Azacitidine Maintenance Fails to Improve Post-Transplant Outcomes in High-Risk AML and MDS

Maintenance treatment with single-agent azacitidine at a dose of 32 mg/m2 daily for five days did not lead to improved survival in patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who had undergone allogeneic hematopoietic cell transplantation (HCT), according to findings from a phase III randomized controlled trial published in Blood Advances.

Despite the disappointing results, “this randomized trial with azacitidine maintenance showed that a prospective trial in the posttransplant setting was feasible and safe but challenging,” the authors, led by Betul Oran, MD, from the University of Texas MD Anderson Cancer Center in Houston, wrote. “We believe the strategy of maintenance therapy merits further study with a goal to reduce the risk of relapse in patients with AML/MDS.”

Based on encouraging phase I/II trial data suggesting a benefit with azacitidine in the posttransplant setting, Dr. Oran and coauthors evaluated whether treatment with single-agent azacitidine maintenance therapy could reduce the risk of relapse and improve survival outcomes after HCT in adults with intermediate-1 or higher-risk MDS or with AML and high-risk features, induction failure, relapse, or in a second complete remission (CR) or beyond at the time of transplant. Those with AML in first CR were eligible for inclusion if they had high-risk features including chromosome 5 or 7 abnormalities or complex karyotype or FLT3 mutations.

Participants were randomized 1:1 to receive 12 monthly cycles of azacitidine (at a dose of 32 mg/m2 per day, administered via subcutaneous injections for 5 days every 4 weeks) or observation (no further treatment). Bone marrow evaluations were performed at one month, three months, six months, and one year after HCT.

The study’s goal was to test the hypothesis that azacitidine provided at least a 50% improvement in median relapse-free survival (RFS) from six to nine months, which required a sample size between 213 and 256 patients. However, from April 2009 through January 2017, a total of only 187 patients were enrolled – 93 in the azacitidine group and 94 in the control group. Patient accrual was slow, the authors noted, and was largely due to failing eligibility and lack of interest of the patient, typically due to concerns about receiving an additional year of chemotherapy.

The median time to enrollment in the trial was 54 days after transplant, and median time to first cycle of azacitidine was 62 days. In the treatment arm, patients received a median of four azacitidine cycles, with only 28% completing the plan-ned 12 cycles. Reasons for study discontinuation included: disease relapse (47%), toxicity (18%), patient’s preference not to continue (15%), infection (11%), logistical reasons (8%), and graft-versus-host disease (GVHD; 4%).

Over a median follow-up of 4.6 years in the azacitidine group and 4.06 years in the control arm, median RFS (primary endpoint) was not significantly improved with azacitidine compared with observation (TABLE). There also was no benefit observed across disease risk subgroups or in secondary endpoints, including overall survival (OS), risk of relapse, or GVHD, the authors reported. The only significant factor that improved RFS and OS was transplant in CR, versus transplant with active disease (hazard ratio [HR] = 0.48 for RFS [p=0.001] and HR=0.53 for OS [p=0.007]).

“This randomized trial … showed that a prospective trial in the posttransplant setting was feasible and safe but challenging.”

—Betul Oran, MD

No unexpected adverse events (AEs) were observed, Dr. Oran and colleagues reported. Approximately 87% of patients in the azacitidine arm and 72% in the control arm experienced an AE. “It is notable that a substantial number of AEs occurred in the control arm and were related to typical posttransplant complications,” the researchers wrote. “Myelosuppression was the only toxicity clearly related to the azacitidine treatment.” The most common grade ≥3 AEs in the azacitidine arm were related to bone marrow suppression (64%), infection (16%), and liver toxicity (10%).

The study authors noted several limitations of this analysis, including slow patient accrual and the difficulty for azacitidine-treated patients to complete all 12 pre-planned treatment cycles, which forced investigators to close the study early. “[Not meeting] eligibility criteria was another major reason of screen failure (41%), highlighting the difficulty of enrollment into clinical trials after [transplant] due to multiple posttransplant complications,” they wrote.

While this study did not confirm the efficacy of azacitidine with the applied dose and schedule, the researchers noted that future randomized trials of posttransplant maintenance strategies “need to incorporate all factors influencing the risk of relapse, including recent cytogenetic, genomic, and measurable residual disease information,” they added. “Only then can we improve our capability to deliver practice-changing, outcome-improving posttransplant therapies.”

The authors report relationships with Celgene, which sponsored this trial.


Oran B, de Lima M, Garcia-Manero G, et al. A phase 3 randomized study of 5-azacitidine maintenance vs observation after transplant in high-risk AML and MDS patients. Blood Adv. 2020;4:5580-5588.