Reduced-Intensity Chemotherapy for Lower-Risk Myelodysplastic Syndromes

The hypomethylating agents (HMA) decitabine and azacitidine are standards of care for high-risk myelodysplastic syndromes (MDS), with treatment administered on the first 5 to 7 days of each 28-day cycle. Investigators now report long-term follow-up of a phase 2 multicenter trial of reduced-intensity therapy in patients with low- and low-intermediate risk MDS (as defined by the International Prognostic Scoring System [IPSS]) who had not received prior HMA treatment.

Patients were randomized to decitabine 20 mg/m² IV or azacitidine 75 mg/m² IV or subcutaneously on days 1 to 3 of 28-day cycles, with treatment continued indefinitely in responding patients. A response-adaptive randomization was employed; as the initial 20-patient cohort showed higher responses with decitabine, more patients were subsequently accrued to that study arm. Baseline mutational profiling of myeloid-related genes was obtained; response assessment included serial bone marrow sampling.

A total of 113 patients were enrolled, including 16 with chronic myelomonocytic leukemia and 6 with MDS/myeloproliferative disease overlap syndrome. Patients received a median of 15 treatment cycles (interquartile range, 6–27). The overall response rate — the primary outcome — was 67% with decitabine versus 48% with azacitidine (P=0.042). Rates of complete remission were 36% with decitabine and 35% with azacitidine, and rates of hematologic improvement were 23% versus 8%. Among 59 transfusion-dependent patients, transfusion independence was more frequent with decitabine. At a median follow-up of 68 months, approximately half of patients had maintained response at 12 months and one fourth at 24 months; median overall survival for the entire group was 33 months. The presence of TP53 mutation was associated with complex karyotype and progression to acute myeloid leukemia.