A phase 3 randomized study of 5-azacitidine maintenance vs observation after transplant in high-risk AML and MDS patients

Abstract

This study investigated the efficacy and safety of azacitidine maintenance in the posttransplant setting based on the encouraging phase 1/2 reports for azacitidine maintenance in patients with acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). Between 2009 and 2017, a total of 187 patients aged 18 to 75 years were entered into a randomized controlled study of posttransplant azacitidine if they were in complete remission. Patients randomized to the treatment arm (n = 93) were scheduled to receive azacitidine, given as 32 mg/m2 per day subcutaneously for 5 days every 28 days for 12 cycles. The control arm (n = 94) had no intervention. Eighty-seven of the 93 patients started azacitidine maintenance. The median number of cycles received was 4; a total of 29 patients relapsed on study, and 23 patients withdrew from the study due to toxicity, patient's preference, or logistical reasons. Median relapse-free survival (RFS) was 2.07 years in the azacitidine group vs 1.28 years in the control group (P = .43). There was also no significant difference for overall survival, with a median of 2.52 years vs 2.56 years in the azacitidine and control groups (P = .85), respectively. Multivariate Cox regression analysis revealed no improvement in RFS or overall survival with the use of azacitidine as maintenance compared with the control group (hazard ratios of 0.73 [95% confidence interval, 0.49-1.1; P = .14] and 0.84 [95% confidence interval, 0.55-1.29; P = .43]) [corrected]. This randomized trial with azacitidine maintenance showed that a prospective trial in the posttransplant setting was feasible and safe but challenging. Although RFS was comparable between the 2 arms, we believe the strategy of maintenance therapy merits further study with a goal to reduce the risk of relapse in patients with AML/MDS. This trial was registered at www.clinicaltrials.gov as #NCT00887068.

Graphical abstract

Figure 1.

Of 93 patients randomized to azacitidine maintenance, 87 started the treatment. The plan was to complete 12 cycles of maintenance treatment for patients randomized to azacitidine maintenance. Patients randomized to the control arm (n = 94) did not receive any intervention. allo-SCT, allogeneic stem cell transplantation; CMML, chronic myelomonocytic leukemia.

Figure 2.

Relapse free and overall survial. The use of subcutaneous 5-azacitidine as posttransplant maintenance strategy was not associated with improved relapse-free survival (A) and overall survival (B) compared with observation arm.

Figure 3.

Relapse and transplant-related mortality incidences. In the randomized, prospective trial, subcutaneous 5-azacitidine did not lead to decreased risk of relapse after transplant in AML/MDS patients (A) but also did not increase transplant-related mortality (B) compared with control group.

Figure 4.

Distribution of AEs. The distribution of maximum grade of AEs by each patient on the azacitidine arm (A) and the control arm (B). The distribution of number of AEs by each patient on the azacitidine arm (C) and the control arm (D). The distribution of total toxicity burden by each patient on the azacitidine arm (E) and the control arm (F).