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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.
The feasibility of attenuated HMA therapy in lower-risk MDS is confirmed in this study, with improved responses for decitabine. Given the marked heterogeneity of MDS and an updated IPSS scoring that incorporates mutational profiling to better define risk groups (NEJM JW Oncol Hematol Sep 2022 and NEJM Evid 2022 Jun 12; [e-pub]), further trial results will be important to identify patients more likely to respond. The emergence of oral formulations for decitabine and azacitidine promises improved patient convenience with the daily dosing schedules and protracted treatment course.
Saski K et al.
Title: Low-dose decitabine versus low-dose azacitidine in lower-risk MDS.
Source: NEJM Evid 2022 Aug 9; [e-pub]. (Abstract/FREE Full Text)