Sustained Survival Benefit Seen With Oral Azacitidine as Maintenance Therapy for AML in First Remission

Maintenance oral azacitidine produced a sustained survival benefit over placebo for patients with acute myeloid leukemia in first remission.

Maintenance treatment with oral azacitidine for patients with acute myeloid leukemia (AML) in first remission after intensive chemotherapy sustained a survival benefit over placebo, according to updated results from the phase 3 QUAZAR AML-001 trial (NCT01757535) presented during the 2021 ASH Annual Meeting and Exposition.

At a data cutoff of September 2020, and with a median follow-up of 51.7 months, the median overall survival (OS) with oral azacitidine was 24.7 months (95% CI, 18.7-30.5) vs 14.8 months (95% CI, 11.7-17.6) with placebo (HR, 0.69; 95% CI, 0.56-0.86; P = .0008). The 3-year OS rates in the investigative and control arms were 37.4% and 27.9%, respectively; these rates at 5 years were 26.2% and 19.2%, respectively.

Long-term (LT) survival of 3 years or longer in both treatment arms were linked with intermediate cytogenetic risk and NPM1 mutation positivity at the time of diagnosis. Moreover, minimal residual disease (MRD) response was also linked with LT survival. Specifically, MRD response on study was noted to be 2 times more frequent with oral azacitidine than with placebo, at 37% and 19%, respectively.

“OS in the primary analysis of the QUAZAR AML-001 study were subject to extensive censoring. With over 1 additional year of survival follow-up, median OS remained unchanged in both treatment arms, but the tails of the oral azacitidine and placebo OS curves showed greater separation at later timepoints than in the primary analysis,” presenting author Andrew H. Wei, MBBS, PhD, of The Alfred Hospital, said in a presentation on the findings. “These updated data indicate oral azacitidine maintenance therapy provides a sustained, LT OS benefit in older patients with AML in first remission.”

It is known that standard intensive induction chemotherapy regimens for patients with AML can produce complete remission (CR) rates that range from 60% to 80% in patients who are 60 years of age or younger; these rates drop to 40% to 60% in those over 60 years. Additionally, most patients who achieve CR with this treatment will relapse, and disease relapse is the largest obstacle to achieving LT OS.

In the placebo-controlled, phase 3 QUAZAR AML-001 trial, investigators set out to evaluate oral azacitidine, a hypomethylating agent with a distinct pharmacokinetic/pharmacodynamic profile from that of injectable azacitidine, as a maintenance option for patients with AML in remission following intensive chemotherapy.

To be eligible for enrollment, patients needed to have de novo or secondary AML, be 55 years of age or older, and be in first CR with intensive chemotherapy with or without consolidation. Patients needed to have an ECOG performance status ranging from 0 to 3 and intermediate- or poor-risk cytogenetics. Moreover, at study enrollment, patients needed to have a neutrophil count of at least 0.5 x 109/L and a platelet count of at least 20 x 109/L.

“Patients with core-binding factor were excluded, as were candidates for hematopoietic stem cell transplantation,” Wei said.

Study participants were randomized 1:1 to receive either oral azacitidine at a daily dose of 300 mg for 2 weeks (n = 238) or placebo (n = 234) for the same period over 28-day treatment cycles. Patients need to be randomized within 4 months of achieving first CR.

Stratification factors included age (55 to 64 years vs 65 years or older), prior myelodysplastic syndrome or chronic myelomonocytic leukemia (yes vs no), cytogenetic risk (intermediate vs poor), and whether they received consolidation treatment (yes vs no).

“Bone marrow assessments were performed every 3 months for the first 2 years, and then every 6 months for the third year, and then afterward, as clinically indicated,” Wei explained. “Patients who had evidence of early blasts with a bone marrow blast count of 5% to 15% could take a 21-day extended schedule of oral azacitidine or placebo. However, patients with a blast count of 15% were required to crease therapy and to go into survival follow-up.”

At the time of the study unblinding in August 2019, patients in the investigative arm were able to take oral azacitidine in an optional extensive phase of the trial, whereas those in the control arm discontinued treatment and were placed in survival follow-up.

The data cutoff for the primary analysis was July 2019. Results showed that at a median follow-up of 41.2 months, oral azacitidine significantly prolonged OS vs placebo, at a median of 24.7 months (95% CI, 18.7-30.5) and 14.8 months (95% CI, 11.7-17.6), respectively (P < .001).

“The tails of the OS curves began to converge after approximately 48 months,” Wei noted. “However, over one-quarter of the study population was still alive in survival follow-up at the primary cutoff. Therefore, the objective of this [new analysis] is to assess the impact on OS with an extra year of additional follow-up.”

In the most recent analysis, at a cutoff of September 2020, 22.7% of patients in the investigative arm were alive and in follow-up vs 15.0% of those in the control arm.

Additional data showed that there was a 9.5% improvement in OS at 3 years with the hypomethylating agent vs placebo, as 37.4% of patients in the investigative arm were alive at that time point vs 27.9% of those in the placebo arm. The 5-year OS rates with oral azacitidine and placebo were 26.2% and 19.2%, respectively, translating to an improvement of 7.0% with the hypomethylating agent.

To determine whether OS was impacted by patient-related factors, investigators compared baseline characteristics between patient subsets. For this analysis, LT survival was defined as patients alive in survival follow-up for at least 3 years from randomization. Non-LT survival was defined as those who died or were censored for OS prior to 3 years.

A total of 140 patients comprised the LT survivor cohort; 83 of these patients received oral azacitidine and 57 patients received placebo. A total of 155 patients made up the non-LT survivor subset who received oral azacitidine.

Compared with the non-LT cohort, LT survivors were noted to be more likely to have intermediate-risk cytogenetics and harbor NPM1 mutations at diagnosis; they were also noted to be negative for MRD at screening following intensive chemotherapy. Additionally, investigators noted that the rate of MRD response, conversion from positivity to negativity, proved to be significantly higher in the LT survivors vs the non-LT survivors (P < .0001).

“Patients in the LT survival cohort after receiving oral azacitidine were slightly younger than those in the non-LT cohort, with a median age of 67 years compared with 69 years; they were also less likely to have poor cytogenetic risk, at 6% vs 19%, respectively,” Wei reported. “Patients with LT survival following azacitidine were more likely to have a NPM1 mutation than non-LT survivors, at 45% vs 19%, respectively, and 23% of patients did not receive consolidation therapy suggesting that even patients receiving induction therapy and going into remission and receiving oral azacitidine were capable of having long-term survival.”

Additionally, fewer patients in the LT survival group were MRD positive at baseline than those in the non-LT group. Thirty-seven percent of patients on the study achieved MRD negativity; however, a higher proportion of patients in the LT survival group because MRD negative on the study vs those in the non-LT survival group, at 76% and 22%, respectively.

“Long-term survivors in the placebo arm had similar characteristics, with fewer patients with LT survival having poor cytogenetic risk, more having NPM1 mutations, and a lower frequency of baseline MRD positivity at study randomization,” Wei concluded. “The only difference was that there was a high proportion of patients who achieved MRD negativity in the oral azacitidine arm vs placebo.”


Wei AH, Döhner H, Sayar H, et al. Long-term overall survival (OS) with oral azacitidine (oral-AZA) in patients with acute myeloid leukemia (AML) in first remission after intensive chemotherapy (IC): updated results from the phase 3 QUAZAR AML-001 trial. Blood. 2021;138(suppl 1):871. doi:10.1182/blood-2021-147501