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Randomized open-label phase II study of decitabine in patients with low- or intermediate-risk myelodysplastic syndromes.

ABSTRACT: This open-label, randomized phase II trial assessed efficacy and tolerability of two low-dose regimens of subcutaneous (SC) decitabine in patients with low- or intermediate-1-risk myelodysplastic syndrome (MDS).Patients received decitabine 20 mg/m(2) SC per day for 3 consecutive days on days 1, 2, and 3 every 28 days (schedule A) or 20 mg/m(2) SC per day once every 7 days on days 1, 8, and 15 every 28 days (schedule B) for up to 1 year. Primary efficacy end point was overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points were HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death.Efficacy and safety populations were identical: schedule A, n = 43; schedule B, n = 22. Median time from MDS diagnosis to treatment was 3.6 months; 89% had de novo MDS. The trial was terminated early on achievement of protocol-defined OIR superiority of schedule A over schedule B; OIR was 23% for schedule A (seven CRs, three HIs) and 23% for schedule B (one mCR, one PR, three HIs). No differences were observed in secondary end points. Median OS was not reached; approximately 70% of patients were alive at 500 days. Patients in schedule A (67%) and schedule B (59%) were RBC/platelet independent on study. The most frequent drug-related adverse events overall were neutropenia (28% v 36%), anemia (23% v 18%), and thrombocytopenia (16% v 32%).In this phase II study, low-dose decitabine showed promising results in patients with low- or intermediate-1-risk MDS.

SUBMITTER: Garcia-Manero G

PROVIDER: S-EPMC4878053 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Randomized open-label phase II study of decitabine in patients with low- or intermediate-risk myelodysplastic syndromes.

Garcia-Manero Guillermo G Jabbour Elias E Borthakur Gautam G Faderl Stefan S Estrov Zeev Z Yang Hui H Maddipoti Sirisha S Godley Lucy A LA Gabrail Nashat N Berdeja Jesus G JG Nadeem Ahmed A Kassalow Laurent L Kantarjian Hagop H

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20130603 20

<h4>Purpose</h4>This open-label, randomized phase II trial assessed efficacy and tolerability of two low-dose regimens of subcutaneous (SC) decitabine in patients with low- or intermediate-1-risk myelodysplastic syndrome (MDS).<h4>Patients and methods</h4>Patients received decitabine 20 mg/m(2) SC per day for 3 consecutive days on days 1, 2, and 3 every 28 days (schedule A) or 20 mg/m(2) SC per day once every 7 days on days 1, 8, and 15 every 28 days (schedule B) for up to 1 year. Primary effica ...[more]

PMID: 23733767

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Project description:IntroductionThe objective of this study was to evaluate the efficacy and safety of decitabine in Chinese patients with myelodysplastic syndrome (MDS).MethodsPatients (≥18 years) who had a de novo or secondary MDS diagnosis according to French-American-British classification and an International Prognostic Scoring System score ≥0.5 were enrolled and randomized (1:1) to one of two decitabine regimens: 3-day treatment (3-h intravenous infusion of 15 mg/m(2) given every 8 h for three consecutive days/cycle/6 weeks) or 5-day treatment (1-h intravenous infusion of 20 mg/m(2) once daily on days 1-5/cycle/4 weeks). After a minimum of 30 patients were assigned to 3-day schedule, the remaining were assigned to the 5-day schedule. The primary efficacy endpoint was the overall response rate (ORR). Secondary outcome measures included hematologic improvement (HI), cytogenetic response rate, the time to acute myeloid leukemia (AML) progression, and overall survival (OS).ResultsIn total, 132 of 135 enrolled patients (3-day treatment, n = 36; 5-day treatment, n = 99) discontinued treatment (major reasons included patient withdrawal/lack of efficacy, n = 48; adverse events, n = 23; and disease progression, n = 22). During the study, 35 of 132 (26.5%) patients from the intent-to-treat (ITT) group achieved significant (P < 0.001) ORR [3-day group (n = 10, 29.4%), P = 0.003; 5-day group (n = 25, 25.5%), P < 0.001]. The HI rate was similar between the 3-day (47.1%) and 5-day groups (48.0%). Cytogenetic response was achieved in 20 of the 30 (66.7%) patients who had a baseline cytogenetic abnormality. Fifty-three (40.2%) AML transformations or deaths occurred and the median AML-free survival time was 23.8 months for all patients from the ITT set; 24-month OS rate was 48.9%. Adverse events of myelosuppression-related disorders (85.6%) and infections (43.2%) were commonly reported.ConclusionDecitabine treatment was efficacious in Chinese patients with MDS with its safety profile comparable to the global studies of decitabine conducted to date.FundingXian-Janssen Pharmaceutical Ltd. China (a company of Johnson & Johnson).Trial registrationClinicalTrials.gov identifier, NCT01751867.

Project description:BackgroundGuadecitabine is a next-generation hypomethylating agent whose active metabolite decitabine has a longer in-vivo exposure time than intravenous decitabine. More effective hypomethylating agents are needed for the treatment of myelodysplastic syndromes. In the present study, we aimed to compare the activity and safety of two doses of guadecitabine in hypomethylating agent treatment-naive or relapsed or refractory patients with intermediate-risk or high-risk myelodysplastic syndromes.MethodsThis phase 2 part of the phase 1/2, randomised, open-label study enrolled patients aged 18 years or older from 14 North American medical centres with International Prognostic Scoring System intermediate-1-risk, intermediate-2-risk, or high-risk myelodysplastic syndromes, or chronic myelomonocytic leukaemia. They were either hypomethylating agent treatment-naive or had relapsed or refractory disease after previous hypomethylating agent treatment as determined by the investigators' judgment. Eligible patients had Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1) using a computer algorithm for dynamic randomisation to subcutaneous guadecitabine 60 or 90 mg/m2 on days 1-5 of a 28-day treatment cycle. Treatment was stratified by previous treatment with hypomethylating agents and neither patients nor investigators were masked. The primary endpoint was overall response (a composite of complete response, partial response, marrow complete response, and haematological improvement) assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01261312.FindingsBetween July 9, 2012, and April 7, 2014, 105 patients were enrolled: 55 (52%) were allocated to guadecitabine 60 mg/m2 (28 patients were treatment-naive and 27 had relapsed or refractory disease after previous hypomethylating agent treatment) and 50 (48%) patients to 90 mg/m2 (23 patients were treatment-naive and 27 had relapsed or refractory disease). Three (3%) patients of 105 did not receive study treatment and were excluded from analyses. Median follow-up was 3·2 years (IQR 2·8-3·5). The proportion of patients achieving an overall response did not significantly differ between dose groups (21 of 53 [40%, 95% CI 27-54] with 60 mg/m2 and 27 of 49 [55%, 95% CI 40-69] with 90 mg/m2; p=0·16). 25 of 49 (51%, 95% CI 36-66) patients who were treatment-naive and 23 of 53 (43%, 30-58) patients with relapsed or refractory disease achieved an overall response. The most common grade 3 or worse adverse events in both groups, regardless of relationship to treatment, were thrombocytopenia (22 [41%] of 53 patients in the 60 mg/m2 group and 28 [57%] of 49 in the 90 mg/m2 group), neutropaenia (21 [40%] and 25 [51%]), anaemia (25 [47%] and 24 [49%]), febrile neutropaenia (17 [32%] and 21 [43%]), and pneumonia (13 [25%] and 15 [31%]). Seven (7%) of 102 patients died due to adverse events (three with 90 mg/m2 and four with 60 mg/m2), and all except one were in the relapsed or refractory cohort. Two deaths were deemed treatment related (septic shock with 60 mg/m2; pneumonia with 90 mg/m2).InterpretationGuadecitabine was clinically active with acceptable tolerability in patients with intermediate-risk and high-risk myelodysplastic syndromes. Responses and overall survival in the relapsed or refractory cohort offer the potential of a new therapeutic option for patients for whom currently available hypomethylating agents are not successful. We therefore recommend guadecitabine at a dose of 60 mg/m2 on a 5-day schedule for these patients.FundingAstex Pharmaceuticals and Stand Up To Cancer.

Project description:BackgroundThe molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear.MethodsWe enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols.ResultsOf the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles.ConclusionsPatients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

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Randomized open-label phase II study of decitabine in patients with low- or intermediate-risk myelodysplastic syndromes.

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Randomized open-label phase II study of decitabine in patients with low- or intermediate-risk myelodysplastic syndromes.

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