Phase I-II Trial of Early Azacitidine after Matched Unrelated Donor Hematopoietic Cell Transplantation

Abstract

Graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic cell transplant (allo-HCT). Azacitidine (AZA) is a hypomethylating agent that has been shown to be effective in preclinical and clinical studies for the prevention of acute GvHD (aGvHD). We sought to determine the maximum tolerated dose (MTD) of AZA when given on day 1-5 in 28-day cycles for 4 cycles, starting from day 7 after allo-HCT, as well as its impact on acute and chronic GvHD, relapse, and overall survival in patients undergoing matched unrelated donor allo-HCT. This study was a single-arm, single-center, open-label phase I-II study with a total of 15 and 38 patients enrolled in the phase I and II portions of the trial, respectively. A standard 3+3 study design was used in phase I, and all patients in phase II received AZA at MTD determined in phase I. The MTD of AZA post-transplant starting at day 7 was 45mg/m2. The phase II part of the study was halted after enrolling 38 out of the 46 planned patients following an interim analysis that suggested futility. Overall, AZA at 45mg/m2 exhibited a side-effect profile consistent with prior reports and had minimal impact on engraftment. The cumulative incidence of clinically significant acute GvHD by day 180 was 39.9% (95% CI 22-53.7%). The incidence of all grades chronic GvHD was 61.4% (95% CI 40.3-75%). At one year, the overall survival was 73.7% (95% CI 60.9-89.1%), and the disease relapse rate was 11.4% (95% CI 0.2-21.3%). Early post-allo-HCT AZA has limited efficacy in preventing acute and chronic GvHD but could have a beneficial effect in preventing disease relapse.