Cytarabine

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Farhad Ravandi - One of the best experts on this subject based on the ideXlab platform.

  • durable overall survival benefit in patients 60 years with relapsed or refractory aml treated with vosaroxin Cytarabine vs placebo Cytarabine updated results from the valor trial
    Blood, 2016
    Co-Authors: Farhad Ravandi, Ellen K Ritchie, Hamid Sayar, Jeffrey E Lancet, Michael Craig, Stephen A Strickland, Gary J Schiller, Elias Jabbour, Harry P Erba, Arnaud Pigneux
    Abstract:

    Background: Prognosis for older patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) is poor, with lower response rates and shorter survival compared with younger patients. Vosaroxin is a first-in-class anticancer quinolone derivative that is active in AML, is minimally metabolized, evades P glycoprotein receptor-mediated efflux, and has activity independent of p53 status. In the phase 3 VALOR trial, overall survival (OS) was significantly improved with vosaroxin plus Cytarabine vs placebo plus Cytarabine in a prespecified analysis in patients ≥ 60 years of age (median OS: 7.1 mo vs 5.0 mo, respectively; HR = 0.75 [95% CI: 0.62-0.92]; P = 0.0030). At the time of the primary analysis (September 2014), patients had been followed for a median of 24.4 months (as estimated by the reverse Kaplan-Meier method). Here, after a median follow-up of 39.9 months, we provide updated survival information for patients ≥ 60 years treated in the VALOR trial. Methods: In VALOR, patients with refractory or first relapsed AML were randomized 1:1 to receive Cytarabine (1 g/m 2 IV over 2 h, d 1-5) plus either vosaroxin (90 mg/m 2 IV over 10 min, d 1, 4; 70 mg/m 2 in subsequent cycles) or placebo. Eligible patients had refractory disease (persistent disease after induction, or first complete remission [CR1] lasting Results:As of Jan 22, 2016, 33/451 patients ≥ 60 years treated in the VALOR trial were alive and in continued follow-up: 23/226 (10.2%) in the vosaroxin/Cytarabine arm and 10/225 (4.4%) in the placebo/Cytarabine arm. Updated OS data in patients ≥ 60 years of age was consistent with the primary analysis, demonstrating a significant improvement with the addition of vosaroxin (Figure; HR = 0.75 [95% CI: 0.62-0.91]; P = 0.0017). The survival benefit associated with vosaroxin/Cytarabine was durable, as demonstrated by the separation of the survival curves through 48 mo . At 24 and 36 mo after randomization, the estimated survival rate was twice as high with vosaroxin/Cytarabine as with placebo/Cytarabine in patients ≥ 60 years (17.0% vs 8.5% and 12.8% vs 6.0%, respectively). The OS benefit was consistent across various age subgroups in the population ≥ 60 years of age; in patients 60-64 years (n = 124), 65-74 years (n = 293), and 75-84 years (n = 34), vosaroxin/Cytarabine treatment increased median survival by 2.9 mo (8.1 vs 5.2 mo; HR = 0.72 [95% CI: 0.49-1.06]), 2.0 mo (7.0 vs 5.0 mo; HR = 0.76 [95% CI: 0.60-0.97]), and 2.2 mo (5.5 vs 3.3 mo; HR = 0.72 [95% CI: 0.36-1.45]) over placebo/Cytarabine treatment, respectively. An improvement in OS was observed among patients ≥ 60 years who received post-treatment transplantation (n = 91; 19.9 mo with vosaroxin/Cytarabine vs 12.2 mo with placebo/cytarbine; HR = 0.70 [95% CI: 0.43-1.13]) and those who did not (n = 360; 5.3 mo vs 3.8 mo, respectively; HR = 0.75 [95% CI: 0.60-0.92]). When analyzed by disease status, the greatest OS benefit was observed in patients ≥ 60 years with refractory disease (n = 210; 6.7 mo with vosaroxin/Cytarabine vs 3.8 mo with placebo/Cytarabine; HR = 0.75 [95% CI: 0.57-1.00]) and those with early relapse (n = 154; 6.5 mo vs 3.9 mo, respectively; HR = 0.62 [95% CI: 0.44-0.87]). In patients ≥ 60 years with late relapse (n = 87), median OS was similar in both treatment arms (9.2 mo with vosaroxin/Cytarabine vs 9.8 mo with placebo/Cytarabine; HR = 1.06 [95% CI: 0.68-1.66]). Conclusions: After a median of 39.9 months of follow-up in the VALOR trial, the OS observed in patients ≥ 60 years of age treated with vosaroxin/Cytarabine remains significantly improved versus placebo/Cytarabine, with a separation of the survival curves through 48 months. The OS benefit is consistent among all older patients, even those ≥ 75 years of age, and is seen in patients with and without post-treatment transplantation. The updated survival data from VALOR continue to support the use of vosaroxin/Cytarabine as a treatment option in patients ≥ 60 years of age with R/R AML. Disclosures Ravandi: BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Ritchie: Novartis: Honoraria, Research Funding; Celgene: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Honoraria; Arian: Speakers Bureau. Vey: Sunesis: Honoraria. Strickland: Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Schiller: Incyte Corporation: Research Funding. Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Erba: Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Juno: Research Funding; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding. Pigneux: Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Horst: Amgen, Novartis, Pfizer, Gilead, Agios: Consultancy; Amgen, Regeneron: Research Funding; Celgene: Honoraria. Recher: Celgene, Sunesis, Amgen, Novartis: Membership on an entity9s Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding. Cortes: ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Roboz: Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding. Craig: Sunesis: Employment, Equity Ownership. Ward: Sunesis Pharmaceuticals: Consultancy, Employment. Smith: Sunesis: Employment, Equity Ownership. Stuart: Agios: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Incyte: Research Funding; Bayer: Research Funding; Celator: Research Funding; Astellas: Research Funding.

  • vosaroxin plus Cytarabine versus placebo plus Cytarabine in patients with first relapsed or refractory acute myeloid leukaemia valor a randomised controlled double blind multinational phase 3 study
    Lancet Oncology, 2015
    Co-Authors: Farhad Ravandi, Ellen K Ritchie, Hamid Sayar, Jeffrey E Lancet, Michael Craig, Stephen A Strickland, Gary J Schiller, Elias Jabbour, Harry P Erba, Arnaud Pigneux
    Abstract:

    Summary Background Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus Cytarabine in patients with relapsed or refractory acute myeloid leukaemia. Methods This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus Cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m 2 intravenously on days 1 and 4 in a first cycle; 70 mg/m 2 in subsequent cycles) plus Cytarabine (1 g/m 2 intravenously on days 1–5) or placebo plus Cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. Findings Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus Cytarabine (n=356) or placebo plus Cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4–8·5) in the vosaroxin plus Cytarabine group and 6·1 months (5·2–7·1) in the placebo plus Cytarabine group (hazard ratio 0·87, 95% CI 0·73–1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus Cytarabine group than in the placebo plus Cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p vs 23 [7%] of 350 in the placebo plus Cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus Cytarabine and in eight (2%) of 350 patients given placebo plus Cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus Cytarabine group than in the placebo plus Cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]). Interpretation Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to Cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia. Funding Sunesis Pharmaceuticals.

  • clofarabine idarubicin and Cytarabine cia as frontline therapy for patients 60 years with newly diagnosed acute myeloid leukemia
    American Journal of Hematology, 2013
    Co-Authors: Aziz Nazha, Guillermo Garciamanero, Farhad Ravandi, Elias Jabbour, Hagop M Kantarjian, Xuelin Huang, Sangbum Choi, Gautam Borthakur, Tapan M Kadia, Marina Konopleva
    Abstract:

    Clofarabine is a second generation nucleoside analogue with activity in adults with acute myeloid leukemia (AML). A phase I trial of clofarabine, idarubicin, and Cytarabine (CIA) in relapsed and refractory AML had shown an overall response rate (ORR) of 48%. To explore this combination further, we conducted a phase II study of (CIA) in patients with newly diagnosed AML ≤60 years. Patients ≥18–60 years with AML and adequate organ function were enrolled. Induction therapy consisted of clofarabine (C) 20 mg m−2 IV daily (days 1–5), idarubicin (I) 10 mg m−2 IV daily (days 1–3), and Cytarabine (A) 1 g m−2 IV daily (days 1–5). Patients in remission received up to six consolidation cycles (C 15 mg m−2 × 3, I 8 mg m−2 × 2, and A 0.75 g m−2 × 3). Fifty-seven patients were evaluable. ORR was 79%. With a median follow up of 10.9 months, the median overall survival (OS) was not reached, the median event-free survival (EFS) was 13.5 months. Most toxicities were ≤grade 2. Four week mortality was 2%. In subgroup analysis, patients ≤40 years had better OS (P = 0.04) and EFS (P = 0.04) compared to patients >40 years. Compared to historical patients treated with idarubicin and cyarabine (IA), the OS and EFS were significantly longer for CIA treated patients. In multivariate analysis, CIA retained its favorable impact on OS compared to IA. Thus, CIA is an effective and safe therapy for patients ≤60 years with newly diagnosed AML. Am. J. Heamtol. 88:961–966, 2013. © 2013 Wiley Periodicals, Inc.

  • a randomized study of clofarabine versus clofarabine plus low dose Cytarabine as front line therapy for patients aged 60 years and older with acute myeloid leukemia and high risk myelodysplastic syndrome
    Blood, 2008
    Co-Authors: Stefan Faderl, Alessandra Ferrajoli, Guillermo Garciamanero, Zeev Estrov, Farhad Ravandi, Deborah A Thomas, Xuelin Huang, Gautam Borthakur, Srdan Verstovsek, Monica Kwari
    Abstract:

    We previously reported the feasibility of clofarabine and Cytarabine combinations in AML. Questions remain as to (1) the therapeutic advantage of this combination and (2) the role of lower doses of clofarabine and Cytarabine in older patients. We have conducted an adaptively randomized study of lower-dose clofarabine with or without low-dose Cytarabine in previously untreated patients with AML aged 60 years and older. Patients received 30 mg/m2 clofarabine intravenously daily for 5 days with or without 20 mg/m2 Cytarabine subcutaneously daily for 14 days as induction. Consolidation consisted of 3 days of clofarabine with or without 7 days of Cytarabine. Seventy patients were enrolled. The median age was 71 years (range, 60-83 years). Sixteen patients received clofarabine and 54 the combination. Overall, 56% achieved complete remission (CR). CR rate was significantly higher with the combination (63% vs 31%; P = .025). Induction mortality was 19% with the combination versus 31% with clofarabine alone ( P = .276). The combination showed better event-free survival (7.1 months vs 1.7 months; P = .04), but not overall survival (11.4 months vs 5.8 months; P = .1). Clofarabine plus low-dose Cytarabine has a higher response rate than clofarabine alone with comparable toxicity. This trial is registered at [www.clinicaltrials.gov][1] as no. [NCT00088218][2]. [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00088218&atom=%2Fbloodjournal%2F112%2F5%2F1638.atom

  • neurologic complications associated with intrathecal liposomal Cytarabine given prophylactically in combination with high dose methotrexate and Cytarabine to patients with acute lymphocytic leukemia
    Blood, 2007
    Co-Authors: Elias Jabbour, Susan Obrien, Alessandra Ferrajoli, Guillermo Garciamanero, Farhad Ravandi, Hagop M Kantarjian, Maria E Cabanillas, Deborah A Thomas
    Abstract:

    Central nervous system (CNS) prophylaxis has led to a significant improvement in the outcome of patients with acute lymphocytic leukemia (ALL). Liposomal Cytarabine (Enzon Pharmaceuticals, Piscataway, NJ; Skye Pharma, San Diego, CA), an intrathecal (IT) preparation of Cytarabine with a prolonged half-life, has been shown to be safe and effective in the treatment of neoplastic meningitis. Liposomal Cytarabine was given for CNS prophylaxis to 31 patients with newly diagnosed ALL. All patients were treated concurrently with hyper-CVAD chemotherapy (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) including high-dose methotrexate (MTX) and Cytarabine on alternating courses. Liposomal Cytarabine 50 mg was given intrathecally on days 2 and 15 of hyper-CVAD and day 10 of high-dose MTX and Cytarabine courses until completion of either 3, 6, or 10 IT treatments, depending on risk for CNS disease. Five patients (16%) experienced serious unexpected neurotoxicity, including seizures, papilledema, cauda equina syndrome (n = 2), and encephalitis after a median of 4 IT administrations of liposomal Cytarabine. Toxicities usually manifested after the MTX and Cytarabine courses. One patient died with progressive encephalitis. After a median follow-up of 7 months, no isolated CNS relapses have been observed. Liposomal Cytarabine given via intrathecal route concomitantly with systemic chemotherapy that crosses the blood-brain barrier such as high-dose MTX and Cytarabine can result in significant neurotoxicity.

Elias Jabbour - One of the best experts on this subject based on the ideXlab platform.

  • durable overall survival benefit in patients 60 years with relapsed or refractory aml treated with vosaroxin Cytarabine vs placebo Cytarabine updated results from the valor trial
    Blood, 2016
    Co-Authors: Farhad Ravandi, Ellen K Ritchie, Hamid Sayar, Jeffrey E Lancet, Michael Craig, Stephen A Strickland, Gary J Schiller, Elias Jabbour, Harry P Erba, Arnaud Pigneux
    Abstract:

    Background: Prognosis for older patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) is poor, with lower response rates and shorter survival compared with younger patients. Vosaroxin is a first-in-class anticancer quinolone derivative that is active in AML, is minimally metabolized, evades P glycoprotein receptor-mediated efflux, and has activity independent of p53 status. In the phase 3 VALOR trial, overall survival (OS) was significantly improved with vosaroxin plus Cytarabine vs placebo plus Cytarabine in a prespecified analysis in patients ≥ 60 years of age (median OS: 7.1 mo vs 5.0 mo, respectively; HR = 0.75 [95% CI: 0.62-0.92]; P = 0.0030). At the time of the primary analysis (September 2014), patients had been followed for a median of 24.4 months (as estimated by the reverse Kaplan-Meier method). Here, after a median follow-up of 39.9 months, we provide updated survival information for patients ≥ 60 years treated in the VALOR trial. Methods: In VALOR, patients with refractory or first relapsed AML were randomized 1:1 to receive Cytarabine (1 g/m 2 IV over 2 h, d 1-5) plus either vosaroxin (90 mg/m 2 IV over 10 min, d 1, 4; 70 mg/m 2 in subsequent cycles) or placebo. Eligible patients had refractory disease (persistent disease after induction, or first complete remission [CR1] lasting Results:As of Jan 22, 2016, 33/451 patients ≥ 60 years treated in the VALOR trial were alive and in continued follow-up: 23/226 (10.2%) in the vosaroxin/Cytarabine arm and 10/225 (4.4%) in the placebo/Cytarabine arm. Updated OS data in patients ≥ 60 years of age was consistent with the primary analysis, demonstrating a significant improvement with the addition of vosaroxin (Figure; HR = 0.75 [95% CI: 0.62-0.91]; P = 0.0017). The survival benefit associated with vosaroxin/Cytarabine was durable, as demonstrated by the separation of the survival curves through 48 mo . At 24 and 36 mo after randomization, the estimated survival rate was twice as high with vosaroxin/Cytarabine as with placebo/Cytarabine in patients ≥ 60 years (17.0% vs 8.5% and 12.8% vs 6.0%, respectively). The OS benefit was consistent across various age subgroups in the population ≥ 60 years of age; in patients 60-64 years (n = 124), 65-74 years (n = 293), and 75-84 years (n = 34), vosaroxin/Cytarabine treatment increased median survival by 2.9 mo (8.1 vs 5.2 mo; HR = 0.72 [95% CI: 0.49-1.06]), 2.0 mo (7.0 vs 5.0 mo; HR = 0.76 [95% CI: 0.60-0.97]), and 2.2 mo (5.5 vs 3.3 mo; HR = 0.72 [95% CI: 0.36-1.45]) over placebo/Cytarabine treatment, respectively. An improvement in OS was observed among patients ≥ 60 years who received post-treatment transplantation (n = 91; 19.9 mo with vosaroxin/Cytarabine vs 12.2 mo with placebo/cytarbine; HR = 0.70 [95% CI: 0.43-1.13]) and those who did not (n = 360; 5.3 mo vs 3.8 mo, respectively; HR = 0.75 [95% CI: 0.60-0.92]). When analyzed by disease status, the greatest OS benefit was observed in patients ≥ 60 years with refractory disease (n = 210; 6.7 mo with vosaroxin/Cytarabine vs 3.8 mo with placebo/Cytarabine; HR = 0.75 [95% CI: 0.57-1.00]) and those with early relapse (n = 154; 6.5 mo vs 3.9 mo, respectively; HR = 0.62 [95% CI: 0.44-0.87]). In patients ≥ 60 years with late relapse (n = 87), median OS was similar in both treatment arms (9.2 mo with vosaroxin/Cytarabine vs 9.8 mo with placebo/Cytarabine; HR = 1.06 [95% CI: 0.68-1.66]). Conclusions: After a median of 39.9 months of follow-up in the VALOR trial, the OS observed in patients ≥ 60 years of age treated with vosaroxin/Cytarabine remains significantly improved versus placebo/Cytarabine, with a separation of the survival curves through 48 months. The OS benefit is consistent among all older patients, even those ≥ 75 years of age, and is seen in patients with and without post-treatment transplantation. The updated survival data from VALOR continue to support the use of vosaroxin/Cytarabine as a treatment option in patients ≥ 60 years of age with R/R AML. Disclosures Ravandi: BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Ritchie: Novartis: Honoraria, Research Funding; Celgene: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Honoraria; Arian: Speakers Bureau. Vey: Sunesis: Honoraria. Strickland: Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Schiller: Incyte Corporation: Research Funding. Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Erba: Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Juno: Research Funding; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding. Pigneux: Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Horst: Amgen, Novartis, Pfizer, Gilead, Agios: Consultancy; Amgen, Regeneron: Research Funding; Celgene: Honoraria. Recher: Celgene, Sunesis, Amgen, Novartis: Membership on an entity9s Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding. Cortes: ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Roboz: Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding. Craig: Sunesis: Employment, Equity Ownership. Ward: Sunesis Pharmaceuticals: Consultancy, Employment. Smith: Sunesis: Employment, Equity Ownership. Stuart: Agios: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Incyte: Research Funding; Bayer: Research Funding; Celator: Research Funding; Astellas: Research Funding.

  • vosaroxin plus Cytarabine versus placebo plus Cytarabine in patients with first relapsed or refractory acute myeloid leukaemia valor a randomised controlled double blind multinational phase 3 study
    Lancet Oncology, 2015
    Co-Authors: Farhad Ravandi, Ellen K Ritchie, Hamid Sayar, Jeffrey E Lancet, Michael Craig, Stephen A Strickland, Gary J Schiller, Elias Jabbour, Harry P Erba, Arnaud Pigneux
    Abstract:

    Summary Background Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus Cytarabine in patients with relapsed or refractory acute myeloid leukaemia. Methods This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus Cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m 2 intravenously on days 1 and 4 in a first cycle; 70 mg/m 2 in subsequent cycles) plus Cytarabine (1 g/m 2 intravenously on days 1–5) or placebo plus Cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. Findings Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus Cytarabine (n=356) or placebo plus Cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4–8·5) in the vosaroxin plus Cytarabine group and 6·1 months (5·2–7·1) in the placebo plus Cytarabine group (hazard ratio 0·87, 95% CI 0·73–1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus Cytarabine group than in the placebo plus Cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p vs 23 [7%] of 350 in the placebo plus Cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus Cytarabine and in eight (2%) of 350 patients given placebo plus Cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus Cytarabine group than in the placebo plus Cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]). Interpretation Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to Cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia. Funding Sunesis Pharmaceuticals.

  • clofarabine idarubicin and Cytarabine cia as frontline therapy for patients 60 years with newly diagnosed acute myeloid leukemia
    American Journal of Hematology, 2013
    Co-Authors: Aziz Nazha, Guillermo Garciamanero, Farhad Ravandi, Elias Jabbour, Hagop M Kantarjian, Xuelin Huang, Sangbum Choi, Gautam Borthakur, Tapan M Kadia, Marina Konopleva
    Abstract:

    Clofarabine is a second generation nucleoside analogue with activity in adults with acute myeloid leukemia (AML). A phase I trial of clofarabine, idarubicin, and Cytarabine (CIA) in relapsed and refractory AML had shown an overall response rate (ORR) of 48%. To explore this combination further, we conducted a phase II study of (CIA) in patients with newly diagnosed AML ≤60 years. Patients ≥18–60 years with AML and adequate organ function were enrolled. Induction therapy consisted of clofarabine (C) 20 mg m−2 IV daily (days 1–5), idarubicin (I) 10 mg m−2 IV daily (days 1–3), and Cytarabine (A) 1 g m−2 IV daily (days 1–5). Patients in remission received up to six consolidation cycles (C 15 mg m−2 × 3, I 8 mg m−2 × 2, and A 0.75 g m−2 × 3). Fifty-seven patients were evaluable. ORR was 79%. With a median follow up of 10.9 months, the median overall survival (OS) was not reached, the median event-free survival (EFS) was 13.5 months. Most toxicities were ≤grade 2. Four week mortality was 2%. In subgroup analysis, patients ≤40 years had better OS (P = 0.04) and EFS (P = 0.04) compared to patients >40 years. Compared to historical patients treated with idarubicin and cyarabine (IA), the OS and EFS were significantly longer for CIA treated patients. In multivariate analysis, CIA retained its favorable impact on OS compared to IA. Thus, CIA is an effective and safe therapy for patients ≤60 years with newly diagnosed AML. Am. J. Heamtol. 88:961–966, 2013. © 2013 Wiley Periodicals, Inc.

  • neurologic complications associated with intrathecal liposomal Cytarabine given prophylactically in combination with high dose methotrexate and Cytarabine to patients with acute lymphocytic leukemia
    Blood, 2007
    Co-Authors: Elias Jabbour, Susan Obrien, Alessandra Ferrajoli, Guillermo Garciamanero, Farhad Ravandi, Hagop M Kantarjian, Maria E Cabanillas, Deborah A Thomas
    Abstract:

    Central nervous system (CNS) prophylaxis has led to a significant improvement in the outcome of patients with acute lymphocytic leukemia (ALL). Liposomal Cytarabine (Enzon Pharmaceuticals, Piscataway, NJ; Skye Pharma, San Diego, CA), an intrathecal (IT) preparation of Cytarabine with a prolonged half-life, has been shown to be safe and effective in the treatment of neoplastic meningitis. Liposomal Cytarabine was given for CNS prophylaxis to 31 patients with newly diagnosed ALL. All patients were treated concurrently with hyper-CVAD chemotherapy (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) including high-dose methotrexate (MTX) and Cytarabine on alternating courses. Liposomal Cytarabine 50 mg was given intrathecally on days 2 and 15 of hyper-CVAD and day 10 of high-dose MTX and Cytarabine courses until completion of either 3, 6, or 10 IT treatments, depending on risk for CNS disease. Five patients (16%) experienced serious unexpected neurotoxicity, including seizures, papilledema, cauda equina syndrome (n = 2), and encephalitis after a median of 4 IT administrations of liposomal Cytarabine. Toxicities usually manifested after the MTX and Cytarabine courses. One patient died with progressive encephalitis. After a median follow-up of 7 months, no isolated CNS relapses have been observed. Liposomal Cytarabine given via intrathecal route concomitantly with systemic chemotherapy that crosses the blood-brain barrier such as high-dose MTX and Cytarabine can result in significant neurotoxicity.

Bob Lowenberg - One of the best experts on this subject based on the ideXlab platform.

  • sense and nonsense of high dose Cytarabine for acute myeloid leukemia
    Blood, 2013
    Co-Authors: Bob Lowenberg
    Abstract:

    High-dose Cytarabine applied during remission induction or as consolidation after attainment of a complete remission has become an established element in the treatment of adults with acute myeloid leukemia. Recent evidence has challenged the need for these exceptionally high-dose levels of Cytarabine. In this review, we present a reappraisal of the usefulness of high-dose Cytarabine for acute myeloid leukemia treatment.

  • Cytarabine dose for acute myeloid leukemia
    The New England Journal of Medicine, 2011
    Co-Authors: Bob Lowenberg, Thomas Pabst, Edo Vellenga, Wim L J Van Putten, Harry C Schouten, Carlos Graux, Bart J Biemond, Peter Sonneveld, Augustin Ferrant, Alois Gratwohl
    Abstract:

    Cytarabine (ara-C) is an important drug in the treatment of acute myeloid leukemia (AML). High-dose Cytarabine (2000 to 3000 mg per square meter of body-surface area) is toxic but results in higher rates of relapse-free survival than does the conventional dose of 100 to 400 mg per square meter. Intermediate dose levels have not been thoroughly evaluated.

Guillermo Garciamanero - One of the best experts on this subject based on the ideXlab platform.

  • clofarabine idarubicin and Cytarabine cia as frontline therapy for patients 60 years with newly diagnosed acute myeloid leukemia
    American Journal of Hematology, 2013
    Co-Authors: Aziz Nazha, Guillermo Garciamanero, Farhad Ravandi, Elias Jabbour, Hagop M Kantarjian, Xuelin Huang, Sangbum Choi, Gautam Borthakur, Tapan M Kadia, Marina Konopleva
    Abstract:

    Clofarabine is a second generation nucleoside analogue with activity in adults with acute myeloid leukemia (AML). A phase I trial of clofarabine, idarubicin, and Cytarabine (CIA) in relapsed and refractory AML had shown an overall response rate (ORR) of 48%. To explore this combination further, we conducted a phase II study of (CIA) in patients with newly diagnosed AML ≤60 years. Patients ≥18–60 years with AML and adequate organ function were enrolled. Induction therapy consisted of clofarabine (C) 20 mg m−2 IV daily (days 1–5), idarubicin (I) 10 mg m−2 IV daily (days 1–3), and Cytarabine (A) 1 g m−2 IV daily (days 1–5). Patients in remission received up to six consolidation cycles (C 15 mg m−2 × 3, I 8 mg m−2 × 2, and A 0.75 g m−2 × 3). Fifty-seven patients were evaluable. ORR was 79%. With a median follow up of 10.9 months, the median overall survival (OS) was not reached, the median event-free survival (EFS) was 13.5 months. Most toxicities were ≤grade 2. Four week mortality was 2%. In subgroup analysis, patients ≤40 years had better OS (P = 0.04) and EFS (P = 0.04) compared to patients >40 years. Compared to historical patients treated with idarubicin and cyarabine (IA), the OS and EFS were significantly longer for CIA treated patients. In multivariate analysis, CIA retained its favorable impact on OS compared to IA. Thus, CIA is an effective and safe therapy for patients ≤60 years with newly diagnosed AML. Am. J. Heamtol. 88:961–966, 2013. © 2013 Wiley Periodicals, Inc.

  • a randomized study of clofarabine versus clofarabine plus low dose Cytarabine as front line therapy for patients aged 60 years and older with acute myeloid leukemia and high risk myelodysplastic syndrome
    Blood, 2008
    Co-Authors: Stefan Faderl, Alessandra Ferrajoli, Guillermo Garciamanero, Zeev Estrov, Farhad Ravandi, Deborah A Thomas, Xuelin Huang, Gautam Borthakur, Srdan Verstovsek, Monica Kwari
    Abstract:

    We previously reported the feasibility of clofarabine and Cytarabine combinations in AML. Questions remain as to (1) the therapeutic advantage of this combination and (2) the role of lower doses of clofarabine and Cytarabine in older patients. We have conducted an adaptively randomized study of lower-dose clofarabine with or without low-dose Cytarabine in previously untreated patients with AML aged 60 years and older. Patients received 30 mg/m2 clofarabine intravenously daily for 5 days with or without 20 mg/m2 Cytarabine subcutaneously daily for 14 days as induction. Consolidation consisted of 3 days of clofarabine with or without 7 days of Cytarabine. Seventy patients were enrolled. The median age was 71 years (range, 60-83 years). Sixteen patients received clofarabine and 54 the combination. Overall, 56% achieved complete remission (CR). CR rate was significantly higher with the combination (63% vs 31%; P = .025). Induction mortality was 19% with the combination versus 31% with clofarabine alone ( P = .276). The combination showed better event-free survival (7.1 months vs 1.7 months; P = .04), but not overall survival (11.4 months vs 5.8 months; P = .1). Clofarabine plus low-dose Cytarabine has a higher response rate than clofarabine alone with comparable toxicity. This trial is registered at [www.clinicaltrials.gov][1] as no. [NCT00088218][2]. [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00088218&atom=%2Fbloodjournal%2F112%2F5%2F1638.atom

  • phase i ii study of oxaliplatin fludarabine Cytarabine and rituximab combination therapy in patients with richter s syndrome or fludarabine refractory chronic lymphocytic leukemia
    Journal of Clinical Oncology, 2008
    Co-Authors: Apostolia Maria Tsimberidou, William G Wierda, William Plunkett, Razelle Kurzrock, Susan Obrien, Alessandra Ferrajoli, Farhad Ravandikashani, Guillermo Garciamanero, Zeev Estrov, Thomas J Kipps
    Abstract:

    Purpose Richter's syndrome (RS) and fludarabine-refractory chronic lymphocytic leukemia (CLL) are associated with poor clinical outcomes. We conducted a phase I-II trial of oxaliplatin, fludarabine, Cytarabine, and rituximab (OFAR) in these diseases. Patients and Methods The OFAR regimen consisted of increasing doses of oxaliplatin (17.5, 20, or 25 mg/m2/d) on days 1 to 4 (phase I), fludarabine 30 mg/m2 on days 2 to 3, Cytarabine 1 g/m2 on days 2 to 3, rituximab 375 mg/m2 on day 3 of cycle 1 and day 1 of subsequent cycles, and pegfilgrastim 6 mg on day 6, every 4 weeks for a maximum of six courses. Dose-limiting toxicity (DLT) was defined as any nonhematologic, treatment-related toxicity ≥ grade 3. Results Fifty patients were treated (20 patients had RS, and 30 had CLL). The highest tolerated oxaliplatin dose was 25 mg/m2, which was the highest dose tested. DLT was not observed. Pharmacodynamic analyses demonstrated enhanced leukemia cell killing by oxaliplatin in the presence of fludarabine and cytarabin...

  • neurologic complications associated with intrathecal liposomal Cytarabine given prophylactically in combination with high dose methotrexate and Cytarabine to patients with acute lymphocytic leukemia
    Blood, 2007
    Co-Authors: Elias Jabbour, Susan Obrien, Alessandra Ferrajoli, Guillermo Garciamanero, Farhad Ravandi, Hagop M Kantarjian, Maria E Cabanillas, Deborah A Thomas
    Abstract:

    Central nervous system (CNS) prophylaxis has led to a significant improvement in the outcome of patients with acute lymphocytic leukemia (ALL). Liposomal Cytarabine (Enzon Pharmaceuticals, Piscataway, NJ; Skye Pharma, San Diego, CA), an intrathecal (IT) preparation of Cytarabine with a prolonged half-life, has been shown to be safe and effective in the treatment of neoplastic meningitis. Liposomal Cytarabine was given for CNS prophylaxis to 31 patients with newly diagnosed ALL. All patients were treated concurrently with hyper-CVAD chemotherapy (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) including high-dose methotrexate (MTX) and Cytarabine on alternating courses. Liposomal Cytarabine 50 mg was given intrathecally on days 2 and 15 of hyper-CVAD and day 10 of high-dose MTX and Cytarabine courses until completion of either 3, 6, or 10 IT treatments, depending on risk for CNS disease. Five patients (16%) experienced serious unexpected neurotoxicity, including seizures, papilledema, cauda equina syndrome (n = 2), and encephalitis after a median of 4 IT administrations of liposomal Cytarabine. Toxicities usually manifested after the MTX and Cytarabine courses. One patient died with progressive encephalitis. After a median follow-up of 7 months, no isolated CNS relapses have been observed. Liposomal Cytarabine given via intrathecal route concomitantly with systemic chemotherapy that crosses the blood-brain barrier such as high-dose MTX and Cytarabine can result in significant neurotoxicity.

Clara D Bloomfield - One of the best experts on this subject based on the ideXlab platform.

  • patients with acute myeloid leukemia and ras mutations benefit most from postremission high dose Cytarabine a cancer and leukemia group b study
    Journal of Clinical Oncology, 2008
    Co-Authors: Andreas Neubauer, Kati Maharry, Krzysztof Mrozek, Christian Thiede, Guido Marcucci, Peter Paschka, Robert J Mayer, Richard A Larson, Clara D Bloomfield
    Abstract:

    Purpose RAS mutations occur in 12% to 27% of patients with acute myeloid leukemia (AML) and enhance sensitivity to Cytarabine in vitro. We examined whether RAS mutations impact response to Cytarabine in vivo. Patients and Methods One hundred eighty-five patients with AML achieving complete remission on Cancer and Leukemia Group B study 8525 and randomly assigned to one of three doses of Cytarabine postremission were screened for RAS mutations. We assessed the impact of Cytarabine dose on cumulative incidence of relapse (CIR) of patients with (mutRAS) and without (wild-type; wtRAS) RAS mutations. Results Thirty-four patients (18%) had RAS mutations. With 12.9 years median follow-up, the 10-year CIR was similar for mutRAS and wtRAS patients (65% v 73%; P .31). However, mutRAS patients receiving high-dose Cytarabine consolidation (HDAC; 3 g/m 2 every 12 hours on days 1, 3, and 5 or 400 mg/m 2 /d 5 days) had the lowest 10-year CIR, 45%, compared with 68% for wtRAS patients receiving HDAC and 80% and 100%, respectively, for wtRAS and mutRAS patients receiving low-dose Cytarabine (LDAC; 100 mg/m 2 /d 5 days; overall comparison, P .001). Multivariable analysis revealed an interaction of Cytarabine dose and RAS status (P .06). After adjusting for this interaction and cytogenetics (core binding factor [CBF] AML v non-CBF AML), wtRAS patients receiving HDAC had lower relapse risk than wtRAS patients receiving LDAC (hazard ratio [HR] 0.67; P .04); however, mutRAS patients receiving HDAC had greater reduction in relapse risk (HR 0.28; P .002) compared with mutRAS patients treated with LDAC. Conclusion AML patients carrying mutRAS benefit from higher Cytarabine doses more than wtRAS patients. This seems to be the first example of an activating oncogene mutation favorably modifying response to higher drug doses in AML. J Clin Oncol 26:4603-4609. © 2008 by American Society of Clinical Oncology

  • postremission therapy in older patients with de novo acute myeloid leukemia a randomized trial comparing mitoxantrone and intermediate dose Cytarabine with standard dose Cytarabine
    Blood, 2001
    Co-Authors: Richard Stone, Deborah T Berg, Stephen L George, Richard K Dodge, Paolo Alberto Paciucci, Philip Schulman, Joseph O Moore, Bayard L Powell, Maria R Baer, Clara D Bloomfield
    Abstract:

    The treatment of older patients with acute myeloid leukemia (AML) remains unsatisfactory, with complete remission (CR) achieved in only approximately 50% and long-term disease-free survival in 10% to 20%. Three hundred eighty-eight patients (60 years of age and older) with newly diagnosed de novo AML were randomly assigned to receive placebo (P) or granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM in a double-blind manner, beginning 1 day after the completion of 3 days of daunorubicin and 7 days of Cytarabine therapy. No differences were found in the rates of leukemic regrowth, CR, or infectious complications in either arm. Of 205 patients who achieved CR, 169 were medically well and were randomized to receive Cytarabine alone or a combination of Cytarabine and mitoxantrone. With a median follow-up of 7.7 years, the median disease-free survival times were 11 months and 10 months for those randomized to Cytarabine or Cytarabine/mitoxantrone, respectively. Rates of relapse, excluding deaths in CR, were 77% for Cytarabine and 82% for Cytarabine/mitoxantrone. Induction randomization had no effect on leukemic relapse rate or remission duration in either postremission arm. Because Cytarabine/mitoxantrone was more toxic and no more effective than Cytarabine, it was concluded that this higher-dose therapy had no benefit in the postremission management of older patients with de novo AML. These results suggest the need to develop novel therapeutic strategies for these patients.

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