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An update on the safety and efficacy of decitabine in the treatment of myelodysplastic syndromes.

ABSTRACT: Myelodysplastic syndromes (MDS) are clonal bone marrow malignancies characterized by peripheral cytopenias and dysplastic changes in the bone marrow with various clinical features. Patients with MDS, in particular those with intermediate-2 (Int-2) and high-risk disease, have a poor prognosis. The mainstay of treatment includes cytoxic chemotherapy and supportive care. Over the last decade, promising results from studies focusing on hypomethylating agents, such as decitabine (5-aza-deoxycytidine) and 5-azacitidine, have led to the expansion of the therapeutic arsenal for MDS. This review presents the current data available on the clinical efficacy and safety profile for decitabine as a treatment for MDS. Although not fully understood, decitabine's antitumor activity may involve its ability to induce hypomethylation and reactivation of genes responsible for cellular differentiation, stimulate an immune response, induce DNA damage/apoptotic response pathways, and/or augment stem cell renewal. Future studies that use epigenetic therapies that combine hypomethylating agents with histone deacetylase inhibitors (HDACi) and head-to-head comparison studies of decitabine and 5-azacitidine will provide valuable pre-clinical and clinical data, enhancing our understanding of these drugs.

SUBMITTER: Garcia JS

PROVIDER: S-EPMC2895778 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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An update on the safety and efficacy of decitabine in the treatment of myelodysplastic syndromes.

Garcia Jacqueline S JS Jain Nitin N Godley Lucy A LA

OncoTargets and therapy 20100624

Myelodysplastic syndromes (MDS) are clonal bone marrow malignancies characterized by peripheral cytopenias and dysplastic changes in the bone marrow with various clinical features. Patients with MDS, in particular those with intermediate-2 (Int-2) and high-risk disease, have a poor prognosis. The mainstay of treatment includes cytoxic chemotherapy and supportive care. Over the last decade, promising results from studies focusing on hypomethylating agents, such as decitabine (5-aza-deoxycytidine) ...[more]

PMID: 20616953

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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 .).

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:The majority of myelodysplastic syndrome (MDS) patients belong to the International Prognostic Scoring System (IPSS) and IPSS-revised (IPSS-R) lower-risk categories. Their precise diagnostics and prognostic stratification is often a challenge, but may ensure the optimization of therapy. The availability of diverse treatment options has significantly improved the quality of life and survival of this group of patients. Anemia is the most relevant cytopenia in terms of frequency and symptoms in lower-risk MDS, and may be treated successfully with erythropoietic stimulating agents, provided a careful selection is performed on the basis of IPSS-R, endogenous erythropoietin levels, and transfusion independence. Doses and duration of therapy of erythropoietic-stimulating agents (ESAs) are critical to determine efficacy. In case a patient fails ESA treatment, the available options may include lenalidomide (approved for del5q positive cases), hypomethylating agents, and a rather large number of experimental agents, whose clinical trials should be offered to a larger number of MDS patients. The choice for second-line treatment must take into account biologic, cytogenetic, and molecular-identified characteristics of individual patients, as well as frailty and comorbidities. Other cytopenias are less frequently presenting as isolated. Specific therapy for thrombocytopenia has been proposed in experimental clinical trials with thrombomimetic agents that have shown good efficacy, but raised some safety concern. Although neutropenia is targeted symptomatically with growth factor supportive care, the immunosuppressive treatments are indicated mainly for pancytopenic, hypoplastic lower-risk MDS; they are not widely used because of their toxicity, despite the fact that they may induce responses. Finally, hematopoietic stem cell transplant is the curative option also for lower-risk MDS and timing should be carefully evaluated, balancing toxicity and the possibility of survival advantage. Finally, even when considered suitable for lower-risk MDS, transplant application is limited to the rarer fit and younger MDS patient.

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An update on the safety and efficacy of decitabine in the treatment of myelodysplastic syndromes.

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An update on the safety and efficacy of decitabine in the treatment of myelodysplastic syndromes.

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