Oral azacitidine extends survival for patients with AML in remission after chemotherapy
Maintenance therapy with oral azacitidine led to statistically significant and clinically meaningful improvements in OS and RFS among patients with acute myeloid leukemia in remission after induction chemotherapy.
Researchers observed the survival benefit regardless of whether patients received consolidation chemotherapy, according to results of the randomized, phase 3 QUAZAR AML-001 study published in The New England Journal of Medicine.
The FDA approved azacitidine tablets (Onureg, Celgene/Bristol Myers Squibb) for this patient population, who could not complete intensive curative therapy such as hematopoietic stem cell transplant, in September based on the results of this trial.
“For patients with AML, although initial chemotherapy is often successful at achieving remission, relapse is common, particularly in older patients not considered suitable candidates for allogeneic stem cell transplant,” Andrew H. Wei, MBBS, FRACP, FRCPA, PhD, head of leukemia research at Alfred Hospital in Melbourne, Australia, told Healio. “Although there was an unmet need for a therapy to maintain remission in such patients, a convenient, safe and effective option with proven capacity to improve survival was not available. The development of oral azacitidine, an orally bioavailable formulation of azacitidine shown to be effective and tolerable when given for 14 out of 28 days each cycle, was therefore considered a suitable candidate as a maintenance therapy to extend remission and prolong survival in older patients after intensive chemotherapy.”
Wei and colleagues assessed the oral azacitidine formulation as maintenance therapy in the double-blind study of 472 adults (median age, 68 years; range, 55-86; 52% men) in first remission after induction chemotherapy for de novo AML (91%) or secondary AML. Patients had intermediate-risk (86%) or poor-risk (14%) cytogenetics and an ECOG performance status of 3 or less.
Researchers randomly assigned patients to 300 mg oral azacitidine (n = 238) or placebo (n = 234) once daily on days 1 to 14 of each 28-day treatment cycle.
OS served as primary endpoint. Secondary endpoints included RFS, health-related quality of life and safety.
Median follow-up was 41.2 months.
Results showed patients assigned oral azacitidine achieved significantly longer median OS (24.7 months vs. 14.8 months; HR = 0.69; 95% CI, 0.55-0.86) and RFS (10.2 months vs. 4.8 months; HR = 0.65; 95% CI, 0.52-0.81), and had a lower 1-year relapse rate (53% vs. 71%).
Patients experienced benefits with oral azacitidine regardless of baseline cytogenetic risk, the number of prior consolidation cycles they received, and complete remission vs. complete remission with incomplete count recovery, according to the researchers.
“Survival was improved among several poor-risk subgroups, including patients unable to receive consolidation therapy and those with detectable [minimal residual disease] or poor cytogenetic risk at treatment baseline,” Wei said.
In addition, oral azacitidine exhibited a manageable safety profile consistent with that of injectable azacitidine. Grade 1 or grade 2 gastrointestinal events were the most common adverse events in both groups. Grade 3 or grade 4 adverse events included neutropenia (41% for oral azacitidine vs. 24% for placebo) and thrombocytopenia (22% vs. 21%).
“Oral azacitidine represents the first FDA-approved, post-remission maintenance therapy for patients with AML,” Wei said. “Future research will focus on the potential for oral azacitidine to improve outcomes after allogeneic stem cell transplant and also the potential for combination with other orally administered AML therapies targeting BCL2, FLT3 or IDH.”
For more information:
Andrew H. Wei, MBBS, FRACP, FRCPA, PhD, can be reached at Alfred Hospital, 55 Commercial Road, Melbourne VIC 3004, Australia; email: andrew.wei@monash.edu.
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