Giulia Benevolo, Florian H. Heidel, Palandri, Francesca, Palumbo, Giuseppe A, Bonifacio, Massimiliano, Breccia, Massimo, Latagliata, Roberto, Martino, Bruno, Polverelli, Nicola, Abruzzese, Elisabetta, Tiribelli, Mario, Nicolosi, Maura, Bergamaschi, Micaela, Tieghi, Alessia, Iurlo, Alessandra, Sgherza, Nicola, Cavazzini, Francesco, Isidori, Alessandro, Binotto, Gianni, Ibatici, Adalberto, Crugnola, Monica, Heidel, Florian, Bosi, Costanza, Bartoletti, Daniela, Auteri, Giuseppe, Catani, Lucia, Cuneo, Antonio, Aversa, Franco, Semenzato, Gianpietro, Cavo, Michele, Vianelli, Nicola, and Benevolo, Giulia
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Male ,Oncology ,Cancer Research ,Ruxolitinib ,medicine.medical_specialty ,Time Factors ,ruxolitinib,myelofibrosis, spleen ,Socio-culturale ,Spleen ,03 medical and health sciences ,0302 clinical medicine ,Hematology ,Internal medicine ,80 and over ,medicine ,Humans ,Myelofibrosis ,Aged ,business.industry ,Aged, 80 and over ,Female ,Middle Aged ,Organ Size ,Rituximab ,Primary Myelofibrosis ,medicine.disease ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,business ,030215 immunology ,medicine.drug - Abstract
NA
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- 2018
24. Ruxolitinib Rechallenge in Resistant/Intolerant MF Patients: Frequency, Therapeutic Effects, and Impact on Outcome
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Antonio Cuneo, Giulia Benevolo, Giuseppe A. Palumbo, Massimiliano Bonifacio, Mario Tiribelli, Giuseppe Auteri, Massimo Breccia, Lucia Catani, Monica Crugnola, Giovanni Caocci, Luigi Scaffidi, Daniela Bartoletti, Michele Cavo, Francesca Palandri, Nicola Polverelli, Roberto M. Lemoli, Elena Maria Elli, Elena Masselli, Bruno Martino, Daniele Cattaneo, Florian H. Heidel, Gianni Binotto, Alessandra Iurlo, Fabrizio Pane, Mauro Krampera, Costanza Bosi, Nicola Vianelli, Roberto Latagliata, Francesco Cavazzini, Novella Pugliese, Rossella Stella, Giorgia Micucci, Gianpietro Semenzato, and Alessia Tieghi
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Ruxolitinib ,Disease status ,medicine.medical_specialty ,business.industry ,INVESTIGATIONAL AGENTS ,Immunology ,Therapeutic effect ,Context (language use) ,Cell Biology ,Hematology ,Biochemistry ,Symptoms score ,Discontinuation ,Internal medicine ,Medicine ,business ,Bristol-Myers ,medicine.drug - Abstract
Introduction: The outcome of patients (pts) with myelofibrosis (MF) who discontinue ruxolitinib (RUX) is poor with scarce therapeutic possibilities (Palandri et al, 2020). However, some evidences suggest that pts may respond to a rechallenge of RUX after drug stop (Gerds et al, 2018). Aims: To investigate in a real-world context: 1) frequency and reasons for rechallenge; 2) therapeutic effects of rechallenge; 3) impact of rechallenge on overall survival (OS) Methods: After IRB approval, a clinical database was created in 20 European Hematology Centers including now retrospective data of 703 MF pts who started RUX from Jan 2011 to Nov 2019. Only chronic phase (CP) pts who stopped RUX for ≥14 days and survived ≥30 days after discontinuation were included. A specific survey collected clinical/laboratory data at RUX stop and at rechallenge, reasons for discontinuation and treatments before rechallenge. OS was estimated from the date of the first/only RUX discontinuation to last contact (log-rank test). Results: A total of 219 CP pts was evaluable for this study. In 60 (27.4%) pts, RUX was re-challenged for ≥14 days after the first discontinuation (RUX-again), while 159 (72.6%) pts discontinued RUX permanently (RUX-stop). The median time from RUX start to stop was of 16.5 and 12.3 mos for RUX-again and RUX-stop pts, respectively (p=0.41). At RUX start, characteristics of RUX-again were: median age 67y (24-88); males 61.7%; PMF 53.3%; median Hb 10.2 g/dl; median PLT/WBC: 249/12.6 x109/l; median RUX starting dose: 15mg BID. Baseline characteristics of RUX-again and RUX-stop pts were comparable. In the 60 RUX-again pts, reasons for discontinuation included loss of/inadequate response (18 pts, 30%) and toxicity (42 pts, 70%). Toxicity included G3-4 thrombocytopenia (38.1%), anemia (26.2%), infections (21.4%), other (14.3%). Conversely, RUX-stop pts discontinued RUX mainly due to loss of/inadequate response (75 pts, 47.2%), while intolerable toxicity occurred in 69 pts (43.4%) (p=0.004) and other causes in 9.4%. At first RUX discontinuation, 35.7% of RUX-again pts presented with large (>10 cm) splenomegaly; median Total Symptoms Score (TSS) was 10 (TSS>20 in 30.4% of pts). The median duration of temporary RUX discontinuation was 2 mos (range 0.5-71.1). During RUX stop, 65% of RUX-again pts did not receive any therapy, 15% received only palliation (steroids, hydroxyurea), while 11.7% switched to investigational agents, 3.3% underwent splenectomy and 5% allogeneic transplantation. Compared to disease status at first RUX stop, at RUX restart there was a significant increase of pts with large splenomegaly and high TSS, while the PLT count was higher and RUX dose significantly lower (Table 1). The median duration of RUX rechallenge was 7.5 mos (0.5-72.7). During the rechallenge, 44.6% and 48.3% pts improved spleen and symptoms, and there was a significant increase in pts with TSS reduction (p=0.01); 8 pts (13.3%) continued RUX with stable/worsening spleen size and improvement in TSS. Conversely, 26.8% and 20% of pts had increase in spleen size and in symptoms, respectively. While Hb levels remained stable, PLT count significantly decreased during rechallenge (p The reasons for temporary discontinuation had no impact on the reduction of spleen/symptoms during rechallenge and on OS. However, comparing RUX-again and RUX-stop pts, RUX-again pts showed a better OS, with a median survival of 41.1 mos and 23.7, respectively in the 2 cohorts (Fig. 1). Conclusions: This real-world study highlights that RUX rechallenge is quite common in CP-MF pts, involving almost 30% of treated pts, particularly when the discontinuation is due to toxicity. The temporary discontinuation, while improving PLT count, generally caused a significant increase in disease burden. After rechallenge, almost 50% of pts achieved clinical responses regardless of reason of first discontinuation. This residual disease control activity, that correlated with improved OS, should be weighed up also given the new therapeutic possibilities available in these pts. Disclosures Palandri: Novartis: Consultancy, Honoraria. Breccia:Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Benevolo:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Cavazzini:Incyte: Honoraria; Pfize: Honoraria; Novartis: Honoraria. Crugnola:Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Heidel:CTI: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Research Funding. Pane:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Cuneo:janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Semenzato:Takeda: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Lemoli:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BerGenBio ASA: Research Funding. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Palumbo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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- 2020
25. Ruxolitinib in elderly patients with myelofibrosis: impact of age and genotype. A multicentre study on 291 elderly patients
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G. Semenzato, Massimiliano Bonifacio, Mario Tiribelli, Daniela Bartoletti, Lucia Catani, Bruno Martino, Micaela Bergamaschi, Florian H. Heidel, Giuseppe A. Palumbo, Gianni Binotto, Francesca Palandri, Antonio Cuneo, Mariella D'Adda, Michele Cavo, Alessandra Iurlo, Massimo Breccia, Alessandro Isidori, Elena Sabattini, Maria Rosaria Sapienza, Nicola Polverelli, Giulia Benevolo, Roberto M. Lemoli, Nicola Sgherza, Umberto Vitolo, Monica Crugnola, Elisabetta Abruzzese, Adalberto Ibatici, Nicola Vianelli, Costanza Bosi, Franco Aversa, Roberto Latagliata, Francesco Cavazzini, Alessia Tieghi, Giovanni Martinelli, Francesca Palandri, Lucia Catani, Massimiliano Bonifacio, Giulia Benevolo, Florian Heidel, Giuseppe A. Palumbo, Monica Crugnola, Elisabetta Abruzzese, Daniela Bartoletti, Nicola Polverelli, Micaela Bergamaschi, Mario Tiribelli, Alessandra Iurlo, Massimo Breccia, Francesco Cavazzini, Alessia Tieghi, Gianni Binotto, Alessandro Isidori, Bruno Martino, Mariella D'Adda, Costanza Bosi, Elena Sabattini, Umberto Vitolo, Franco Aversa, Adalberto Ibatici, Roberto M. Lemoli, Nicola Sgherza, Antonio Cuneo, Giovanni Martinelli, Giampietro Semenzato, Michele Cavo, Nicola Vianelli, Maria R. Sapienza, and Roberto Latagliata
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0301 basic medicine ,elderly ,high molecular risk ,high molecular risk mutations ,myelofibrosis ,ruxolitinib ,Ruxolitinib ,medicine.medical_specialty ,Genotype ,Socio-culturale ,Hematology ,Older population ,03 medical and health sciences ,0302 clinical medicine ,myelofibrosi ,Older patients ,Risk Factors ,Internal medicine ,Nitriles ,Medicine ,Humans ,Myelofibrosis ,Aged ,Janus Kinases ,Retrospective Studies ,business.industry ,Age Factors ,elderly, high molecular risk, high molecular risk mutations, myelofibrosis, ruxolitinib ,medicine.disease ,Mutation ,Primary Myelofibrosis ,Pyrazoles ,Survival Analysis ,Treatment Outcome ,Peripheral blood ,Discontinuation ,030104 developmental biology ,Pyrimidines ,030220 oncology & carcinogenesis ,high molecular risk mutation ,business ,medicine.drug - Abstract
Ruxolitinib is a JAK1/2 inhibitor that may control myelofibrosis (MF)-related splenomegaly and symptoms and can be prescribed regardless of age. While aging is known to correlate with worse prognosis, no specific analysis is available to confirm that ruxolitinib is suitable for use in older populations. A clinical database was created in 23 European Haematology Centres and retrospective data on 291 MF patients treated with ruxolitinib when aged ≥65 years were analysed in order to assess the impact of age and molecular genotype on responses, toxicities and survival. Additional mutations were evaluated by a next generation sequencing (NGS) approach in 69 patients with available peripheral blood samples at the start of ruxolitinib treatment. Compared to older (age 65-74 years) patients, elderly (≥75 years) showed comparable responses to ruxolitinib, but higher rates of drug-induced anaemia and thrombocytopenia and worse survival. Nonetheless, the ruxolitinib discontinuation rate was comparable in the two age groups. Number and types of molecular abnormalities were comparable across age groups. However, the presence of high molecular risk (HMR) mutations significantly affected survival, counterbalancing the effect of aging. Indeed, elderly patients with
- Published
- 2018
26. L’endocrinologia del parto
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Domenico Arduini and Costanza Bosi
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Philosophy ,Humanities - Abstract
Il parto e un processo fisiologico finemente coordinato da un complesso insieme biochimico-ormonale, che ne determina il timing di inizio, l’evoluzione e il suo espletamento. La prima parte della gravidanza e caratterizzata dalla presenza in circolo di sostanze che ne favoriscono l’evoluzione e la durata, attraverso il mantenimento della quiescenza uterina, affinche il travaglio non si inneschi prima del tempo. Presso il termine della gestazione, invece, si assiste a uno switch a favore delle sostanze che determinano l’attivazione miometriale e l’espulsione del feto.
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- 2017
27. Author response for 'Impact of 2016‐WHO diagnosis of early and overt primary myelofibrosis on presentation and outcome of 232 patients treated with ruxolitinib'
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Elena Maria Elli, Robin Foà, Nicola Polverelli, Micaela Bergamaschi, Alessandro Isidori, Monica Crugnola, Massimiliano Bonifacio, Bruno Martino, Giuseppe A. Palumbo, Francesca Palandri, Daniele Cattaneo, Daniela Bartoletti, Gianni Binotto, Massimo Breccia, Nicola Vianelli, Mauro Krampera, Giuseppe Auteri, Roberto M. Lemoli, Costanza Bosi, Florian H. Heidel, Giulia Benevolo, Antonio Cuneo, F. Cavazzini, A. Iurlo, E Abruzzese, Nicola Sgherza, Michele Cavo, Alessia Tieghi, Mario Tiribelli, and Roberto Latagliata
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Pediatrics ,medicine.medical_specialty ,Ruxolitinib ,business.industry ,medicine ,Presentation (obstetrics) ,Myelofibrosis ,medicine.disease ,business ,Outcome (game theory) ,medicine.drug - Published
- 2019
28. Impact of 2016 WHO diagnosis of early and overt primary myelofibrosis on presentation and outcome of 232 patients treated with ruxolitinib
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Elisabetta Abruzzese, Nicola Vianelli, Massimiliano Bonifacio, Elena Maria Elli, Giulia Benevolo, Antonio Cuneo, Francesca Palandri, Monica Crugnola, Nicola Sgherza, Robin Foà, Mario Tiribelli, Massimo Breccia, Alessandra Iurlo, Daniela Bartoletti, Alessandro Isidori, Mauro Krampera, Giuseppe A. Palumbo, Alessia Tieghi, Nicola Polverelli, Roberto M. Lemoli, Giuseppe Auteri, Gianni Binotto, Florian H. Heidel, Micaela Bergamaschi, Michele Cavo, Roberto Latagliata, Bruno Martino, Francesco Cavazzini, Daniele Cattaneo, Costanza Bosi, Palandri, Francesca, Palumbo, Giuseppe A, Abruzzese, Elisabetta, Iurlo, Alessandra, Polverelli, Nicola, Elli, Elena, Bonifacio, Massimiliano, Bergamaschi, Micaela, Martino, Bruno, Tiribelli, Mario, Benevolo, Giulia, Tieghi, Alessia, Sgherza, Nicola, Isidori, Alessandro, Binotto, Gianni, Crugnola, Monica, Heidel, Florian, Cavazzini, Francesco, Bosi, Costanza, Auteri, Giuseppe, Cattaneo, Daniele, Foà, Robin, Lemoli, Roberto M, Cuneo, Antonio, Krampera, Mauro, Bartoletti, Daniela, Cavo, Michele, Vianelli, Nicola, Breccia, Massimo, and Latagliata, Roberto
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Male ,Cancer Research ,Ruxolitinib ,EARLY PMF ,MYELOFIBROSIS ,OVERT PMF ,RUXOLITINIB ,Heart disease ,0302 clinical medicine ,Essential ,Diagnosis ,80 and over ,Thrombocythemia ,Molecular Targeted Therapy ,Aged, 80 and over ,Hematology ,General Medicine ,Organ Size ,Middle Aged ,Neoplasm Proteins ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Toxicity ,Female ,Thrombocythemia, Essential ,medicine.drug ,Cohort study ,Adult ,medicine.medical_specialty ,Adolescent ,Anemia ,Socio-culturale ,Antineoplastic Agents ,World Health Organization ,Diagnosis, Differential ,03 medical and health sciences ,Internal medicine ,Nitriles ,medicine ,Humans ,Myelofibrosis ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,business.industry ,Clinical Laboratory Techniques ,Retrospective cohort study ,Early Diagnosis ,Janus Kinase 2 ,Primary Myelofibrosis ,Pyrazoles ,Spleen ,medicine.disease ,Pyrimidines ,Differential ,Differential diagnosis ,business ,030215 immunology - Abstract
The 2016 WHO criteria identified early primary myelofibrosis (PMF) as an individual entity with milder clinical features and better outcome compared with overt PMF. Here, we compared early and overt PMF patients treated with ruxolitinib in terms of baseline clinical/laboratory characteristics, response, and toxicity to treatment. We observed that early-PMF patients achieve better and more stable spleen and symptoms responses, with significantly lower rates of hematological toxicities. No differences in overall and leukemia-free survival were detected between the two cohorts. The application of 2016 WHO criteria is crucial to identify those PMF patients who deserve a stricter monitoring during treatment.
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- 2019
29. Azacitidine and Lenalidomide in Higher-Risk Myelodysplastic Syndromes. Long-Term Results of a Randomized Phase II Multicenter Study and Impact of Cytogenetic Scores and Mutational Status on Long-Lasting Responses
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Sarah Parisi, Patrizia Tosi, Andrea Pellagatti, Jacqueline Boultwood, Miriam Fogli, Maria Benedetta Giannini, Barbara Castagnari, Lucio Cocco, Matilde Y. Follo, Anna Candoni, Monica Crugnola, Cristina Clissa, Sara Mongiorgi, Carlo Finelli, Michele Cavo, Domenico Russo, Isabella Capodanno, Giovanna Leonardi, Costanza Bosi, Gian Matteo Rigolin, and Maurizio Miglino
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Long lasting ,Oncology ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Immunology ,Azacitidine ,Cell Biology ,Hematology ,Long term results ,medicine.disease ,Biochemistry ,stomatognathic diseases ,Multicenter study ,Internal medicine ,medicine ,Mutational status ,business ,Lenalidomide ,medicine.drug - Abstract
Introduction. The association of Azacitidine (AZA) and Lenalidomide (LEN), either administered concurrently or sequentially, has proven effective in Myelodysplastic Syndromes (MDS), however the optimum dose and schedule remains unknown. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in higher-risk MDS pts. Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the IWG criteria (Cheson, 2006). Moreover, the aim of this analysisis is to enucleate the clinical and biological features of pts who showed long-lasting (≥ 20 cycles) responses. Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS with IPSS risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles. For responder pts the same treatment was continued until disease progression or unacceptable toxicity. Results. From March 2013, 44 pts (27 males), median age: 72 (48-83 yrs) were enrolled, from 13 hematologic Centers. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. Treatment was given for a median of 8.5 (1-68) cycles; in ARM 1: 9 (1-68) cycles; in ARM 2: 8 (1-63) cycles, respectively. Median follow-up: 15 (2-77) months. 10/44 pts (22.7%) did not complete at least 6 cycles of treatment for causes other than disease progression, and were not considered evaluable for response. Among the 34/44 pts (77.3%) evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. Intention-to-treat (ITT) analysis: ORR: 59.1%. First response was observed after a median of 2 (1-8) cycles. The Best Response achieved was: CR: 8 pts (23.5%) (ITT: 18.1%), PR: 1 pt (2.9%) (ITT: 2.2%), mCR: 3 pts (8.8%) (ITT: 6.8%), HI: 8 pts (23.5%) (ITT: 18.1%), mCR+HI: 6 pts (17.6%) (ITT: 13.6%). Median duration of hematologic response: 10.5 months. 37 pts (84.1%) died , and 20 pts (45.4%) showed progression to AML. Grade >2 non haematological toxicity: 54.5%. Median OS: 15 months. OS was significantly longer in responder pts as compared to the other pts (28 vs 7 months, p2 non haematological toxicity (ARM 1: 66.7%; ARM 2: 43.5%), AML incidence (ARM 1: 33.3%; ARM 2: 56.5%; p=0.2150) and OS (ARM 1: 14 months; ARM 2: 16 months). However, among responder pts, sequential treatment showed a longer clinical benefit, as compared to combined treatment. Responder pts of ARM 2 showed a significantly longer median duration of response (18 vs 6 months, p=0.0481), a longer median duration of therapy (28 vs 10 months, p=0.0870; 20 vs 10 cycles, p=0.1181), more long-lasting (≥ 20 cycles) responses (34.8% vs 9.5%, p=0.1017) and a longer OS (35 vs 26 months, p=0.3868), as compared to responder pts of ARM 1. Overall, 10/44 long-responder pts (22.7%) received ≥ 20 cycles; 5/10 pts (50%) achieved CR. IPSS risk: Intermediate-2 (8 pts); High (2 pts); IPSS-R risk: Intermediate (2 pts); High (6 pts); Very High (2 pts); IPSS cytogenetic risk: Good (5 pts); Intermediate (3 pts); Poor (2 pts); IPSS-R cytogenetic risk: Good (5 pts); Intermediate (4 pts); Very Poor (1 pt); 4/6 patients with altered karyotype achieved cytogenetic remission; it is noteworthy that the only 3 pts of the entire series who showed no gene mutations at baseline are included in this subset of long-responders pts, while 5/10 pts showed at baseline ≥ 1 prognostically unfavorable gene mutations (none with TP53 mutations), with variable VAFs during treatment. Moreover all long-responder pts showed a common gene mutation on SOD2 gene, and mutations on PLCG2 gene. Conclusions. Our results confirm the efficacy of both AZA+LEN treatment regimens in higher-risk MDS pts, in terms of ORR and OS, although sequential treatment was associated with a longer clinical benefit among responder pts. A subset of pts (22,7 %) with less unfavorable cytogenetic and molecular characteristics showed a long-lasting response to treatment. Disclosures Finelli: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees. Crugnola:BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Rigolin:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria.
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- 2020
30. Risk Factors for Progression to Blast Phase and Outcome in 589 Patients with Myelofibrosis Treated with Ruxolitinib: Real-World Evidence
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Florian H. Heidel, Giuseppe A. Palumbo, Nicola Sgherza, Giulia Benevolo, Mario Tiribelli, Lucia Catani, Uros Markovic, Massimo Breccia, Nicola Vianelli, Mauro Krampera, Bruno Martino, Daniele Cattaneo, Alessia Tieghi, Alessandro Isidori, Malgorzata Monika Trawinska, Giuseppe Auteri, Francesca Palandri, Alessandra Iurlo, Monica Crugnola, Massimiliano Bonifacio, Costanza Bosi, Nicola Polverelli, Micaela Bergamaschi, Katia Codeluppi, Roberto M. Lemoli, Antonio Cuneo, Michele Cavo, Davide Griguolo, Roberto Latagliata, Francesco Cavazzini, Gianpietro Semenzato, Elisabetta Abruzzese, Elena Maria Elli, Daniela Bartoletti, and Gianni Binotto
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Ruxolitinib ,medicine.medical_specialty ,business.industry ,Immunology ,Salvage treatment ,Cell Biology ,Hematology ,Real world evidence ,Blast Phase ,Biochemistry ,Prognostic score ,Internal medicine ,Medicine ,Treatment strategy ,Electronic database ,business ,Median survival ,medicine.drug - Abstract
Introduction. Blast phase (BP) is the terminal and most incurable phase of myelofibrosis (MF) and occurs in a not negligible fraction of patients (pts). In the pre-ruxolitinib (RUX) era, peripheral blasts, thrombocytopenia, unfavorable cytogenetics, and high risk category were identified as predictors of BP. RUX is the standard of care for symptomatic MF; however, information on clinical/laboratory correlates of BP in RUX-treated pts is not available. Aims. The primary objective of the study is to assess real-world data on incidence, risk factors and outcome of BP in RUX-treated MF pts. Methods. A multicentre observational retrospective study on RUX-treated MF pts was conducted in 20 European Hematology Centers. Data were extracted from an electronic database that included consecutive pts treated with RUX from June 2011. Data cut-off was June 2019. Risk category was assessed at RUX start according to the Dynamic International Prognostic Score System (DIPSS) or the Myelofibrosis Secondary to PV and ET Collaboration Prognostic Model (MYSEC-PM) in pts with post-Polycythemia Vera (PV)/post-Essential Thrombocythemia (ET) MF (secondary MF, SMF). A time-to-event (BP) analysis was conducted with Fine & Gray model with death/time of stem cell transplant as competing risks. Variables tested for association with BP were: age≥65yr, sex, transfusion-dependency, PLT Results . Overall, 589 MF pts were included and observed for 1833 pt-yrs from RUX start (median, 35.4 mos). Diagnosis was PMF in 304 pts (51.6%), PPV-MF in 164 pts (27.8%) or PET-MF in 121 (20.6%); 58.4% males. Molecular status was: JAK2V617F (82.5%), CALR (11.3%) and MPLW515K/L (1.1%); 5.1% were triple negatives. Overall, 368 (62.5%) pts received ≥1 cytoreductive therapy before RUX, specifically: HU, n. 357; alkylating agents, n. 47; anagrelide, n. 33; and IFN, n. 29. Median time from MF diagnosis to RUX start was 1.3 yrs. DIPSS for the whole cohort was: INT-1 (52.9%), INT-2 (40.1%), and HIGH (7%). DIPSS distribution in PMF pts was: INT-1 (47.8%), INT-2 (45.7%), and HIGH (6.5%), while SMF pts were categorized at LOW (11.1%), INT-1 (43.1%), INT-2 (31.2%) and HIGH (14.6%) risk according to the MYSEC-PM. Overall, 65 (11%) developed BP. In 61 pts, BP caused RUX withdrawal after a median time of 1.2 yrs (0.7-6.2); in 4 pts BP occurred after RUX stop (median time: 2.4 yrs). BP incidence rate was 3.6 x100 pt-yrs and was comparable in PMF and SMF (p=0.1). In univariate analysis, the probability of BP evolution for the PMF cohort was significantly reduced by previous IFN use (p=0.001). In SMF, predictors for BP in univariate analysis were PLT High DIPSS risk significantly predicted BP in PMF (p=0.04, HR [95% CI]: 2.6 [1.1-6.5]) but not in SMF (p=0.40). In this latter cohort, only the MYSEC-PM was associated with BP (p=0.02, HR 1.7 [95% CI]: [1.1-2.8]) (Fig.1). Estimated HRs, in reference to the lower score category, were: 1.10 for INT-1, 1.82 for INT-2, and 4.04 for HIGH risk. HR for HIGH risk, comparing to all lower risk groups, was 3.53 (95% CI: 1.53-8.11). Overall, 54 (81.8%) BP pts died and median survival was 2.8 mos. Survival after BP was not influenced by type of MF, previous response to RUX, and type of salvage treatment. Conclusions. Thrombocytopenia and peripheral blasts at RUX start identified pts at higher risk of BP in SMF, while previous IFN use was associated with reduced BP evolution in both PMF and SMF, suggesting a possible disease-modifying action of this agent. Also, this analysis supports the ability of MYSEC-PM in predicting BP in pts with SMF. Despite RUX use, outcome after BP remained dismal, confirming the need for newer treatment strategies. Disclosures Palandri: Novartis: Consultancy, Honoraria. Breccia:Incyte: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Tiribelli:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Benevolo:Novartis Pharmaceuticals: Consultancy. Bonifacio:Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Iurlo:Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Elli:Novartis: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Sgherza:Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Crugnola:Novartis: Honoraria; Incyte: Honoraria. Isidori:Janssen: Honoraria; Novartis: Honoraria; Gilead: Honoraria. Heidel:Novartis: Consultancy, Research Funding; Celgene: Consultancy; CTI: Consultancy. Latagliata:Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Trawinska:Novartis: Consultancy, Honoraria. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Cuneo:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavo:takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria. Palumbo:Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Hospira: Honoraria; Teva: Honoraria.
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- 2019
31. Differences in presenting features, outcome and prognostic models in patients with primary myelofibrosis and post-polycythemia vera and/or post-essential thrombocythemia myelofibrosis treated with ruxolitinib. New perspective of the MYSEC-PM in a large multicenter study
- Author
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Costanza Bosi, Franco Aversa, Elisabetta Abruzzese, Nicola Vianelli, Giulia Benevolo, G. Semenzato, Bruno Martino, Daniele Cattaneo, Adalberto Ibatici, Nicola Polverelli, Daniela Bartoletti, Nicola Sgherza, Massimiliano Bonifacio, Roberto Latagliata, Francesca Palandri, Francesco Di Raimondo, Francesco Cavazzini, Micaela Bergamaschi, Michele Cavo, Massimo Breccia, Mariella D'Adda, Alessandra Iurlo, Alessandro Isidori, Maria Letizia Bacchi Reggiani, Giuseppe A. Palumbo, Luigi Scaffidi, Alessia Tieghi, Gianni Binotto, Antonio Cuneo, Monica Crugnola, Francesco Soci, Roberto M. Lemoli, Mario Tiribelli, Lucia Catani, Giuseppe Auteri, Malgorzata Monika Trawinska, Florian H. Heidel, Domenico Penna, Domenico Russo, and Palandri F, Palumbo GA, Iurlo A, Polverelli N, Benevolo G, Breccia M, Abruzzese E, Tiribelli M, Bonifacio M, Tieghi A, Isidori A, Martino B, Sgherza N, D'Adda M, Bergamaschi M, Crugnola M, Cavazzini F, Bosi C, Binotto G, Auteri G, Latagliata R, Ibatici A, Scaffidi L, Penna D, Cattaneo D, Soci F, Trawinska M, Russo D, Cuneo A, Semenzato G, Di Raimondo F, Aversa F, Lemoli RM, Heidel F, Reggiani MLB, Bartoletti D, Cavo M, Catani L, Vianelli N.
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Ruxolitinib ,medicine.medical_specialty ,Anemia ,Socio-culturale ,Myelofibrosis ,Gastroenterology ,MYSEC-PM ,Efficacy ,03 medical and health sciences ,Essential ,0302 clinical medicine ,Polycythemia vera ,Internal medicine ,Nitriles ,Risk scores ,Humans ,Medicine ,Thrombocythemia ,Polycythemia Vera ,Survival rate ,Janus Kinases ,business.industry ,Essential thrombocythemia ,IPSS ,Myelofibrosi ,Hematology ,Prognosis ,medicine.disease ,Primary Myelofibrosis ,Pyrazoles ,Survival Rate ,Thrombocythemia, Essential ,Pyrimidines ,International Prognostic Scoring System ,030220 oncology & carcinogenesis ,Risk score ,business ,IPSS, MYSEC-PM, Myelofibrosis, Risk scores, Ruxolitinib ,030215 immunology ,medicine.drug - Abstract
Recently, the myelofibrosis secondary to PV and ET prognostic model (MYSEC-PM) was introduced to assess prognosis in myelofibrosis (MF) secondary to polycythemia vera and essential thrombocythemia (post-PV and post-ET MF), replacing the International Prognostic Scoring System (IPSS) and/or Dynamic IPSS (DIPSS) that was applied for primary MF (PMF). In a cohort of 421 ruxolitinib (RUX)-treated patients (post-PV and post-ET MF: 44.2%), we evaluated the following: (1) disease phenotype, responses, and toxicity to RUX; and (2) performance of the MYSEC-PM in post-PV or post-ET ME. While the IPSS failed to correctly stratify post-PV or post-ET MF patients at diagnosis, the MYSEC-PM identified 4 risk categories projected at significantly different survival probability (P < .001). Additionally, the MYSEC-PM maintained a prognostic value in post-PV and post-ET MF also when used over time, at RUX start. Notably, the MYSEC-PM reclassified 41.8% and 13.6% of patients into a lower and higher risk category, respectively. Finally, patients at intermediate-1 risk had significantly higher spleen responses and lower hematological toxicities compared to higher risk patients. Compared to PMF, post-PV and post-ET MF presented a more hyperproliferative disease, with higher leukocyte and/or platelet count and hemoglobin levels both at diagnosis and at RUX start. Despite comparable response rates, post-PV and post-ET MF had lower rate of RUX-induced anemia and thrombocytopenia at 3 and 6 months. The study validates MYSEC-PM in post-PV and post-ET MF prognostication. Post-PV or post-ET MF represents a separate entity compared to PMF in terms of clinical manifestations and toxicity to RUX. (C) 2018 Elsevier Inc. All rights reserved.
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- 2018
32. Fetal head circumference and subpubic angle are independent risk factors for unplanned cesarean and operative delivery
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Domenico Arduini, Elisa Aiello, Giuseppe Rizzo, Francesco D'Antonio, and Costanza Bosi
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Adult ,medicine.medical_specialty ,Cephalometry ,3D ultrasound ,dystocia ,head circumference ,labor ,operative delivery ,subpubic angle ,unplanned cesarean section ,Logistic regression ,Ultrasonography, Prenatal ,Labor Presentation ,Pelvis ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Pregnancy ,Risk Factors ,medicine ,Fetal distress ,Humans ,Fetal head ,030212 general & internal medicine ,Prospective Studies ,Prospective cohort study ,Gynecology ,030219 obstetrics & reproductive medicine ,business.industry ,Cesarean Section ,Cephalic presentation ,Area under the curve ,Obstetrics and Gynecology ,General Medicine ,medicine.disease ,Gestation ,Female ,Settore MED/40 - Ginecologia e Ostetricia ,business ,Head - Abstract
Introduction To ascertain whether combined ultrasound assessment of fetal head circumference (HC) and maternal subpubic angle (SPA) prior to the onset of labour may predict the likelihood of an unplanned operative delivery (UOD) in nulliparous women at term. Material and methods Prospective cohort study of singleton pregnancies in cephalic presentation. Pregnancies experiencing UOD secondary to fetal distress were excluded. HC was assessed transabdominally and SPA values were obtained from a reconstructed coronal plane on three-dimensional (3D) ultrasound performed translabially at 36–38 weeks of gestation. Maternal characteristics, HC expressed as multiple of median, and SPA were compared according to the mode of delivery. Logistic regression and receiver operating characteristics curve analyses were used to analyze the data. Results 597 pregnancies were included in the study. Spontaneous vaginal delivery occurred in 70.2% of the cases and UOD was required in 29.8%. There was no difference in pregnancy characteristics and birthweight between women who had a spontaneous vaginal birth compared with UOD. The HC multiple of median was larger (1.00 ± 0.02 vs. 1.03 ± 0.02, p ≤ 0.0001), whereas SPA was narrower in the UOD group (124.02 ± 13.64 vs. 102.61 ± 16.13, p ≤ 0.0001). At logistic regression, SPA (OR 0.91, 95% CI 0.89–0.93), HC multiple of median (OR 1.13, 95% CI 1.09–1.17) and maternal height (OR 0.95, 95% CI 0.92–0.99) were independently associated with UOD. When combined, the diagnostic accuracy of a predictive model integrating HC, SPA and maternal height was highly predictive of UOD with an area under the curve of 0.904 (95% CI 0.88–0.93). Conclusions Ultrasound assessment of fetal HC and maternal SPA after 36 weeks of gestation can identify a subset of women at higher risk of UOD during labor, for whom early planned delivery might be beneficial.
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- 2017
33. Baseline factors associated with response to ruxolitinib: An independent study on 408 patients with myelofibrosis
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Micaela Bergamaschi, Alessia Tieghi, Bruno Martino, Monica Crugnola, Massimo Breccia, Adalberto Ibatici, Nicola Vianelli, Massimiliano Bonifacio, Giulia Benevolo, Mariella D'Adda, Barbara Anaclerico, Michele Cavo, Marco Spinsanti, Elisa Cerqui, Roberto Latagliata, Francesco Cavazzini, Elisabetta Abruzzese, Giuseppe A. Palumbo, Federico De Marchi, Giovanna De Matteis, Costanza Bosi, Roberto M. Lemoli, Franco Aversa, Elena Sabattini, Ambra Di Veroli, Francesco Di Raimondo, Renato Fanin, Luigi Scaffidi, Maria Letizia Bacchi Reggiani, Antonio Cuneo, Domenico Russo, Mario Tiribelli, Lucia Catani, Francesca Palandri, Umberto Vitolo, Nicola Polverelli, Francesco Merli, Palandri, Francesca, Palumbo, Giuseppe Alberto, Bonifacio, Massimiliano, Tiribelli, Mario, Benevolo, Giulia, Martino, Bruno, Abruzzese, Elisabetta, D'Adda, Mariella, Polverelli, Nicola, Bergamaschi, Micaela, Tieghi, Alessia, Cavazzini, Francesco, Ibatici, Adalberto, Crugnola, Monica, Bosi, Costanza, Latagliata, Roberto, Di Veroli, Ambra, Scaffidi, Luigi, de Marchi, Federico, Cerqui, Elisa, Anaclerico, Barbara, De Matteis, Giovanna, Spinsanti, Marco, Sabattini, Elena, Catani, Lucia, Aversa, Franco, Di Raimondo, Francesco, Vitolo, Umberto, Lemoli, Roberto Massimo, Fanin, Renato, Merli, Francesco, Russo, Domenico, Cuneo, Antonio, Bacchi Reggiani, Maria Letizia, Cavo, Michele, Vianelli, Nicola, and Breccia, Massimo
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medicine.medical_specialty ,Ruxolitinib ,Bone marrow transplant ,Socio-culturale ,Myelofibrosis ,Clinical biochemistry ,predictive factor ,03 medical and health sciences ,0302 clinical medicine ,Disease severity ,myelofibrosi ,Internal medicine ,medicine ,myelofibrosis ,predictive factors ,response ,ruxolitinib ,splenomegaly ,Hematology ,business.industry ,Response ,University hospital ,medicine.disease ,Transplantation ,Oncology ,030220 oncology & carcinogenesis ,Splenomegaly ,Predictive factors ,Clinical Research Paper ,business ,030215 immunology ,medicine.drug - Abstract
// Francesca Palandri 1 , Giuseppe Alberto Palumbo 2 , Massimiliano Bonifacio 3 , Mario Tiribelli 4 , Giulia Benevolo 5 , Bruno Martino 6 , Elisabetta Abruzzese 7 , Mariella D’Adda 8 , Nicola Polverelli 9 , Micaela Bergamaschi 10 , Alessia Tieghi 11 , Francesco Cavazzini 12 , Adalberto Ibatici 13 , Monica Crugnola 14 , Costanza Bosi 15 , Roberto Latagliata 16 , Ambra Di Veroli 17 , Luigi Scaffidi 3 , Federico de Marchi 4 , Elisa Cerqui 8 , Barbara Anaclerico 18 , Giovanna De Matteis 19 , Marco Spinsanti 1 , Elena Sabattini 1 , Lucia Catani 1 , Franco Aversa 14 , Francesco Di Raimondo 2 , Umberto Vitolo 5 , Roberto Massimo Lemoli 10 , Renato Fanin 4 , Francesco Merli 11 , Domenico Russo 9 , Antonio Cuneo 12 , Maria Letizia Bacchi Reggiani 20 , Michele Cavo 1 , Nicola Vianelli 1 and Massimo Breccia 16 1 Institute of Hematology “L. and A. Seragnoli”, Sant'Orsola-Malpighi University Hospital, Bologna, Italy 2 Division of Hematology, AOU 'Policlinico-V.Emanuele', Catania, Italy 3 Department of Hematology, University of Verona, Verona, Italy 4 Division of Hematology and BMT, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy 5 Division of Hematology, Citta della Salute e della Scienza Hospital, Torino, Italy 6 Division of Hematology, Azienda Ospedaliera 'Bianchi Melacrino Morelli', Reggio Calabria, Italy 7 Division of Hematology, Ospedale S. Eugenio, Roma, Italy 8 Division of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy 9 Unit of Blood Diseases and Stem Cell Transplantation, ASST Spedali Civili di Brescia, Brescia, Italy 10 Division of Hematology, IRCCS AOU San Martino-IST, Genova, Italy 11 Department of Hematology, A.O. Arcispedale Santa Maria Nuova – IRCCS, Reggio Emilia, Italy 12 Division of Hematology, University of Ferrara, Ferrara, Italy 13 Division of Hematology and Bone Marrow Transplant, IRCCS San Martino-IST, Genova, Italy 14 Division of Hematology, AOU of Parma, Parma, Italy 15 Department of Hematology and Bone Marrow Transplantation, A.O. of Piacenza, Italy 16 Division of Cellular Biotechnologies and Hematology, University Sapienza, Roma, Italy 17 Division of Hematology, Policlinico Tor Vergata, Roma, Italy 18 Division of Hematology, Ospedale S. Giovanni, Roma, Italy 19 Department of Life and Reproduction Sciences, Section of Clinical Biochemistry, University of Verona, Verona, Italy 20 Division of Cardiology, University of Bologna, Bologna, Italy Correspondence to: Francesca Palandri, email: francesca.palandri@unibo.it Keywords: myelofibrosis, splenomegaly, response, ruxolitinib, predictive factors Received: March 29, 2017 Accepted: May 15, 2017 Published: June 27, 2017 ABSTRACT In patients with Myelofibrosis (MF) treated with ruxolitinib (RUX), the response is unpredictable at therapy start. We retrospectively evaluated the impact of clinical/laboratory factors on responses in 408 patients treated with RUX according to prescribing obligations in 18 Italian Hematology Centers. At 6 months, 114 out of 327 (34.9%) evaluable patients achieved a spleen response. By multivariable Cox proportional hazard regression model, pre-treatment factors negatively correlating with spleen response were: high/intermediate-2 IPSS risk ( p =0.024), large splenomegaly ( p =0.017), transfusion dependency ( p =0.022), platelet count 2 years ( p =0.048). Also, patients treated with higher (≥10 mg BID) average RUX doses in the first 12 weeks achieved higher response rates ( p =0.019). After adjustment for IPSS risk, patients in spleen response at 6 months showed only a trend for better survival compared to non-responders. At 6 months, symptoms response was achieved by 85.5% of 344 evaluable patients; only a higher (>20) Total Symptom Score significantly correlated with lower probability of response ( p
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- 2017
34. PF674 OUTCOME OF PATIENTS WITH MYELOFIBROSIS AFTER RUXOLITINIB DISCONTINUATION: ROLE OF DISEASE STATUS AND TREATMENT STRATEGIES IN 218 PATIENTS
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Francesca Palandri, Nicola Sgherza, Florian H. Heidel, E Abruzzese, G. Semenzato, Alessandro Isidori, F. Di Raimondo, Costanza Bosi, Elena Maria Elli, M Crugnola, Mauro Krampera, Nicola Polverelli, Davide Griguolo, Robert Foa, G.A. Palumbo, F. Cavazzini, Bruno Martino, Umberto Vitolo, Roberto M. Lemoli, Daniele Cattaneo, Nicola Vianelli, Alessia Tieghi, Massimo Breccia, Malgorzata Monika Trawinska, Giuseppe Auteri, A. Iurlo, Michele Cavo, Giulia Benevolo, Mario Tiribelli, Gianni Binotto, Lucia Catani, Luigi Scaffidi, Roberto Latagliata, Antonio Cuneo, Massimiliano Bonifacio, Micaela Bergamaschi, and Daniela Bartoletti
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Ruxolitinib ,Disease status ,medicine.medical_specialty ,business.industry ,Hematology ,medicine.disease ,Outcome (game theory) ,Discontinuation ,Internal medicine ,medicine ,Treatment strategy ,Myelofibrosis ,business ,medicine.drug - Published
- 2019
35. Comparison of Two Different Therapeutic Regimens with Azacitidine and Lenalidomide (Combined versus Sequential) in Higher-Risk Myelodysplastic Syndromes. Update of Long-Term Results of a Randomized Phase II Multicenter Study
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Sara Mongiorgi, Barbara Castagnari, Anna Candoni, Carlo Finelli, Lucio Cocco, Michele Cavo, Isabella Capodanno, Patrizia Tosi, Andrea Pellagatti, Maria Benedetta Giannini, Gian Matteo Rigolin, Miriam Fogli, Sarah Parisi, Cristina Clissa, Jacqueline Boultwood, Domenico Russo, Giovanna Leonardi, Matilde Y. Follo, Monica Crugnola, Costanza Bosi, and Marco Gobbi
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Oncology ,medicine.medical_specialty ,Intention-to-treat analysis ,Surrogate endpoint ,business.industry ,Myelodysplastic syndromes ,Immunology ,Azacitidine ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Combined Modality Therapy ,030212 general & internal medicine ,Adverse effect ,business ,030217 neurology & neurosurgery ,medicine.drug ,Lenalidomide - Abstract
Introduction. The association of Azacitidine (AZA) and Lenalidomide (LEN), either administered concurrently (Sekeres, 2010; 2012; 2017), or sequentially (Platzbecker, 2013; Di Nardo 2015; Mittelman 2016; Narayan 2016) has proven effective in Myelodysplastic Syndromes (MDS), however the optimum dose and schedule remains unknown. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in higher-risk MDS pts. Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the IWG criteria (Cheson, 2006). Secondary endpoints: a) rate of CR; b) duration of responses; c) overall survival (OS). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS with IPSS risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles. For responder patients the same treatment was continued until disease progression or unacceptable toxicity. Results. From March 2013, 44 pts (27 males), median age: 72 (48-83 yrs) were enrolled, from 13 hematologic Centers. At baseline, IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled because of severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts. In 5 pts (11.4%) del(5q) was present (additional cytogenetic alterations: 1 in 1 pt, and > 1 in 4 pts , respectively). 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. Treatment was given for a median of 8.5 (1-52) cycles; in ARM 1: 9 (1-51) cycles; in ARM 2: 8 (1-52) cycles, respectively. Median follow-up: 15 (2-54) months; 47 (37-54) months for survivors. 10/44 pts (22.7%) did not complete at least 6 cycles of treatment for causes other than disease progression (6 pts for adverse events, 2 pts for consent withdrawal and 2 pts for medical decision), and were not considered evaluable for response. Among the 34/44 pts (77.3%) evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. Intention-to-treat (ITT) analysis: ORR: 59.1%. First response was observed after a median of 2 (1-8) cycles. The Best Response achieved was: CR: 8 pts (23.5%) (ITT: 18.1%), PR: 1 pt (2.9%) (ITT: 2.2%), mCR: 3 pts (8.8%) (ITT: 6.8%), HI: 8 pts (23.5%) (ITT: 18.1%), mCR+HI: 6 pts (17.6%) (ITT: 13.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). Among the 27 pts (21 evaluable for response) with an abnormal karyotype at baseline, ORR was 66.7% (ITT: 51.8%) and 4 pts achieved complete cytogenetic response. Median duration of hematologic response: 10.5 months. 34 pts (77,3%) died , and 17 pts (38.6%) showed progression to AML. Grade >2 non haematological toxicity: 54.5%. Median OS: 15 months. No significant differences between the 2 arms were observed, in terms of ORR (ARM 1: 76.5%, ITT: 61.9%; ARM 2: 76.5%, ITT: 56.5%), CR rate (ARM 1: 17.6%, ITT: 14.3%; ARM 2: 29.4%, ITT: 21.7%), grade >2 non haematological toxicity (ARM 1: 66.7%; ARM 2: 43.5%), AML incidence (ARM 1: 28.6%; ARM 2: 47.8%) and OS (ARM 1: 14 months; ARM 2: 16 months), but the median response duration was significantly longer in ARM 2 (18 months) as compared to ARM 1 (6 months) (p=0.0459). At the time of last analysis, 5/44 (11.4%) patients, 1/21 (4.8%) in ARM 1, and 4/23 (17.4%) in ARM 2, were still maintaining the haematological response, and were still in treatment, after 54, 54, 52, 51 and 37 months, and after 52, 51, 33, 48 and 35 cycles of therapy, respectively. The changes observed during treatment in mutational status of inositide-specific genes and microRNA expression profiling were related to clinical outcome, predicting a negative response to therapy. Conclusions. Our results confirm the efficacy of both AZA+LEN treatment regimens in higher-risk MDS pts, in terms of ORR and OS, although pts treated with the sequential regimen showed a significantly longer duration of haematological response. Disclosures Finelli: Celgene: Other: speaker fees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: speaker fees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees. Candoni:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Merck SD: Honoraria, Speakers Bureau. Gobbi:Novartis: Consultancy; Janssen: Consultancy; Ariad: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees. Rigolin:Gilead: Research Funding. Cavo:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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- 2018
36. Outcome of Patients with Myelofibrosis after Ruxolitinib Failure: Role of Disease Status and Treatment Strategies in 214 Patients
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Nicola Vianelli, Elena Maria Elli, Antonio Cuneo, Giuseppe Auteri, Alessia Tieghi, Gianni Binotto, Nicola Polverelli, Mauro Krampera, Elisabetta Abruzzese, Lucia Catani, Francesco Di Raimondo, Costanza Bosi, Gianpietro Semenzato, Franco Aversa, Roberto Latagliata, Daniele Cattaneo, Francesco Cavazzini, Luigi Scaffidi, Massimiliano Bonifacio, Michele Cavo, Roberto M. Lemoli, Robin Foà, Nicola Sgherza, Giuseppe A. Palumbo, Umberto Vitolo, Francesca Palandri, Alessandra Iurlo, Giulia Benevolo, Massimo Breccia, Alessandro Isidori, Micaela Bergamaschi, Monica Crugnola, and Daniela Bartoletti
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Ruxolitinib ,medicine.medical_specialty ,Disease status ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Fedratinib ,Discontinuation ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Survival probability ,030220 oncology & carcinogenesis ,Family medicine ,medicine ,Treatment strategy ,Myelofibrosis ,business ,030215 immunology ,medicine.drug - Abstract
Introduction . Ruxolitinib (RUX) is the only targeted therapy available for the treatment of myelofibrosis (MF)-related splenomegaly and symptoms. Significant clinical responses may be achieved in around 50% of patients (pts). However, half of responding pts lose the response over time. Aims . To report the outcome of a large cohort of MF pts after RUX failure, in terms of disease status, treatment strategies and survival. Methods . A clinical database was created in 23 European Hematology Centers including retrospective data of 537 MF pts treated with RUX from Jan 2011 to July 2018. Updated information at the date of July 15th 2018 was available in 442 pts who were included in the present analysis. Spleen and symptoms response (SR & SyR) to RUX were evaluated according to the 2013 IWG-MRT criteria. RUX-related toxicity and infections were graded according to the WHO scale. Overall (OS) was estimated from the date of RUX discontinuation to the date of death or last contact, using the Kaplan-Meyer method (log-rank test). Results . After a median follow-up of 30.5 months (1.7-84.3), 214 out of 442 evaluable (48.4%) pts had discontinued RUX. 43 (20.1%) died while on therapy because of: MF progression (34.9%), infections (25.6%), heart disease (16.3%), second neoplasia (7%), hemorrhages (7%), other (9.2%). The median follow-up after RUX discontinuation for the remaining 171 pts was 11.3 months (0.5-66.7). Causes of RUX discontinuation were: drug-related toxicity (28.6%), loss/lack of response (23.4%), MF progression (12.3%), acute leukemia (AL) (13.4%), allogeneic stem cell transplantation (ASCT) (11.1%), second solid neoplasia (4.1%), other unrelated causes (i.e. pts decision; 7.1%). After stopping RUX, 68 pts received 1 line of therapy, 21 received 2 lines and 9 received >2 treatments; 73 pts did not receive any therapy. Treatments received after RUX discontinuation, alone or in combination, included hydroxyurea (HU) (n. 61, 62.2%), ASCT (n. 20, 20.4%), second-generation JAK2 inhibitors (momelotinib/fedratinib/pacritinib) (n. 11, 11.2%), splenectomy (n. 7, 7.1%), azacytidine/decitabine (n. 5, 5.1%), chemotherapy (n. 4, 4.1%), investigational agents (imetelstat/PRM151: n. 4), danazole (n. 4), erythropoietin-stimulating agents (ESA) (n. 4). A total of 95 pts (55.6%) died after RUX discontinuation, because of: MF progression (30.5%), AL (25.4%), infections (14.7%), second neoplasia (9.5%), hemorrhages (4.2%), heart disease (4.2%), ASCT (4.2%), thrombosis (2.1%), other (5.2). Median survival time from RUX stop of the 171 evaluable pts was 22.6 mos (95% CI, 13.2-30.7). Among baseline features, survival after discontinuation was significantly influenced by the dynamic international prognostic score (DIPSS) category (p During therapy, 45 out of 153 (29.4%) and 123 out of 161 (76.4%) evaluable pts achieved a SR and a SyR at any time. Survival was not affected by the previous response to RUX at any time-point. Conversely, survival significantly differed according to the reason for stopping RUX, with pts discontinuing because of AL evolution/second solid neoplasia having the worst outcome (Figure 1a, p Discussion . After RUX failure, very limited therapeutic options are available and the prognosis of MF pts is dismal, particularly for those pts starting RUX with advanced stage disease (i.e. high DIPSS category and transfusion dependency). Also, disease evolution into AL and occurrence of a second solid neoplasia significantly reduced life expectancy. In chronic phase pts, survival probability may be improved by the use of medical therapies that are still in the experimental phase. Novel investigational agents are needed. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Abruzzese:BMS: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Aversa:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Astellas: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cuneo:Gilead: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Foà:ROCHE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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- 2018
37. Presentation and Outcome of 199 Patients with 2016 Who Diagnosis of Early and Overt Primary Myelofibrosis Treated with Ruxolitinib
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Gianni Binotto, Nicola Sgherza, Massimo Breccia, Daniele Cattaneo, Malgorzata Monika Trawinska, Alessandro Isidori, Nicola Vianelli, Roberto Latagliata, Gianpietro Semenzato, Francesco Cavazzini, Micaela Bergamaschi, Lucia Catani, Michele Cavo, Monica Crugnola, Daniela Bartoletti, Luigi Scaffidi, Giulia Benevolo, Giuseppe A. Palumbo, Giuseppe Auteri, Nicola Polverelli, Massimiliano Bonifacio, Francesco Di Raimondo, Costanza Bosi, Elena Maria Elli, Franco Aversa, Elisabetta Abruzzese, Antonio Cuneo, Mauro Krampera, Francesca Palandri, Roberto M. Lemoli, Alessandra Iurlo, Umberto Vitolo, Alessia Tieghi, and Robin Foà
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Ruxolitinib ,medicine.medical_specialty ,business.industry ,Immunology ,Context (language use) ,Cell Biology ,Hematology ,Hemoglobin levels ,medicine.disease ,Biochemistry ,Response to treatment ,Prognostic score ,Transplantation ,Internal medicine ,Cox proportional hazards regression ,medicine ,Myelofibrosis ,business ,medicine.drug - Abstract
Introduction . The 2016 WHO criteria identified early primary myelofibrosis (early-PMF) as an individual entity with different clinical/laboratory presentations and a significantly better outcome compared to overt PMF. No information is available on the therapeutic effects of ruxolitinib (RUX) in the context of each disease separately. Aims . To report the differences between early and overt PMF patients (pts) treated with RUX in terms of baseline clinical/laboratory characteristics, response to treatment and toxicity. Methods . A clinical database was created in 23 European Hematology Centers including retrospective data of 537 MF pts treated with RUX from Jan 2011 to July 2018. Spleen and symptoms response (SR & SyR) to RUX were evaluated according to the 2013 IWG-MRT criteria. Hematologic toxicity and infections were graded according to the WHO scale. Overall survival (OS) and progression-free survival (PFS) were estimated from diagnosis using the Cox proportional hazards regression model, with adjustment for the dynamic international prognostic score system (DIPSS) and left-truncation. Results . A total of 199 pts had a diagnosis of early (n. 59, 29.7%) or overt (n. 140, 70.3%) PMF confirmed by bone marrow biopsy at RUX start and were included in this analysis. At RUX start, median age was 68.4 yrs (26.5-88.9) and 66.3% of pts had a spleen palpable at ≥10 cm below the left costal margin (LCM) (median spleen length: 12 cm). Median hemoglobin value and total symptoms score (TSS) were 10.5 g/dL and 20 (0-80), respectively. DIPSS distribution was: intermediate-1 (50.5%), intermediate-2 (42.1%), high (7.4%). Molecular status was: JAK2V617F 72.3%, CALR 13.7%, MPLW515K/L 3.1%, triple-negative 5%. Median time from diagnosis to RUX start was 22.4 mos (0.1-394). Compared to overt PMF pts, pts with early PMF started RUX with higher hemoglobin levels (median, 11.6 vs 10.4 g/dl, p=0.01) and lower circulating blast counts (p At 3 and 6 months, 43.1% and 48.9% of early-PMF pts achieved a SR, compared to 27.9% and 31.3% of overt-MF pts (p=0.04 and p=0.04, respectively). The rate of SyR was also higher in early-PMF pts at 3 months (82.5% vs 68.8%, p=0.05) and at 6 months (90.0 vs 73.7, p=0.02). In the first 12 months from RUX start, anemia/thrombocytopenia of all grades occurred in 75.6%/43.1% and 86.3%/60.0% of early and overt PMF pts, respectively (p=0.11 and p=0.03). At 3 months, anemia was more frequent in overt PMF pts (94.7% vs 80.0%, p=0.01), with 32.6% of pts having a grade 3-4 anemia compared to 17.8% in early PMF (p=0.02). The incidence of thrombocytopenia was also higher in overt PMF at 3 (51.5% vs 36.2%, p=0.05) and 6 (52.9% vs 35.8%, p=0.04) months, with only 2.2% and 2.5% of pts having a grade 3-4 thrombocytopenia, respectively. Seventy-five pts had at least one grade ≥2 infectious episode during RUX therapy. Considering death as competing risk, the cumulative risk of infections grade ≥2 was comparable in the two cohorts (p=0.4). Overall, 108 pts discontinued RUX (52.5% and 55.0% of early and overt PMF pts, p=0.7). Evolution into acute leukemia (AL) occurred in 21 pts. After a median follow-up of 23 months, 69 pts died (19 early), specifically because of progression of myelofibrosis (38%), AL (16.9%), infections (11.3%), hemorrhage/thrombosis (12.6%), second neoplasias (8.5%) or transplant-associated toxicity (2.8%), other causes (9.9%). OS (p=0.88) and PFS (p=0.86) were comparable in early and overt PMF pts. Conclusions . This study indicates for the first time that early PMF represents a category of pts that is projected to have better responses and lower toxicities from RUX treatmemt. In the setting of RUX therapy, a WHO-defined diagnosis may contribute to better identify pts who may deserve a strict monitoring during treatment. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Ariad: Consultancy. Foà:INCYTE: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau. Vitolo:Takeda: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Sandoz: Speakers Bureau. Aversa:Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cuneo:Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria.
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- 2018
38. Prognostic Role of Neutrophil to Lymphocyte Ratio (NLR) in Myelofibrosis Patients Treated with Ruxolitinib: A Multi-Center Experience
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Alessandra Romano, Gianpietro Semenzato, Nicola Polverelli, Srdan Verstovsek, Antonio Cuneo, Daniele Cattaneo, Francesco Di Raimondo, Monica Crugnola, Nicola Sgherza, Lucia Catani, Umberto Vitolo, Costanza Bosi, Elena Maria Elli, Daniela Bartoletti, Francesco Cavazzini, Franco Aversa, Francesca Palandri, Giulia Benevolo, Giuseppe A. Palumbo, Alessandro Isidori, Alessandra Iurlo, Gianni Binotto, Nicola Vianelli, Lucia Masarova, Michele Cavo, Luca Scalise, Micaela Bergamaschi, Massimiliano Bonifacio, Luigi Scaffidi, and Alessia Tieghi
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medicine.medical_specialty ,Ruxolitinib ,business.industry ,education ,Immunology ,Bone marrow fibrosis ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Clinical trial ,Internal medicine ,Cohort ,medicine ,Progression-free survival ,Neutrophil to lymphocyte ratio ,Myelofibrosis ,business ,health care economics and organizations ,Progressive disease ,medicine.drug - Abstract
Background Myelofibrosis (MF) is featured by an inflammatory condition that can also drive the progression of disease. Ruxolitinib (RUX) is the-first-in-class Jak1/2 inhibitor approved for treatment for MF. Clinical benefits of RUX are presumably derived from reduction of inflammatory cytokines even if the exact mechanism remains unclear. Recent reports have identified the ratio between absolute neutrophils count (ANC) and absolute lymphocyte count (ALC), called NLR, as a simple parameter that mirrors the inflammatory status and the myeloid associated immune suppression. In various malignancies NLR has been indicated as predictor of progression free survival (PFS) and overall survival (OS). Our preliminary work in a single-center experience showed that patients with NLR>6 before RUX start had a lower chance to obtain > 50% spleen reduction in the first 12 weeks or a complete resolution of splenomegaly at 24 weeks. Objective : We proposed to test NLR=6 as bio-marker in MF to apply into clinical practice as a possible predictor of response to RUX. Methods We used two separate cohorts to validate NLR (as a continuous variable and as a cut off 6) as predictor of response to RUX bases on our preliminary data from healthy volunteers (data not shown). Cohort (#1) including 111 MF patients from MD Anderson Cancer Center treated with RUX on phase 1/2 clinical trial from 2007 to 2010; and cohort (#2) including 367 patients treated at 18 Italian centers between years 2012 - 2018. Spleen responses to RUX treatment, PFS and OS were independently validated in cohorts #1 and 2. As cohort 1 included patients treated on clinical trial, spleen was assessed by MRI before and after 24 weeks of RUX therapy, and by physical examination at week 12. In cohort #2, spleen size was assessed by physical examination before, after 12 and 24 weeks of RUX continuous treatment in a real-life setting. NLR was calculated using data obtained from the complete blood count before RUX start and correlated with driver mutations, early spleen reduction, progression free survival (PFS), defined as time from RUX start to last follow-up or progressive disease (including progression to acute myeloid leukemia, ≥20% blasts in peripheral blood or bone marrow, AML) or death for any reason; and overall survival (OS). Results : Clinical and demographics characteristics of patients in each cohort are summarized in Table 1. In cohort #1 we found that NLR was lower in patients with lower bone marrow fibrosis (grade 0-1: 6.2±0.8 versus grade 2-3: 7.3±0.8, p=0.03). Similarly, in cohort #2, patients with grade 0-1 bone marrow fibrosis had lower NLR than those carrying grade 2-3 bone marrow fibrosis (7.7±0.7 versus 10.6±1.3, p=0.04). NLR was higher in patients carrying JAK2 (V617F) mutation (mean +/- SD, 6.4±0.6 vs 5.3±0.5, p=0.02 in cohort 1 and 9.1±0.6 vs 5.0±0.5, p=0.002 in cohort 2). While in cohort 1 NLR appeared lower in CALR (exon 9 indel) mutated patients, the difference was statistically significant in cohort 2 (5.4±0.8 vs 8.9±0.6, p=0.03). In both cohorts, there were no differences in NLR in either triple negative or MPL (exon 10) patients. In cohort 1, the mean percentage change from baseline in palpable spleen length was −47.7% at week 12 and −53.4% at week 24. NLR=6 was able to identify at baseline early response to RUX with 66.9% sensitivity and 72.3% specificity (HR 1.68, p=0.01). Patients with NLR>6 before RUX start had a lower chance to obtain a complete resolution of splenomegaly at 24 weeks (p=0.001). These observations were confirmed in cohort 2 where NLR > 6 was able to identify at baseline early response to RUX with 50.3% sensitivity and 67.7% specificity (HR 1.56, p=0.01). The mean percentage change from baseline in palpable spleen length was −60.3% at week 12 and −66.7% at week 24. Patients with NLR>6 before RUX start had a lower chance to obtain a complete resolution of splenomegaly at 24 weeks (p At the time of this analysis, 84/111 (75.6%) patients in cohort 1 and 122/367 (33.2%) in cohort 2 had died (p 6 was not a predictor of PFS or OS. Conclusions : NLR before RUX start could serve as a useful, simple and early predictor of spleen response in MF patients; and it positively correlates with JAK2 mutation and higher fibrosis grade. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vitolo:Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau. Cuneo:Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Aversa:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria. Cavo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Takeda: Honoraria, Research Funding; Celgene: Honoraria. Verstovsek:Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees.
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- 2018
39. Efficacy and Safety of Ruxolitinib in Elderly Patients (> 75 years) with Myelofibrosis
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Adalberto Ibatici, Francesca Palandri, Massimiliano Bonifacio, Bruno Martino, Barbara Anaclerico, Margherita Perricone, Costanza Bosi, Mariella D'Adda, Luca Petriccione, Monica Crugnola, Michele Cavo, Giulia Benevolo, Micaela Bergamaschi, Nicola Polverelli, Ambra Di Veroli, Mario Tiribelli, Giuseppe A. Palumbo, Massimo Breccia, Nicola Vianelli, Alessia Tieghi, Alessandro Andriani, Malgorzata Monika Trawinska, Marco Montanaro, Roberto Latagliata, Francesco Cavazzini, and Antonia Centra
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medicine.medical_specialty ,Ruxolitinib ,Anemia ,ruxolitinib ,Immunology ,Population ,Socio-culturale ,myelofibrosis ,elderly patients ,comorbidities ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,Internal medicine ,medicine ,education ,Myelofibrosis ,education.field_of_study ,Acute leukemia ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Discontinuation ,030220 oncology & carcinogenesis ,Cohort ,myelofibrosis, ruxolitinib, elderly patients, comorbidities ,business ,030215 immunology ,medicine.drug - Abstract
Background. Ruxolitinib (RUX) is the first commercially available JAK1/2 inhibitor that may control splenomegaly and systemic symptoms related to myelofibrosis (MF). Despite MF occur frequently in elderly patients (pts), no data are yet available on RUX efficacy and safety in this particularly frail population. Methods We report on 100 pts [M/F 57/43, median age at diagnosis 75.7 years, interquartile range (IQR) 72.3 - 78.0, median age at baseline of RUX treatment 77.7 years, IQR 76.2 - 80.3] with WHO-defined MF treated with RUX when aged ≥ 75 years. Data were extracted from the whole cohort of 408 pts of any age collected in a database involving 22 Italian Centers. Comorbidities were recorded at the time of diagnosis and classified according to the Charlson Comorbidity Index (CCI). Response to RUX was evaluated according to IWG-MRT criteria. Results Main clinical features after stratification according to age at RUX start are reported in Table 1. Compared to younger pts, elderly pts carried a higher number of co-morbidities and had lower hemoglobin and platelet values, thus starting RUX with lower doses. Time from diagnosis to RUX start was comparable among the two cohorts (median 15.5 months, IQR 4.6 - 66.7, vs 20.8 months, IQR 4.1 - 66.0, p=0.74). According to IWG criteria, a spleen response was achieved by 37 out of 90 (41.1%) evaluable elderly pts compared to 115 out of 272 (42.2%) pts Drug-related anemia (Hb Evolution into acute leukemia occurred in 8 (8.0%) elderly pts and in 22 (7.1%) younger pts, respectively (p=0.78), with a similar evolution-free survival from RUX initiation (p=0.35). As expected, 43 (43.0%) elderly pts and 53 (17.3%) younger pts died (p The 4-year cumulative Event-Free Survival (taking into account: RUX discontinuation, blastic evolution and death for any cause) was 30.1% (95% CI: 16.2 - 44.0) in elderly pts and 46.1% (95% CI 37.3 - 54.9) in younger subjects, respectively (p=0.002). Conclusions. Despite the elderly carried a higher number of comorbidities and were treated with lower starting and titrated doses of RUX,RUX was feasible and effective in this setting, achieving clinical responses similar to younger subjects, with comparable toxicity rates. Thus, the study do not support to restrain the use of RUX based on older age and comorbidities. Figure Figure. Disclosures Latagliata: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Bonifacio:Ariad Pharmaceuticals: Consultancy; Amgen: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Tiribelli:Novartis: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. Cavo:Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Celgene: Honoraria, Research Funding. Breccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria.
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- 2016
40. Predictors for Response to Ruxolitinib in Real-Life: An Observational Independent Study on 408 Patients with Myelofibrosis
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Francesco Merli, Federico De Marchi, Adalberto Ibatici, Elisa Cerqui, Micaela Bergamaschi, Michele Cavo, Francesco Di Raimondo, Umberto Vitolo, Bruno Martino, Giulia Benevolo, Barbara Anaclerico, Massimo Breccia, Nicola Polverelli, Renato Fanin, Mario Tiribelli, Costanza Bosi, Giuseppe A. Palumbo, Luigi Scaffidi, Monica Crugnola, Elisabetta Abruzzese, Mariella D'Adda, Roberto M. Lemoli, Nicola Vianelli, Francesca Palandri, Ambra Di Veroli, Roberto Latagliata, Massimiliano Bonifacio, Francesco Cavazzini, Antonio Cuneo, Alessia Tieghi, and Domenico Russo
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Ruxolitinib ,medicine.medical_specialty ,ruxolitinib ,Immunology ,Socio-culturale ,myelofibrosis ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,myelofibrosis, ruxolitinib, predictors of response ,Disease severity ,Internal medicine ,medicine ,In real life ,Myelofibrosis ,Univariate analysis ,business.industry ,Disease progression ,Cell Biology ,Hematology ,medicine.disease ,predictors of response ,030220 oncology & carcinogenesis ,Observational study ,business ,Bristol-Myers ,030215 immunology ,medicine.drug - Abstract
Background: Response to ruxolitinib (RUX), the only JAK1/2 inhibitor commercially available for the treatment of Myelofibrosis (MF) may vary among patients (pts) and is largely unpredictable at therapy start. Therefore, pts' selection is based only on clinical needs. Aims: To evaluate the impact of pre-treatment clinical/laboratory factors, as well as RUX dose, on response to RUX in a cohort of "real-life" MF pts. Methods: A multicenter observational study on WHO-defined MF was conducted in 18 Italian Hematology Centers. Data were extracted from a database that included retrospective data on pts treated before January 2015. Subsequently, data were prospectively collected and updated at a 6-month interval.Response to RUX was evaluated according to IWG-MRT criteria. Results: Between June 2011 and Apr 2016, 408 pts with PMF (54.4%), or postET (27.7%) / post-PV (17.9%) were treated with RUX. At RUX start, baseline characteristics were (median): age, 68.5 y (range, 26.5-89); ≥65 y, 63.5%; male, 56.4%; hemoglobin (Hb), 10.7 g/dL (7-16.7); transfusion-dependence 27.9%; PLT, 256×109/L (50-1887); PLT Molecular data were available for 332 pts (81.4%) and was positive in 81% (JAK2V617F), 6.3% (CALR), 1% (MPLW515K/L); 2.7% (triple negative). 30 pts (9%) were JAK2V617Fnegative but did not receive further molecular evaluation. Karyotype was abnormal in 55 (26%) out of 210 evaluable pts (unfavorable: 8.1%). Median follow-up from MF diagnosis was 3.8 yr (0.3-29.6) and median RUX exposure was 20 mos (3-56.2). Overall, 152 out of 365 (42%) pts with spleen ≥5cm achieved a spleen response at any time during RUX therapy. At 3 and 6 mos, the response was achieved by 26.6% and 34.4% of evaluable pts, respectively. In univariate analysis, pre-treatment factors negatively correlating with spleen response were: transfusion dependence, platelet count ≤200x109/l, spleen palpable ≥10 cm below costal margin, grade 3 marrow fibrosis, intm-2/high IPSS risk and interval between MF diagnosis and RUX start ≥2y. Three variables remained significant in multivariate regression logistic analysis: large splenomegaly (HR: 2.05, 95%CI: 1.1-3.7; p=0.02), time-interval ≥2y (HR: 1.78, 95%CI:1.0-3.1; p=0.04) and transfusion dependency (HR: 1.95, 95%CI:1.0-3.7; p=0.04). Spleen response significantly correlated with the average RUX dose in the first 12 wks, with pts treated with doses ≥10 mg BID having better response rates (47.3% vs 26.6% if dose 360 pts had a TSS >10 at RUX start and 319 (88.6%) achieved a symptom response. In multivariate analysis, factors associated with worse responses were: transfusion dependency (HR: 3.15, 95%CI 1.5-6.4, p=0.001) and a baseline TSS >20 (HR: 6.7, 95%CI 3.2-13.8, p Drug-related anemia (acquisition of transfusion dependency or Hb 80 (19.6%) pts discontinued RUX because of: lack/loss of response (28.8%); drug-related toxicity (27.5%, specifically: thrombocytopenia, 16.2%; infection, 6.3%; anemia, 5%); disease progression with/without acute evolution (8.8%); death (13.8%); allogeneic transplant (8.8%); 2ndneoplasia (3.8%); other unrelated causes (8.5%). Summary/Conclusion: In a real-life setting, IWG-MRT-defined spleen and symptoms response rates were observed in 42% and 88.6% of evaluable pts, respectively. Disease severity (in terms of transfusion dependency and large splenomegaly) and a delay in RUX start ≥2yr from diagnosis identified pts with lower spleen response rates. Titrated doses Disclosures Palumbo: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Shire: Honoraria; Roche: Honoraria. Bonifacio:Novartis: Research Funding; Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Ariad Pharmaceuticals: Consultancy; Pfizer: Consultancy. Tiribelli:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Gilead: Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures. Fanin:Novartis: Speakers Bureau. Merli:Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Breccia:Ariad: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria; Pfizer: Honoraria.
- Published
- 2016
41. Assessment of cerebellar vermis biometry at 18–32 weeks of gestation by three-dimensional ultrasound examination
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Costanza Bosi, Domenico Arduini, Maria Elena Pietrolucci, Silvia Mammarella, Estelle Dijmeli, and Giuseppe Rizzo
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Biometry ,Pregnancy Trimester, Third ,Interclass correlation ,Gestational Age ,Ultrasonography, Prenatal ,Imaging, Three-Dimensional ,Pregnancy ,Reference Values ,Cerebellum ,Humans ,Medicine ,Fetal head ,3D ultrasound ,Observer Variation ,Reproducibility ,medicine.diagnostic_test ,business.industry ,Reproducibility of Results ,Obstetrics and Gynecology ,Gestational age ,Anatomy ,Sagittal plane ,Nomograms ,Cross-Sectional Studies ,medicine.anatomical_structure ,Pregnancy Trimester, Second ,Pediatrics, Perinatology and Child Health ,Cerebellar vermis ,Regression Analysis ,Gestation ,Female ,Settore MED/40 - Ginecologia e Ostetricia ,business - Abstract
The purpose of this study was to construct reference limits for cerebellar vermis (CV) dimensions measured on images reconstructed from three-dimensional (3D) ultrasonography and to evaluate these measurements reproducibility.3D ultrasound volumes were acquired transabdominally from an axial view of the fetal head in 342 fetuses cross-sectionally studied between 18 to 32 weeks of gestation. Offline analysis of fetal brain midsagittal plane was used to evaluate length and area of CV. The agreement between two-dimensional (2D) and 3D measurements as well as the interobserver variability in 3D measurements were assessed by interclass correlation coefficients (ICC).Adequate visualization of the midsagittal plane was obtained in 96.7% of the fetuses. CV length (r = 0.89, p 0.0001) and CV area (r = 0.93, p 0.0001) showed a significant linear growth with gestation. A good agreement was found between measurements from either 2D or 3D ultrasound views (CV length ICC 0.943, CV area ICC 0.940) as well as between measured obtained by different observers (CV length ICC 0.965, CV area ICC 0.905).Measurements of the CV can be obtained from the midsagittal plane of fetal brain reconstructed from 3D volumes acquired transabdominally. The constructed nomograms may facilitate the diagnosis of cerebellar abnormalities.
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- 2012
42. OP19.02: Maternal-fetal Doppler assessment in early labour and perinatal and delivery outcomes: a multicentre study
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Andrea Dall'Asta, Costanza Bosi, F. Figueras, Domenico Arduini, A. Cancemi, Giuseppe Rizzo, Tiziana Frusca, and Tullio Ghi
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Pediatrics ,medicine.medical_specialty ,Reproductive Medicine ,Radiological and Ultrasound Technology ,business.industry ,Obstetrics and Gynecology ,Medicine ,Maternal fetal ,Radiology, Nuclear Medicine and imaging ,General Medicine ,business - Published
- 2017
43. Addition of Lenalidomide to Azacitidine in Higher Risk Myelodysplastic Syndromes. Long-Term Results of a Randomized Phase II Multicenter Study
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Matilde Y. Follo, Anna Candoni, Lucio Cocco, Barbara Castagnari, Sara Mongiorgi, Diego Russo, Andrea Pellagatti, Carlo Finelli, Gian Matteo Rigolin, Patrizia Tosi, Giovanna Leonardi, Jacqueline Boultwood, Costanza Bosi, Michele Cavo, Paolo Avanzini, Marilena Barraco, Cristina Clissa, Marco Gobbi, Monica Crugnola, and Maria Benedetta Giannini
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Azacitidine ,Hematology ,Long term results ,medicine.disease ,Multicenter study ,Internal medicine ,medicine ,business ,Lenalidomide ,medicine.drug - Published
- 2017
44. Association of Azacitidine and Lenalidomide (Combined vs Sequential Treatment) in High-Risk Myelodysplastic Syndromes. Final Results of a Randomized Phase II Multicenter Study
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Sara Mongiorgi, Anna Candoni, Matilde Y. Follo, Cristina Clissa, Sarah Parisi, Maria Benedetta Giannini, Carlo Finelli, Marco Gobbi, Michele Cavo, Paolo Avanzini, Monica Crugnola, Giovanna Leonardi, Giuseppe Visani, Costanza Bosi, Marta Stanzani, Domenico Russo, Patrizia Tosi, Lucio Cocco, Gian Matteo Rigolin, and Barbara Castagnari
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medicine.medical_specialty ,azacitidine ,Immunology ,Azacitidine ,lenalidomide ,macromolecular substances ,Neutropenia ,Biochemistry ,Gastroenterology ,NO ,Internal medicine ,otorhinolaryngologic diseases ,Clinical endpoint ,MDS ,Medicine ,Adverse effect ,Lenalidomide ,business.industry ,Myelodysplastic syndromes ,MDS, azacitidine, lenalidomide, clinical trial ,clinical trial ,Cell Biology ,Hematology ,medicine.disease ,Sequential treatment ,carbohydrates (lipids) ,stomatognathic diseases ,International Prognostic Scoring System ,business ,medicine.drug - Abstract
Introduction. Azacitidine (AZA) is able to induce hematologic responses in 50-60 % of patients (pts) with Myelodysplastic Syndromes (MDS) and moreover to prolong survival in higher risk MDS pts. Recently, several studies have evaluated the efficacy and safety of combining, in high-risk MDS pts, AZA with Lenalidomide (LEN), either administered concurrently (Sekeres, 2010; 2012), or sequentially (Platzbecker, 2013), in both cases showing promising results, although in a limited number of pts. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in high-risk MDS pts (IPSS score risk: High or INT-2). Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the International Working Group (IWG) criteria (Cheson, 2006). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (WHO 2008 classification) with International Prognostic Scoring System (IPSS) risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles (32 weeks). For responder patients (CR, PR, mCR, or HI) the same treatment was continued until disease progression or unacceptable toxicity. A sample size of 44 pts was planned. Results. From March 2013, 44 pts (27 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, WHO diagnosis was: RCMD: 2 pts; RCMD-RS: 1 pt ; RAEB-1: 11 pts; RAEB-2: 30 pts; IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled because of severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts; IPSS cytogenetic risk was: Good: 17 pts; Intermediate: 11 pts; Poor: 14 pts; N.D.: 2 pts. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. At the time of this analysis, enrolment of the planned 44 pts was completed. 34/44 pts (77.3%) completed ≥ 6 cycles of treatment, and are evaluable for response. The remaining 10 pts (4 in ARM 1 and 6 in ARM 2) are not evaluable for response, as they discontinued treatment before completing the 6th cycle because of adverse events (6 pts, 13.6%), consent withdrawal (2 pts, 4.5%) or medical decision (2 pts, 4.5%), respectively. Treatment was given for a median of 8 (1-28) cycles; in ARM 1: 9 (1-22) cycles, in ARM 2: 8 (1-28) cycles, respectively. Among the 34 pts evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. The Best Response achieved was: CR: 8 pts (23.5%), PR: 1 pt (2.9%), mCR: 3 pts (8.8%), HI: 8 pts (23.5%), mCR+HI: 6 pts (17.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). First Response was detected after a median of 2 (1-8) cycles. Responder pts were: 13/17 (ORR: 76.5 %) in ARM 1 (3 CR; 1 PR; 1 mCR; 4 HI, 4 mCR+HI), and 13/17 (ORR: 76.5 %) in ARM 2 (5 CR; 2 mCR; 4 HI; 2 mCR+HI), respectively. Overall, the median duration of response was 8.5 (2-23) months: 6 (2-19) months in ARM 1; 16 (2-23) months in ARM 2. A grade > 2 non hematologic toxicity was observed in 24/44 (54.5 %) pts (ARM 1: 66.7%; ARM 2: 43.5%). 27/44 pts (61.4 %) (ARM 1: 61.9%; ARM 2: 60.9%) had a dose reduction of LEN because of hematologic or non-hematologic toxicity. 22 pts (50%) died (ARM 1: 47.6%; ARM 2: 52.2%). 14 pts (31.8%) (ARM 1: 23.8%; ARM 2: 39.1%) showed progression to AML. Overall, median survival was 13 (1-28) months; ARM 1: 13 (1-25) months; ARM 2: 14 (2-28) months. Conclusions. Our results confirm the efficacy of both AZA + LEN treatment regimens in high-risk MDS pts. Moreover, at a molecular level, a significant increase of phosphoinositide-specific phospholipase C (PI-PLC) beta1 and/or PI-PLCgamma1 expression was associated with a favourable clinical response to treatment. Responder cases also showed an increase of Beta-globin expression, hinting at a specific contribution of LEN on erythroid activation Disclosures Finelli: Janssen: Other: Speaker; Novartis: Other: Speaker; Celgene: Other: Speaker, Research Funding. Visani:Celgene: Research Funding. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria.
- Published
- 2015
45. An increased expression of PI-PLCβ1 is associated with myeloid differentiation and a longer response to azacitidine in myelodysplastic syndromes
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Cristina Clissa, Anna Maria Billi, Sara Mongiorgi, Carlo Finelli, Lucia Manzoli, Lucio Cocco, Michele Malagola, Giulia Ramazzotti, Matilde Y. Follo, Giulia Adalgisa Mariani, Marilisa Quaranta, Sarah Parisi, Costanza Bosi, Domenico Russo, Marta Stanzani, Cocco, Lucio, Finelli, Carlo, Mongiorgi, Sara, Clissa, Cristina, Russo, Domenico, Bosi, Costanza, Quaranta, Marilisa, Malagola, Michele, Parisi, Sarah, Stanzani, Marta, Ramazzotti, Giulia, Mariani, Giulia A., Billi, Anna Maria, Manzoli, Lucia, and Follo, Matilde Y.
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Myeloid ,phospholipase C β1 ,Immunology ,Azacitidine ,Phospholipase C beta ,epigenetic therapy ,Biology ,Gene Expression Regulation, Enzymologic ,Internal medicine ,Gene expression ,medicine ,Immunology and Allergy ,Humans ,Myeloid Cells ,hematological malignancies ,Cyclin D3 ,Transcription factor ,Aged ,Aged, 80 and over ,Myelodysplastic syndromes ,Cell Differentiation ,Cell Biology ,gene expression ,methylation ,Middle Aged ,medicine.disease ,Hematologic Response ,medicine.anatomical_structure ,Myelodysplastic Syndromes ,Hematological malignancie ,Female ,Epigenetic therapy ,medicine.drug ,Follow-Up Studies ,Signal Transduction - Abstract
This study tested the hypothesis that PI-PLCβ1 is associated with myeloid differentiation and that its expression could be useful for predicting the response of MDS patients to azacitidine, as the clinical effect of epigenetic treatments is often detectable only after several cycles of therapy. To this end, PI-PLCβ1 was quantified on 70 MDS patients (IPSS risk: 13 Low, 20 Int-1, 31 Int-2, 6 High) at baseline and during the first 3 cycles of azacitidine. Results were then compared with the hematologic response, as assessed after the sixth cycle of azacitidine therapy. Overall, 60 patients completed 6 cycles of azacitidine, and for them, a clinical and molecular evaluation was possible: 37 of these patients (62%) showed a specific increase of PI-PLCβ1 mRNA within the first 3 cycles, which was associated with a longer duration of response and with an increased myeloid differentiation, as evidenced by PI-PLCγ2 induction and the recruitment of specific myeloid-associated transcription factors to the PI-PLCβ1 promoter during azacitidine response. Moreover, the increase of cyclin D3 gene expression throughout all of the therapy showed that PI-PLCβ1-dependent signaling is indeed activated in azacitidine responder patients. Taken together, our results show that PI-PLCβ1 quantification in MDS predicts the response to azacitidine and is associated with an increased myeloid differentiation.
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- 2014
46. Early Increase of Phospholipase Cbeta1 (PI-PLCbeta1) Gene Expression Predicts Azacitidine Responsiveness in MDS Patients
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Marco Gobbi, Lucia Manzoli, Cristina Clissa, Costanza Bosi, Marilisa Quaranta, Matilde Y. Follo, Domenico Russo, Michele Baccarani, Carla Filì, Carlo Finelli, Giovanni Martinelli, Sara Mongiorgi, Stefania Paolini, Anna Maria Billi, Lucio Cocco, Matilde Y Follo, Carlo Finelli, Cristina Clissa, Sara Mongiorgi, Carla Filì, Costanza Bosi, Marilisa Quaranta, Stefania Paolini, Anna Maria Billi, Marco Gobbi, Michele Baccarani, Domenico Russo, Giovanni Martinelli, Lucia Manzoli, and Lucio Cocco
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Disease progression ,Azacitidine ,SIGNAL TRANSDUCTION ,Complete remission ,Cancer ,MYELODISPLASTIC SYNDROME ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Hematologic Response ,Internal medicine ,Toxicity ,Gene expression ,Pi ,Medicine ,business ,medicine.drug - Abstract
Abstract 1289 Introduction. Azacitidine (AZA) is a DNA methyltransferase inhibitor currently approved for the treatment of high-risk MDS patients, which has been demonstrated to be feasible and effective also in low-risk MDS (Fenaux P et al, Lancet Oncol 2009; Musto P et al, Cancer 2010). However, at least 4 or 6 cycles of therapy are required for assessing the hematologic response, and predictive markers of responsiveness are still lacking. PI-PLCbeta1 plays a role in the MDS progression to AML and is a specific target for AZA therapy (Follo MY et al, PNAS 2009). Indeed, PI-PLCbeta1 has been demonstrated to be a dynamic marker for responsiveness to demethylating therapy, in that PI-PLCbeta1 mRNA increase or decrease could be associated with favourable response or failure, respectively. Stemming from these data, in this study we further investigated the role of PI-PLCbeta1 in MDS patients during AZA therapy. Methods. The study included 60 patients, 22 low-risk MDS (WHO: RA, RARS, RCMD, RAEB-1, and IPSS risk Low or Int-1), and 38 high-risk MDS (WHO: RCMD, RAEB-1, RAEB-2, and IPSS risk Int-1 or High). All the patients received a minimum of 6 cycles, in the absence of disease progression or unacceptable toxicity. Hematologic response was defined according to the revised IWG criteria (Cheson et al, Blood 2006). Positive clinical responses were defined as: Complete Remission (CR), Partial Remission (PR) or Hematologic Improvement (HI). At a molecular level, for each patient we quantified the amount of PI-PLCbeta1 mRNA at baseline and before each cycle of AZA therapy. PI-PLCbeta1 ratio was calculated as the mean expression of PI-PLCbeta1 at cycles 1 to 3, as compared with the baseline level within the same subject. In case the mean value of PI-PLCbeta1 gene expression during the cycles 1 to 3 was above the baseline level, we defined it as a “PI-PLCbeta1 early increase”. On the contrary, a “stable PI-PLCbeta1” expression was observed when subjects did not show any increase during the first three cycles of therapy, as compared with baseline. Results. Patients' median age was 69 years (range 37–85) and the median follow-up was 23 months (range 1–103). The median number of AZA cycles was 11 (range 3–59) for high-risk MDS, and 8 (range 1–8) for low-risk MDS. Positive clinical responses were observed in 37/60 (62%) of the MDS patients (7 CR, 1 PR, 29 HI). In particular, 13/22 (59%) of our low-risk MDS and 24/38 (63%) of our high-risk MDS patients showed a positive clinical response to AZA, with 4 CR, 1 PR, and 19 HI in high-risk MDS, and 3 CR and 10 HI in low-risk MDS. Overall survival (OS), Progression-Free Survival (PFS), and Overall Response Rate (ORR) were analyzed using a Kaplan-Meier method, considering p-values Conclusions. Taken together, our data confirm the role of PI-PLCbeta1 as a dynamic marker of response to AZA and show that the detection of an increase in PI-PLCbeta1 gene expression within the first three cycles of AZA therapy is associated with a better clinical outcome and a longer hematological response. Further analyses are needed to confirm in a larger group of patients the predictive role of PI-PLCbeta1 mRNA detection during AZA therapy. Disclosures: No relevant conflicts of interest to declare.
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- 2012
47. Authors' response to Letter from A. Toi: cerebellar vermis area versus perimeter
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Giuseppe Rizzo, Estelle Dijmeli, Maria Elena Pietrolucci, Domenico Arduini, Costanza Bosi, and Silvia Mammarella
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medicine.medical_specialty ,Cerebellum ,business.industry ,Obstetrics and Gynecology ,Anatomy ,Audiology ,Perimeter ,medicine.anatomical_structure ,Pediatrics, Perinatology and Child Health ,medicine ,Cerebellar vermis ,Settore MED/40 - Ginecologia e Ostetricia ,Ultrasonography ,business - Published
- 2014
48. Impact of Comorbidities and Body Mass Index in Myelofibrosis Patients Treated with Ruxolitinib: A Retrospective Analysis
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Mariella D'Adda, Elisa Cerqui, Massimo Breccia, Alessia Tieghi, Antonio Lazzaro, Micaela Bergamaschi, Antonio Cuneo, Giuseppe Cimino, Monica Crugnola, Fulvio Massaro, Francesca Palandri, Roberto M. Lemoli, Renato Fanin, Matteo Molica, Domenico Russo, Giuliana Alimena, Michele Cavo, Roberto Latagliata, Francesco Cavazzini, Nicola Polverelli, Marco Spinsanti, Mario Tiribelli, Nicola Vianelli, Alessandro Andriani, Angelo Fama, Costanza Bosi, Franco Aversa, Massimiliano Bonifacio, Francesca Celesti, and Luigi Scaffidi
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Brachial Plexus Neuritis ,medicine.medical_specialty ,Ruxolitinib ,medicine.diagnostic_test ,Anemia ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Positron emission tomography ,medicine ,Retrospective analysis ,Radiology ,business ,Myelofibrosis ,Body mass index ,medicine.drug - Abstract
Background: Comorbidities and body mass index (BMI) are significantly associated with outcome in patients (pts) who receive continue treatment with tyrosine kinase inhibitors (TKIs), such as in Ph+ leukemias. Ruxolitinib (RUX) is the first JAK1/2 inhibitor that may induce spleen/symptom responses and improve quality of life in pts with myelofibrosis (MF). Up-to-date, no data are available on the impact of comorbidities and BMI on pts treated with RUX. Aims: To evaluate the impact of comorbidities and BMI on responses, overall survival (OS) and maintenance of RUX dose in a large cohort of pts. Methods: Data were extracted from an electronic database that included retrospective data on pts treated before January 2015 in 16 Italian Hematology centers. Response to RUX was evaluated according to IWG-MRT criteria. BMI was calculated at the time of start of RUX and classified according to WHO criteria. Comorbidities were recorded at the time of start of RUX and classified according to the Charlson Comorbidity Index (CCI). Overall survival (OS) was calculated from the date of RUX start to the time of death or to last follow-up, whichever came first. Results: Between June 2011 and Apr 2016, 289 pts with PMF (52.6%), or PET-MF (17%) or PPV-MF (30.4%) were treated with RUX in participating Centers. At RUX start, median age was 68.4 years (range 39-89) with a male prevalence (56.4%); International Prognostic Score System (IPSS) was intermediate (intm)-1 (15.6%), intm-2 (45.3%), high (39.1%). Transfusion dependence and spleen enlargement were present in 26.6% and 96.9% of pts, respectively (69.6% with spleen≥ 10 cm). Median total symptom score (TSS) was 20 (range 0-70). JAK2V617F was present in 80.3% of 234 evaluable pts. Median follow-up from MF diagnosis was 3.8 yr (range 0.3-29.6) and median RUX exposure was 20 months (3-56.2). Overall, comorbidities were evaluable in 275 pts. CCI stratification showed the absence of comorbidities in 100 pts (36.4%), one comorbidity in 63 pts (22.9%) and two or more in 112 pts (40.7%). Compared to pts with CCI 2y from MF diagnosis was lower if CCI≥2 (33.9% vs 54%, p=0.001). Higher CCI did not correlate with lower spleen response (achieved by 45.2% vs 34.7%, p=0.09), TSS response (90.1% vs 83.2%, p=0.11), and higher incidence of RUX-induced anemia (Hb OS was significantly higher in pts with CCI BMI was evaluable in 269 pts: 169 pts (62.8%) were classified as under-weight/normal for a BMI Summary: In MF pts treated with RUX, BMI and comorbidities did not influence the achievement of spleen/symptom responses, maintenance of RUX dose or onset of drug-related anemia. Although CCI stratification correlated with survival, as in Ph+ leukemias treated with TKIs, the achievement of a spleen response was able to counterbalance the negative prognostic effect of a higher CCI. Consequently, higher BMI and CCI should not be regarded as contraindication to RUX therapy. Figure Figure. Disclosures Breccia: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Bonifacio:Ariad Pharmaceuticals: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding. Cimino:Bristol-Mayer: Honoraria; Celgene: Honoraria. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.
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- 2016
49. Role of Nuclear Inositide Signalling and microRNA Signature in Myelodysplastic Syndromes during Azacitidine and Lenalidomide Therapy
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Lucia Manzoli, Matilde Y. Follo, Andrea Pession, Marco Gobbi, Carlo Finelli, Sarah Parisi, Annalisa Astolfi, Cristina Clissa, Sara Mongiorgi, Lucio Cocco, Monica Crugnola, Stefano Ratti, Marilena Barraco, Domenico Russo, Marta Stanzani, and Costanza Bosi
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Myeloid ,Combination therapy ,Myelodysplastic syndromes ,Immunology ,Azacitidine ,Cell Biology ,Hematology ,Biology ,Cell cycle ,medicine.disease ,Biochemistry ,Demethylating agent ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,medicine ,Cancer research ,Epigenetic therapy ,medicine.drug ,Lenalidomide - Abstract
Phosphoinositide-specific phospholipase C (PI-PLC) gamma1 is involved in erythroid differentiation, via activation of the Akt/PI-PLCgamma1 pathway, and its increase has been associated with erythropoiesis in MDS cells. On the other hand, PI-PLCbeta1 is a nuclear inositide-dependent enzyme implicated in the regulation of hematopoietic differentiation. Interestingly, PI-PLCbeta1 increase plays an important predictive role in the response of MDS cells to epigenetic therapy. Indeed, PI-PLCbeta1 promoter is specifically hypomethylated by azacitidine, a demethylating agent that is clinically used in MDS to improve patients' overall survival and delay the AML evolution. Moreover, azacitidine is currently studied in combination with lenalidomide, to sustain both myeloid and erythroid lineages and balance MDS cell proliferation and differentiation. However, the molecular effects of this combination therapy on inositide signalling pathways and microRNA expression are still unclear. This study included 44 patients diagnosed with high-risk MDS who were given azacitidine and lenalidomide. Patients were considered clinically evaluable after at least 6 cycles of treatment. Molecular analyses were performed at baseline and during the therapy. At first, Real-Time PCR and immunocytochemical experiments were performed to determine PI-PLCbeta1 and PI-PLCgamma1 expression. Then, we also carried out cell cycle analyses and studied both PI-PLCbeta1 methylation status and the expression of erythroid-specific molecules, i.e. Globin genes. On the other hand, to further investigate the effect of the combination therapy on epigenetic mechanisms, we analyzed microRNA expression at baseline and during the treatment. In particular, we started by comparing the 4th cycle of the therapy to baseline, and in case of significant differences, for responder patients, we carried out microRNA profiling at the 8th cycle of the therapy or during the follow-up. Our study included 44 patients, but only 28 subjects were clinically evaluable, with an overall response rate of 78.6% (22/28 cases). At a molecular level, a significant increase of PI-PLCbeta1 expression was associated with a favourable clinical response to the combination therapy. Moreover, responder cases also showed an increased expression of Beta-Globin and PI-PLCgamma1, hinting at a specific contribution of lenalidomide on erythroid activation. On the other hand, the frequent demethylation of PI-PLCbeta1 promoter in responder cases could be specifically linked to azacitidine. Furthermore, MDS cells treated with azacitidine and lenalidomide not only showed an increased G0/G1 phase of cell cycle, but also microRNA expression was affected. In fact, responder and non responder cases showed a specific molecular pattern of microRNAs and, interestingly, some of these microRNAs can target or are strictly associated with inositide signalling pathways. Our results show that the combination of azacitidine and lenalidomide in high-risk MDS patients can be important to induce PI-PLCbeta1, and possibly PI-PLCgamma1. These enzymes can regulate cell cycle, myeloid and erythroid differentiation, thus improving peripheral cytopenia. On the other hand, a specific microRNA signature is important to make a molecular distinction between responder and non responder cases, so that their expression or interactions, possibly with PI-PLCs or other nuclear inositides, can be important to disclose new mechanisms in MDS pathogenesis and identify new predictive markers for the assessment of the response to azacitidine and lenalidomide therapy. Disclosures Gobbi: Novartis: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding; Roche: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Celgene: Consultancy; Takeda: Consultancy. Finelli:Novartis: Other: Speaker fees; Celgene: Other: Speaker fees; Celgene: Research Funding.
- Published
- 2016
50. Azacitidine and Lenalidomide (Combined vs Sequential Treatment) in Higher-Risk Myelodysplastic Syndromes. Long-Term Results of a Randomized Phase II Multicenter Study
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Cristina Clissa, Marilena Barraco, Matilde Y. Follo, Domenico Russo, Maria Benedetta Giannini, Sara Mongiorgi, Marco Gobbi, Michele Cavo, Sarah Parisi, Paolo Avanzini, Anna Candoni, Monica Crugnola, Carlo Finelli, Giuseppe Visani, Giovanna Leonardi, Barbara Castagnari, Lucio Cocco, Gian Matteo Rigolin, Marta Stanzani, Patrizia Tosi, and Costanza Bosi
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azacitidine ,medicine.medical_specialty ,MDS, azacitidine, lenalidomide, phase II trial ,lenalidomide ,Immunology ,macromolecular substances ,Neutropenia ,Biochemistry ,Gastroenterology ,NO ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,MDS ,medicine ,Clinical endpoint ,030212 general & internal medicine ,phase II trial ,Adverse effect ,Lenalidomide ,business.industry ,Myelodysplastic syndromes ,Incidence (epidemiology) ,Cell Biology ,Hematology ,medicine.disease ,Hematologic Response ,Surgery ,stomatognathic diseases ,International Prognostic Scoring System ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Introduction. Azacitidine (AZA) is the standard of care of higher-risk myelodysplastic syndromes (MDS), but the duration of clinical response is limited, and outcome after AZA failure is dismal. Several studies have demonstrated the efficacy and safety of combining AZA with Lenalidomide (LEN), either administered concurrently or sequentially, however the optimum dose and schedule for this combination remains unknown. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in higher-risk MDS pts (IPSS score risk: High or INT-2), and to look for possible biomarkers able to predict response. Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the International Working Group (IWG) criteria (Cheson, 2006). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (WHO 2008 classification) with International Prognostic Scoring System (IPSS) risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles (32 weeks). For responder patients (CR, PR, mCR, or HI) the same treatment was continued until disease progression or unacceptable toxicity. A sample size of 44 pts was planned. Results. From March 2013, 44 pts (27 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled because of severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts. In 5 pts (11.4%) del(5q) was present. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. 34/44 pts (77.3%) completed ≥ 6 cycles of treatment, and are evaluable for response. The remaining 10 pts (4 in ARM 1 and 6 in ARM 2) are not evaluable for response, as they discontinued treatment before completing the 6th cycle because of adverse events (6 pts, 13.6%), consent withdrawal (2 pts, 4.5%) or medical decision (2 pts, 4.5%), respectively. Treatment was given for a median of 8.5 (1-37) cycles; in ARM 1: 9 (1-32) cycles, in ARM 2: 8 (1-37) cycles, respectively. 6 pts (ARM 1: 2; ARM 2: 4) are still on treatment. Pts have been followed for a median of 15 (2-37) months for all subjects, for a median of 32 (18-37) months for survivors. Among the 34 pts evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. The Best Response achieved was: CR: 8 pts (23.5%), PR: 1 pt (2.9%), mCR: 3 pts (8.8%), HI: 8 pts (23.5%), mCR+HI: 6 pts (17.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). First Response was detected after a median of 2 (1-8) cycles. The median duration of hematologic response was 10.5 months. A grade > 2 non hematologic toxicity was observed in 54.5 % of pts, and an emerging (from grade 0-2 to > 2) hematologic toxicity in 27.3% of pts. In 61.4% of pts LEN dose was reduced because of hematologic or non-hematologic toxicity. 32 pts (72.7%) died , and 17 pts (38.6%) showed progression to AML. Median overall survival (OS) was 15 months. No significant differences between the 2 arms were observed, in terms of ORR, CR rate, toxicity, AML incidence and OS, but there was a trend (although still not significant) towards a longer median duration of response in the sequential arm: ARM 1: 6 months; ARM 2: 18 months (p=0.0847). MDS cells showed alterations of the inositide-dependent signalling as well as an altered microRNA profile. In particular, responder cases showed a frequent downregulation of miR-3613 and mir-4668, that were upregulated in non responder cases. Further analyses are ongoing. Conclusions. Our results confirm the efficacy of both AZA+LEN treatment regimens in higher-risk MDS pts, in terms of ORR, although the sequential schedule seems to induce more durable responses. Moreover, possible relationships with signal transduction pathways and microRNA profile are under evaluation. Disclosures Finelli: Novartis: Other: Speaker fees; Celgene: Other: Speaker fees; Celgene: Research Funding. Gobbi:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Roche: Honoraria; Takeda: Consultancy; Gilead: Honoraria; Celgene: Consultancy; Mundipharma: Consultancy, Research Funding. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.
- Published
- 2016
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