Decitabine improves patient outcomes in myelodysplastic syndromes

Abstract

BACKGROUNDAberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy. Decitabine indirectly depletes methylcytosine and causes hypomethylation of target gene promoters.METHODSA total of 170 patients with MDS were randomized to receive either decitabine at a dose of 15 mg/m2 given intravenously over 3 hours every 8 hours for 3 days (at a dose of 135 mg/m2 per course) and repeated every 6 weeks, or best supportive care. Response was assessed using the International Working Group criteria and required that response criteria be met for at least 8 weeks.RESULTSPatients who were treated with decitabine achieved a significantly higher overall response rate (17%), including 9% complete responses, compared with supportive care (0%) (P < .001). An additional 12 patients who were treated with decitabine (13%) achieved hematologic improvement. Responses were durable (median, 10.3 mos) and were associated with transfusion independence. Patients treated with decitabine had a trend toward a longer median time to acute myelogenous leukemia (AML) progression or death compared with patients who received supportive care alone (all patients, 12.1 mos vs. 7.8 mos [P = 0.16]; those with International Prognostic Scoring System intermediate‐2/high‐risk disease, 12.0 mos vs. 6.8 mos [P = 0.03]; those with de novo disease, 12.6 mos vs. 9.4 mos [P = 0.04]; and treatment‐naive patients, 12.3 mos vs. 7.3 mos [P = 0.08]).CONCLUSIONSDecitabine was found to be clinically effective in the treatment of patients with MDS, provided durable responses, and improved time to AML transformation or death. The duration of decitabine therapy may improve these results further. Cancer 2006. © 2006 American Cancer Society.

Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group

“…This-at first counterintuitive-clinical finding was confirmed in MDS [27,28] and AML [7,8]. While these trials were ongoing, Breems et al [23] first described the novel cytogenetic poor-risk category of MK in AML.…”

Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients ≥60 years old

“…The earliest clinical data of HMAs in AML patients were noncomparative trials mostly involving individuals unfit for IC [17][18][19][20]25]. Next, subgroup analyses of large prospective phase III trials of Aza or Dec demonstrated superior outcomes for HMA over best supportive care in AML patients with marrow blast counts of 20-30% [21,30,33]. HMA have subsequently been evaluated in multiple trials for elderly AML patients with more aggressive disease.…”

Epigenetic cancer therapy: rationales, targets and drugs

“…5-Azacytidine and decitabine have shown significant clinical benefit in the treatment of myelodysplastic syndrome (Silverman et al, 2002;Kantarjian et al, 2006) and are also used for the treatment of myeloid leukemias. Both drugs are particularly effective when administered at low doses, which are sometimes below 10% of their maximum tolerated doses (Issa and Kantarjian, 2009).…”