34 results on '"Costanza Bosi"'
Search Results
2. Determinants of Covid19 disease and of survival after Covid19 in MPN patients treated with ruxolitinib
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Francesca Palandri, Elena M. Elli, Giuseppe Auteri, Massimiliano Bonifacio, Giulia Benevolo, Florian H. Heidel, Simona Paglia, Malgorzata M. Trawinska, Costanza Bosi, Elena Rossi, Mario Tiribelli, Alessia Tieghi, Alessandra Iurlo, Nicola Polverelli, Giovanni Caocci, Gianni Binotto, Francesco Cavazzini, Eloise Beggiato, Daniela Cilloni, Caterina Tatarelli, Francesco Mendicino, Maurizio Miglino, Monica Bocchia, Monica Crugnola, Camilla Mazzoni, Andrea D. Romagnoli, Giovanni Rindone, Sara Ceglie, Alessandra D’Addio, Eleonora Santoni, Daniele Cattaneo, Daniela Bartoletti, Roberto M. Lemoli, Mauro Krampera, Antonio Cuneo, Gianpietro C. Semenzato, Roberto Latagliata, Elisabetta Abruzzese, Nicola Vianelli, Michele Cavo, Alessandro Andriani, Valerio De Stefano, Giuseppe A. Palumbo, and Massimo Breccia
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Oncology ,Hematology - Published
- 2023
3. 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
4. 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
5. 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
6. 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
- Published
- 2020
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. 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
18. PI-PLCβ-1 and activated Akt levels are linked to azacitidine responsiveness in high-risk myelodysplastic syndromes
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Lucia Manzoli, Sara Mongiorgi, Carlo Finelli, Matilde Y. Follo, Michele Baccarani, Lucio Cocco, Alberto M. Martelli, Costanza Bosi, Giovanni Martinelli, Wl Blalock, Follo MY, Finelli C, Bosi C, Martinelli G, Mongiorgi S, Baccarani M, Manzoli L, Blalock WL, Martelli AM, and Cocco L
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Cancer Research ,Proto-Oncogene Proteins c-akt ,Myelodysplastic syndromes ,Azacitidine ,PI-PLCbeta1, Akt, Azacitidine, High-Risk MDS ,Phospholipase C beta ,Hematology ,Biology ,medicine.disease ,Oncology ,Immunology ,Pi ,Cancer research ,medicine ,Protein kinase B ,medicine.drug - Abstract
PI-PLCbeta-1 and activated Akt levels are linked to azacitidine responsiveness in high-risk myelodysplastic syndromes
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- 2007
19. Anti-Leukemic and Anti-GVHD Effects of Campath-1H in Acute Lymphoblastic Leukemia Relapsed after Stem-Cell Transplantation
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Ernesto Vigna, Michele Malagola, Giovanni Martinelli, Michele Bianchini, Stavroula Gaitani, Giuseppe Visani, Michele Baccarani, Pier Paolo Piccaluga, Costanza Bosi, Michela Rondoni, PICCALUGA PP, MARTINELLI G, MALAGOLA M, RONDONI M, BIANCHINI M, VIGNA E, BOSI C, GAITANI S, VISANI G, and BACCARANI M.
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Adult ,Male ,Cancer Research ,Adolescent ,Antibodies, Neoplasm ,medicine.drug_class ,medicine.medical_treatment ,Graft vs Host Disease ,Salvage therapy ,Antineoplastic Agents ,Hematopoietic stem cell transplantation ,Antibodies, Monoclonal, Humanized ,Monoclonal antibody ,Donor lymphocyte infusion ,Recurrence ,medicine ,Humans ,Alemtuzumab ,Salvage Therapy ,business.industry ,Hematopoietic Stem Cell Transplantation ,Antibodies, Monoclonal ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Transplantation ,Treatment Outcome ,surgical procedures, operative ,medicine.anatomical_structure ,Oncology ,Immunology ,Drug Evaluation ,Female ,Bone marrow ,Stem cell ,business ,medicine.drug - Abstract
Despite aggressive approaches, including second transplant, donor lymphocyte infusion and several new agents, the prognosis of acute lymphoid leukemia (ALL) patients relapsing after stem-cell transplantation (SCT) remains poor. Monoclonal-antibodies (moAb) could provide a useful tool in this setting. In particular, anti-CD52 moAb is useful in lymphoid malignancies. We thus treated as compassionate with campath-1H 3 ALL patients relapsed after SCT. In 2 cases we observed a reduction of peripheral blood and/or bone marrow blasts. In 1 case a GVHD grade reduction was observed. Larger trials are required in order to define the role of campath-1H in ALL.
- Published
- 2004
20. Phosphoinositide-phospholipase C beta1 mono-allelic deletion is associated with myelodysplastic syndromes evolution into acute myeloid leukemia
- Author
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Lucio Cocco, Sara Mongiorgi, Alberto M. Martelli, Lucia Manzoli, Carlo Finelli, Michele Baccarani, Giovanni Martinelli, Cristina Clissa, Matilde Y. Follo, Costanza Bosi, Follo MY, Finelli C, Clissa C, Mongiorgi S, Bosi C, Martinelli G, Baccarani M, Manzoli L, Martelli AM, and Cocco L.
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Adult ,Male ,Cancer Research ,Myeloid ,Phospholipase C beta ,Gene Expression ,In situ hybridization ,law.invention ,law ,hemic and lymphatic diseases ,Phosphoinositide phospholipase C ,medicine ,Humans ,Polymerase chain reaction ,In Situ Hybridization, Fluorescence ,Aged ,Aged, 80 and over ,business.industry ,Phospholipase C gamma ,Reverse Transcriptase Polymerase Chain Reaction ,Myelodysplastic syndromes ,Myeloid leukemia ,Cancer ,Middle Aged ,medicine.disease ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Oncology ,Myelodysplastic Syndromes ,Immunology ,Cancer research ,Disease Progression ,Female ,business ,Gene Deletion - Abstract
Purpose To evaluate the association between the presence of phosphoinositide-phospholipase C β1 (PI-PLCβ1) mono-allelic deletion with the clinical outcome of myelodysplastic syndromes (MDS) patients. Methods PI-PLCβ1, PI-PLCβ4, and PI-PLCγ1 cytogenetic investigations were performed on 80 newly diagnosed MDS patients (18 low risk, 26 intermediate 1, 18 intermediate 2, 18 high risk) comparing the results with the clinical outcome of the patients. Moreover, fluorescent in situ hybridization results were validated by real-time polymerase chain reaction (PCR). Finally, PI-PLCβ1 gene and protein expression were assessed by both real-time PCR and immunocytochemical experiments. Results Collectively, 35 (43.75%) of 80 of the MDS patients showed a specific mono-allelic deletion of PI-PLCβ1. Kaplan-Meier analysis revealed a significant association (P < .0001) between the PI-PLCβ1 mono-allelic deletion and a higher risk of evolution into acute myeloid leukemia (AML), since 23 of 35 MDS patients (65.7%) bearing the PI-PLCβ1 mono-allelic deletion evolved into AML. Even in multivariate analysis, the PI-PLCβ1 mono-allelic deletion retained a higher significance, with a P < .001, as a prognostic factor of evolution into AML (odds ratio [OR] 1.83; 95% CI, 2.26 to 17.24; P = .00045). Finally, PI-PLCβ1 deletion was related to an altered gene and protein expression. Conclusion PI-PLCβ1 mono-allelic deletion is associated with a worse clinical outcome in MDS patients, hinting at the identification of a new group at higher risk of AML evolution and representing a reliable prognostic tool. Moreover, targeting PI-PLCβ1 pathways might emerge as a new therapeutic strategy for MDS.
- Published
- 2009
21. PKR is activated in MDS patients and its subcellular localization depends on disease severity
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William L. Blalock, Cristina Clissa, Sara Mongiorgi, Costanza Bosi, Matilde Y. Follo, Am Martelli, Lucio Cocco, Giovanni Martinelli, C Finelli, Follo MY, Finelli C, Mongiorgi S, Clissa C, Bosi C, Martinelli G, Blalock WL, Cocco L, and Martelli AM.
- Subjects
Cell Nucleus ,Cancer Research ,Cytoplasm ,business.industry ,viruses ,virus diseases ,macromolecular substances ,Hematology ,biochemical phenomena, metabolism, and nutrition ,Subcellular localization ,Bioinformatics ,Protein kinase R ,Severity of Illness Index ,eIF-2 Kinase ,Oncology ,Disease severity ,Risk Factors ,hemic and lymphatic diseases ,Myelodysplastic Syndromes ,Severity of illness ,Immunology ,Medicine ,Humans ,business - Abstract
PKR is activated in MDS patients and its subcellular localization depends on disease severity
- Published
- 2008
22. The Akt/mammalian target of rapamycin signal transduction pathway is activated in high-risk myelodysplastic syndromes and influences cell survival and proliferation
- Author
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Lucio Cocco, Veronica Papa, Costanza Bosi, Sara Mongiorgi, Massimo Libra, Francesca Chiarini, C Finelli, Matilde Y. Follo, Alberto M. Martelli, Giovanni Martinelli, Alessandra Cappellini, Follo, Matilde Y., Mongiorgi, Sara, Bosi, Costanza, Cappellini, Alessandra, Finelli, Carlo, Chiarini, Francesca, Papa, Veronica, Libra, Massimo, Martinelli, Giovanni, Cocco, Lucio, and Martelli, Alberto M.
- Subjects
Male ,Cancer Research ,Antibodie ,Protein Kinase ,Sialic Acid Binding Ig-like Lectin 3 ,Cell Cycle Proteins ,Apoptosis ,HL-60 Cell ,chemistry.chemical_compound ,Antibody Specificity ,Risk Factors ,hemic and lymphatic diseases ,Leukocytes ,Sirolimu ,LY294002 ,Phosphorylation ,Cell Growth Processe ,TOR Serine-Threonine Kinase ,TOR Serine-Threonine Kinases ,Ribosomal Protein S6 Kinases, 70-kDa ,Adaptor Proteins ,Middle Aged ,Immunohistochemistry ,Cell biology ,CD ,Oncology ,Phosphoprotein ,Differentiation ,Female ,Signal Transducing ,Aged ,Antibodies ,Antigens ,Myelomonocytic ,Cell Growth Processes ,Cell Lineage ,Cell Survival ,HL-60 Cells ,Humans ,Mononuclear ,Myelodysplastic Syndromes ,Phosphoproteins ,Protein Kinases ,Proto-Oncogene Proteins c-akt ,Ribosomal Protein S6 Kinases ,70-kDa ,Signal Transduction ,Sirolimus ,Human ,Myelodysplastic Syndrome ,Antigens, Differentiation, Myelomonocytic ,P70-S6 Kinase 1 ,Biology ,Antigens, CD ,Neoplastic transformation ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Adaptor Proteins, Signal Transducing ,Cell growth ,Risk Factor ,RPTOR ,Apoptosi ,chemistry ,Leukocytes, Mononuclear ,Cancer research - Abstract
The Akt/mammalian target of rapamycin (mTOR) signaling pathway is important for both cell growth and survival. In particular, an impaired regulation of the Akt/mTOR axis has been strongly implicated in mechanisms related to neoplastic transformation, through enhancement of cell proliferation and survival. Myelodysplastic syndromes (MDS) are a group of heterogeneous hematopoietic stem cell disorders characterized by ineffective hematopoiesis and by a high risk of evolution into acute myelogenous leukemia (AML). The pathogenesis of the MDS evolution into AML is still unclear, although some recent studies indicate that aberrant activation of survival signaling pathways could be involved. In this investigation, done by means of immunofluorescent staining, we report an activation of the Akt/mTOR pathway in high-risk MDS patients. Interestingly, not only mTOR was activated but also its downstream targets, 4E-binding protein 1 and p70 ribosomal S6 kinase. Treatment with the selective mTOR inhibitor, rapamycin, significantly increased apoptotic cell death of CD33(+) (but not CD33(-)) cells from high-risk MDS patients. Rapamycin was ineffective in cells from healthy donors or low-risk MDS. Moreover, incubation of high-risk MDS patient CD34(+) cells with rapamycin decreased the in vitro clonogenic capability of these cells. In contrast, the phosphoinositide 3-kinase inhibitor, LY294002, did not significantly affect the clonogenic activity of high-risk MDS cells. Taken together, our results indicate that the Akt/mTOR pathway is critical for cell survival and proliferation in high-risk MDS patients. Therefore, this signaling network could become an interesting therapeutic target for treating more advanced MDS cases. The Akt/mammalian target of rapamycin (mTOR) signaling pathway is important for both cell growth and survival. In particular, an impaired regulation of the Akt/mTOR axis has been strongly implicated in mechanisms related to neoplastic transformation, through enhancement of cell proliferation and survival. Myelodysplastic syndromes (MDS) are a group of heterogeneous hematopoietic stem cell disorders characterized by ineffective hematopoiesis and by a high risk of evolution into acute myelogenous leukemia (AML). The pathogenesis of the MDS evolution into AML is still unclear, although some recent studies indicate that aberrant activation of survival signaling pathways could be involved. In this investigation, done by means of immunofluorescent staining, we report an activation of the Akt/mTOR pathway in high-risk MDS patients. Interestingly, not only mTOR was activated but also its downstream targets, 4E-binding protein 1 and p70 ribosomal S6 kinase. Treatment with the selective mTOR inhibitor, rapamycin, significantly increased apoptotic cell death of CD33+ (but not CD33-) cells from high-risk MDS patients. Rapamycin was ineffective in cells from healthy donors or low-risk MDS. Moreover, incubation of high-risk MDS patient CD34+ cells with rapamycin decreased the in vitro clonogenic capability of these cells. In contrast, the phosphoinositide 3-kinase inhibitor, LY294002, did not significantly affect the clonogenic activity of high-risk MDS cells. Taken together, our results indicate that the Akt/mTOR pathway is critical for cell survival and proliferation in high-risk MDS patients. Therefore, this signaling network could become an interesting therapeutic target for treating more advanced MDS cases. ©2007 American Association for Cancer Research.
- Published
- 2007
23. 98 CLINICAL RESPONSE TO THE ASSOCIATION OF AZACITIDINE AND LENALIDOMIDE IN HIGH-RISK MYELODYSPLASTIC SYNDROMES. A RANDOMIZED PHASE II MULTICENTER STUDY
- Author
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Gian Matteo Rigolin, Cristina Clissa, Diego Russo, Michele Cavo, Sarah Parisi, Paolo Avanzini, Matilde Y. Follo, Marta Stanzani, Carlo Finelli, Barbara Castagnari, Monica Crugnola, Giuseppe Visani, Costanza Bosi, Marco Gobbi, Maria Benedetta Giannini, Patrizia Tosi, Anna Candoni, Giovanna Leonardi, and Lucio Cocco
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Azacitidine ,Hematology ,medicine.disease ,Multicenter study ,Internal medicine ,medicine ,business ,medicine.drug ,Lenalidomide - Published
- 2015
24. Frequent Elevation of Akt Kinase Phosphorylation in Blood Marrow and Peripheral Blood Mononuclear Cells from High Risk myelodysplastic Syndrome Patients
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Matilde Y. Follo, Alberto M. Martelli, Tiziana Grafone, Maria Nyakern, Giovanni Martinelli, Pier Paolo Piccaluga, C Finelli, P. L. Tazzari, Lucio Cocco, Costanza Bosi, Nyåkern M, Tazzari PL, Finelli C, Bosi C, Follo MY, Grafone T, Piccaluga PP, Martinelli G, Cocco L, and Martelli AM.
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Apoptosis ,Bone Marrow Cells ,HL-60 Cells ,Biology ,Peripheral blood mononuclear cell ,Jurkat Cells ,Risk Factors ,Internal medicine ,hemic and lymphatic diseases ,Serine ,Tumor Cells, Cultured ,medicine ,Humans ,PTEN ,Phosphorylation ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Aged ,Aged, 80 and over ,Hematology ,Myelodysplastic syndromes ,PTEN Phosphohydrolase ,Myeloid leukemia ,Middle Aged ,Flow Cytometry ,medicine.disease ,Immunohistochemistry ,medicine.anatomical_structure ,Oncology ,Myelodysplastic Syndromes ,Immunology ,Leukocytes, Mononuclear ,biology.protein ,Cancer research ,Female ,Bone marrow ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is known to play an important role in antiapoptotic signaling and has been implicated in the aggressiveness of a number of different human cancers including acute myeloid leukemia (AML). The progression of myelodysplastic syndromes (MDSs) to AML is thought to be associated with abrogation of apoptotic control mechanisms. However, little is known about signal transduction pathways which may be involved in enhanced survival of MDS cells. In this report, we have performed immunocytochemical and flow cytometric analysis to evaluate the levels of activated Akt in bone marrow or peripheral blood mononuclear cells from patients diagnosed with MDS. We observed high levels of Ser473 phosphorylated Akt (p-Akt) staining in 90% of the cases (n=22) diagnosed as high-risk MDS, whereas mononuclear cells from normal bone marrow or low-risk MDS patients showed low or absent Ser473 p-Akt staining. Furthermore, all high-risk MDS patients also demonstrated high expression of the Class I PI3K p110delta catalytic subunit and a decreased expression of PTEN. Taken together, our results suggest that Akt activation might be one of the factors contributing to the decreased apoptosis rate observed in patients with high-risk MDS.
- Published
- 2006
25. Addition of Lenalidomide (LEN) to Azacitidine (AZA) (Combined vs Sequential Treatment) in High-Risk Myelodysplastic Syndromes (MDS): A Randomized Phase II Multicenter Study
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Lucio Cocco, Monica Crugnola, Giovanna Leonardi, Costanza Bosi, Giuseppe Visani, Matilde Y. Follo, Anna Candoni, Gian Matteo Rigolin, Carlo Finelli, Domenico Russo, Marco Gobbi, Marta Stanzani, Michele Cavo, Paolo Avanzini, Maria Benedetta Giannini, Barbara Castagnari, Cristina Clissa, and Patrizia Tosi
- Subjects
Oncology ,azacitidine ,medicine.medical_specialty ,MDS, azacitidine, lenalidome, phase II trial ,Immunology ,Azacitidine ,Context (language use) ,macromolecular substances ,Biochemistry ,Sudden death ,NO ,Internal medicine ,MDS ,medicine ,phase II trial ,Lenalidomide ,lenalidome ,business.industry ,Myelodysplastic syndromes ,Cell Biology ,Hematology ,medicine.disease ,Surgery ,stomatognathic diseases ,International Prognostic Scoring System ,business ,Refractory cytopenia with multilineage dysplasia ,Febrile neutropenia ,medicine.drug - Abstract
Introduction. Azacitidine (AZA) as single agent has been shown to improve overall survival in high-risk myelodysplastic syndromes (MDS), with an overall response rate (ORR) of 50-60% (Silverman 2002; 2006; Fenaux 2009). However as a significant proportion of patients (pts) do not respond to treatment, and moreover, as the the duration of therapeutic response to AZA is limited, several attempts have been made to associate AZA with other drugs, with the aim to improve the outcome. In particular, the addition of lenalidomide (LEN) to AZA, either administered concurrently (Sekeres, 2010; 2012), or sequentially (Platzbecker, 2013), has shown promising results, although these data await confirmation by larger series of pts. The aim of this study was to evaluate the efficacy (ORR) and safety of the combination vs the sequential use of AZA and LEN in high-risk MDS pts. Moreover, as in previous studies we demonstrated that the increase in PI-PLCβ1 gene expression during AZA treatment is related to haematological response and frequently anticipates the response (Follo, 2009; 2012), another aim of our study was to assess the evaluation of PI-PLCβ1 expression as early predictive biomarker of response also with the association of AZA and LEN, and to look for other possible biomarkers able to predict response, as the mutational status assessed by next generation sequency (NGS). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (according to 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 treatment for both arms was planned for 8 cycles (32 weeks) in the absence of disease progression or unacceptable toxicity. A sample size of 44 pts was planned. Results. From March 2013, 40 pts (23 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, WHO diagnosis was: Refractory Cytopenia with Multilineage Dysplasia (RCMD): 3 pts; Refractory Anemia with Excess of Blasts-1 (RAEB-1): 9 pts; RAEB-2: 23 pts; MDS-unclassified (MDS-U): 5 pts; IPSS risk was: Intermediate-2: 29 pts; High: 6 pts; not determined (N.D.) (because of lack of cytogenetic data): 5 pts. (all with RAEB-2). IPSS cytogenetic risk was: intermediate in 10 pts and high in 9 pts (3 with complex karyotypes and 6 with isolated -7 or 7q-). 5 pts showed del5q (in 3 cases in the context of a complex karyotype, and in 1 case associated with another single additional cytogenetic alteration). 2 pts had therapy-related MDS. 21 pts (52.5%) were transfusion-dependent at baseline. 19 pts were randomly assigned to ARM 1, and 21 pts to ARM 2. At the time of this analysis, 22/40 pts (55%) completed ≥ 6 cycles of treatment, and are evaluable for response. 13/22 pts (59,1%) showed a favourable response to treatment, following the International Working Group (IWG) criteria (Cheson, 2006): 2 pts achieved Complete Remission (CR), 2 pts attained Partial Remission (PR), 2 pts showed Marrow Complete Remission (mCR), and 7 pts obtained Hematological Improvement (HI), while the 9 non responder pts maintained a Stable Disease (SD). Responder pts were 7/10 (70%) in ARM 1 (2 CR; 1 PR; 4 HI), and 6/12 (50%) in ARM 2 (1 CR; 1 PR; 2 mCR; 2 HI), respectively. Median time to first response: 2 (2-7) months. A significant toxicity (grade > 2) was observed in 10/40 (25%) pts. 15/40 pts (37,5%) had a dose reduction of LEN because of hematologic or non-hematologic toxicity. 8 pts (20%) early discontinued therapy before completing the planned 8 cycles, because of prolonged thrombocytopenia (1 pt), death (3 pts), evolution into acute myeloid leukemia (AML) (2 pts) and withdrawal of consent (2 pts), respectively. Causes of death were: febrile neutropenia, myocardial infarction and sudden death, respectively . Conclusions. Our results, although preliminary, seem to confirm the feasibility of the association of AZA and LEN in high-risk MDS pts. More data are needed in order to compare the efficacy and safety of combined vs sequential treatment and vs AZA monotherapy. Moreover, possible relationships with signal transduction pathways and with mutational status are under evaluation. Disclosures Finelli: Celgene: Research Funding, Speaker Other; Novartis: Speaker, Speaker Other; Janssen: Speaker, Speaker Other. Off Label Use: Lenalidomide in higher-risk MDS and AML. Cavo:Celgene: Consultancy, Honoraria, Speakers Bureau.
- Published
- 2014
26. P-296 Long-lasting hematologic response to azacitidine in myelodysplastic syndromes: Multicenter retrospective study of 36 patients
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Costanza Bosi, Massimo Breccia, Maria Benedetta Giannini, Gianluca Gaidano, Michele Cavo, Monica Crugnola, Giovanni Martinelli, Cristina Clissa, M. A. Aloe Spiriti, M.T. Voso, Carlo Finelli, Antonella Poloni, Virginia Naso, and Matilde Y. Follo
- Subjects
Long lasting ,Cancer Research ,Pediatrics ,medicine.medical_specialty ,business.industry ,Myelodysplastic syndromes ,Azacitidine ,Retrospective cohort study ,Hematology ,medicine.disease ,Hematologic Response ,Oncology ,medicine ,business ,medicine.drug - Published
- 2013
27. 241 Role of inositide signalling regulation in higher-risk MDS patients during epigenetic therapy
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Costanza Bosi, Lucio Cocco, Matilde Y. Follo, Sara Mongiorgi, Cristina Clissa, Carlo Finelli, Michele Baccarani, Lucia Manzoli, and Giovanni Martinelli
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Cancer Research ,Signalling ,Oncology ,business.industry ,Medicine ,Hematology ,business ,Bioinformatics ,Epigenetic therapy - Published
- 2011
28. P033 The Akt/mTOR signal transduction pathway is activated in high risk myelodysplastic syndromes and influences cell survival and proliferation
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Sara Mongiorgi, Carlo Finelli, Francesca Chiarini, A.M. Martelli, Lucio Cocco, Massimo Libra, Matilde Y. Follo, Costanza Bosi, Veronica Papa, A. Cappellini, Giovanni Martinelli, and Michele Baccarani
- Subjects
Cancer Research ,Oncology ,business.industry ,Myelodysplastic syndromes ,Cancer research ,Medicine ,Hematology ,Signal transduction ,business ,medicine.disease ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell survival - Published
- 2007
29. Presence or the Emergence of a F317L BCR-ABL Mutation May Be Associated With Resistance to Dasatinib in Philadelphia Chromosome–Positive Leukemia
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Francesca Palandri, Simona Soverini, Alessandra Gnani, Sabrina Colarossi, Simona Luatti, Daniela Cilloni, Giulia Marzocchi, Michele Baccarani, Nicoletta Testoni, Ilaria Iacobucci, Giuseppe Saglio, Fausto Castagnetti, Stefania Paolini, Pier Paolo Piccaluga, Costanza Bosi, Panagiota Giannoulia, Giovanni Martinelli, Gianantonio Rosti, Michela Rondoni, S. Soverini, G. Martinelli, S. Colarossi, A. Gnani, F. Castagnetti, G. Rosti, C. Bosi, S. Paolini, M. Rondoni, P. P. Piccaluga, F. Palandri, P. Giannoulia, G. Marzocchi, S. Luatti, N. Testoni, I. Iacobucci, D. Cilloni, G. Saglio, and M. Baccarani
- Subjects
DASATINIB ,Cancer Research ,Mutation ,Philadelphia Chromosome Positive ,ABL ,business.industry ,Drug resistance ,medicine.disease ,medicine.disease_cause ,Dasatinib ,Leukemia ,Myelogenous ,Oncology ,F317L BCR-ABL mutation ,medicine ,Cancer research ,Neoplasm ,business ,medicine.drug - Abstract
No abstract available.
- Published
- 2006
30. Molecular monitoring of acute myeloid leukemia associated with inv(16): threshold of CBFβ/MYH11 transcript copy number above which relapse occurs and below which continuous Complete Remission is likely
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Marilina Amabile, Pier Paolo Piccaluga, Silvia Buonamici, B Giannini, Michele Baccarani, Giovanni Martinelli, Michele Malagola, Simona Soverini, Giuseppe Visani, Alessandro Isidori, Francesca Bonifazi, Carolina Terragna, and Costanza Bosi
- Subjects
Genetics ,Cancer Research ,business.industry ,Complete remission ,Myeloid leukemia ,Hematology ,biochemical phenomena, metabolism, and nutrition ,Text mining ,Oncology ,hemic and lymphatic diseases ,Cancer research ,MYH11 ,Medicine ,CBFbeta-MYH11 ,business - Abstract
Molecular monitoring of acute myeloid leukemia associated with inv(16): threshold of CBF β /MYH11 transcript copy number above which relapse occurs and below which continuous Complete Remission is likely
- Published
- 2003
31. C033 Quantification of phosphoinositidephospholipase C (PI-PLC) beta 1 gene promoter methylation predicts the responsiveness to azacitidine in myelodysplastic syndromes
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A.M. Martelli, Carlo Finelli, Matilde Y. Follo, Francesca Chiarini, Lucia Manzoli, Giovanni Martinelli, Michele Baccarani, Costanza Bosi, Cristina Clissa, Sara Mongiorgi, and Lucio Cocco
- Subjects
Beta-1 adrenergic receptor ,Cancer Research ,Oncology ,Myelodysplastic syndromes ,Azacitidine ,Cancer research ,medicine ,Promoter ,Hematology ,Methylation ,Biology ,medicine.disease ,medicine.drug - Published
- 2009
32. Efficacy and safety of echoguided catheterisation approach in oncological and hematological patients. Report on 843 consecutive patients
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Elena Trabacchi, P. Mordenti, Luigi Cavanna, Antonio Lazzaro, Costanza Bosi, Annalisa Arcari, Patrizia Bernuzzi, Raffaella Bertè, Carlo Filippo Moroni, Elisa Anselmi, and Daniele Vallisa
- Subjects
Cancer Research ,medicine.medical_specialty ,Bone marrow transplantation ,business.industry ,medicine.medical_treatment ,Ultrasound ,Infusional chemotherapy ,Lumen (anatomy) ,Surgery ,Parenteral nutrition ,Oncology ,medicine ,business ,Sternocleidomastoid muscle ,Internal jugular vein ,Central venous catheter - Abstract
19581 Background: A central venous catheter (CVC) represents the most frequently adopted intravenous line for patients undergoing infusional chemotherapy, bone marrow transplantation (BMT) and parenteral nutrition. The aim of this study was to explore the feasibility and safety of CVC insertion under ultrasound (US) control. US offers the advantage of real-time, multiplanar imaging as well as Doppler analysis. Methods: The echoguided approach allowed us to insert CVC in right supraclavicular site nearby the clavicular head of sternocleidomastoid muscle. Using a 7.5-MHz probe we were able to perform a real time control of the hip of the needle while it was inserted in the last side of internal jugular vein. At the end of the procedure chest Rx was executed to evaluate CVC position and to detect pneumotorax. Mainly Sekalon Seldy, Becketon Dickinson was employed. For PBSC collection, 14-gauge Arrow double lumen revealed to be highly efficacious (46 PBSC collections, no one failure). Results: From November 1999 to December 2006 the echoguided CVC insertion method was applied 1003 times in 843 patients. The procedure was applied 288 times in haematological malignancies, in 698 solid tumors, in 3 neurological autoimmune diseases. Among solid tumors colon carcinoma was the first indication, while gastric carcinoma the second. Among haematological patients: non-Hodgkin lymphoma was the first indication, then acute leukemia. Ten patients underwent allogenic BMT and 92 autologous BMT. Nine in 1003 procedures failed (1%). Failures were caused by: arterial puncture in 3, CVC dislocation in 1, vein collapse in 3 and no efficacious “eco window” in 2. No pneumotorax was registered. The safety of this procedure was confirmed by 35 catheterisations obtained with platelets under 20000/μl, by 7 procedure with prothrombin activity under 50%. In 44 patients catheter was inserted with neutrophil count below 100/μl and in 66 below 500/μl without any increase in infections. Mean time of catheter permanence was 151 days with 1,7 infectious events every 1000 days of permanence. Symptomatic deep veins thrombotic complications were 9 (1%). Conclusions: This procedure is safe, cheap with high accuracy and success rate, and above all US-guidance avoids pneumothorax. No significant financial relationships to disclose.
- Published
- 2007
33. Mutations at Residues 315 and 317 in the ABL Kinase Domain Are the Main Cause of Resistance to Dasatinib in Philadelphia-Positive (Ph+) Leukemia Patients (pts)
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Nicoletta Testoni, Pier Paolo Piccaluga, Francesca Palandri, Simona Luatti, Elisabetta Abruzzese, Costanza Bosi, Panagiota Giannoulia, Simona Soverini, Alessandra Gnani, Michela Rondoni, Fausto Castagnetti, Stefania Paolini, Gianantonio Rosti, Ilaria Iacobucci, Giulia Marzocchi, Sabrina Colarossi, Michele Baccarani, and Giovanni Martinelli
- Subjects
Oncology ,medicine.medical_specialty ,Mutation ,ABL ,business.industry ,Immunology ,Mutant ,Imatinib ,Cell Biology ,Hematology ,medicine.disease ,medicine.disease_cause ,Biochemistry ,Discontinuation ,Dasatinib ,Leukemia ,Internal medicine ,medicine ,Mutation testing ,business ,medicine.drug - Abstract
Dasatinib (BMS-354825) is a second-generation BCR-ABL inhibitor active against several imatinib-insensitive BCR-ABL mutant forms. We have treated in the phase II program with dasatinib a total of forty-five Ph+ pts who were resistant to or intolerant of imatinib. At the time of writing, twenty pts have failed to respond to or relapsed on dasatinib therapy. In order to assess which pre-existent or emerging ABL kinase domain (KD) mutations are challenging for dasatinib clinical efficacy, we retrospectively analyzed ABL KD sequences before the start of treatment and every month thereafter, until dasatinib discontinuation. Mutation monitoring was done by D-HPLC, followed by sequencing in D-HPLC-positive cases. Eight pts had primary resistance to dasatinib (Table 1). In all cases, a T315I or a F317L mutation was already detectable before the onset of treatment or became detectable after one month. The mutations persisted up to the time of disease progression, which occurred at a median of 1.5 months (range, 1–4) from dasatinib start. Twelve pts had acquired resistance to dasatinib (Table 1). Relapse occurred after a median of 7.5 months (range, 3–15) from dasatinib start. Mutation analysis performed before the onset of treatment showed that five of these pts had a wild-type ABL sequence, while the remaining seven pts had evidence of various imatinib-resistant KD mutations (G250E, Y253H, E255K, D276G, M351T). At the time of relapse, however, most of the original mutant clones had disappeared, whereas mutations at residues 315 (T315I or T315A) and/or 317 (F317L or F317I) had invariably emerged in all but one pt. This pt was found to have developed a novel K356R mutation which is now under characterization. Our results indicate that residues 315 and 317 are mutation hotspots in dasatinib-resistant pts, according to the experimental observation that they are both involved in inhibitor binding. They also provide a proof of principle that novel, inhibitor-specific mutant variants (i.e., T315A, F317I, K356R) may be selected, and raise some concerns about the limitations of single-agent treatment in the long term disease control of advanced phase-CML or Ph+ ALL pts. Supported by European LeukemiaNet, AIL, AIRC, FIRB and PRIN projects. Table 1 Pt Disease Mutation(s) before dasatinib start Best HR Best CgR Months on dasatinib Mutation(s) at relapse NE, not evaluated Primary resistance 1 CML/AP WT NR none 4 T315I 2 CML/AP T315I NR NE 1 T315I 3 CML/myBC T315I NR NE 1 T315I 4 CML/myBC F317L NR none 3 F317L 5 CML/lyBC T315I NR NE 1 T315I 6 Ph+ ALL T315I, M351T, L387M NR NE 2 T315I, M351T, L387M 7 Ph+ ALL T315I NR NE 1 T315I 8 Ph+ ALL F359V NR NE 2 T315I Acquired resistance 9 CP WT CHR minor 15 T315I 10 CML/myBC G250E NEL none 8 F317L 11 CML/lyBC Y253H CHR complete 9 CHR T315I 12 CML/lyBC WT CHR complete 4 T315I 13 CML/lyBC E255K CHR none 3 E255K, T315I 14 CML/lyBC D276G CHR complete 7 T315I 15 CML/lyBC WT CHR partial 9 F317L 16 Ph+ ALL E255K CHR NE 4 T315I 17 Ph+ ALL Y253H CHR complete 13 T315A, F317L, D276G 18 Ph+ ALL M351T CHR complete 13 M351T, F317L 19 Ph+ ALL WT CHR complete 6 F317I 20 Ph+ ALL WT CHR complete 4 K356R
- Published
- 2006
34. High doses of recombinant erythropoietin alfa for myelodysplastic syndromes: High incidence of responses in patients with low pre-treatment serum erythropoietin concentrations
- Author
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J. El-Cheikh, Michela Rondoni, Michele Baccarani, Michele Malagola, E. Vigna, Giovanni Martinelli, Finelli, and Costanza Bosi
- Subjects
Cancer Research ,medicine.medical_specialty ,Serum erythropoietin ,business.industry ,Anemia ,Myelodysplastic syndromes ,macromolecular substances ,medicine.disease ,Gastroenterology ,Regimen ,Oncology ,Erythropoietin ,Internal medicine ,Immunology ,otorhinolaryngologic diseases ,medicine ,High doses ,In patient ,High incidence ,business ,medicine.drug - Abstract
6683 Background: Severe symptomatic anemia is common in patients (pts) with myelodysplastic syndromes (MDS). Recombinant human erythropoietin (rHuEPO), at a dosage of 30–70.000 U/week, has proven effective in 20–30 % of cases. Recently, a different schedule of rHuEPO administration (40.000 U twice weekly) has shown to be effective in lymphoid malignancies and solid tumors. Methods: From September 2001, 18 pts with low-or-intermediate risk MDS were treated with rHuEPO alfa because of symptomatic anemia (Hb < 10 g/dl). The pts received a high doses rHuEPO regimen: 40.000 U twice weekly, for the first month, followed by a single weekly dose of 40.000 as maintenance treatment, for at least 8 weeks. Only pts with a pre-treatment serum EPO < 200 U/l were selected for rHuEPO treatment Results: 7 pts have a follow-up < 2 months, and are still under evaluation. All the 11 valuable pts (6 males, median age: 72, range 35–81 yrs), showed a favourable response. 4 pts were transfusion-dependent. Among them, 2 pts no mo...
- Published
- 2004
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