Oral Azacitidine in AML Maintenance Boosts Overall Survival 31%

The study's primary end point, overall survival, showed that patients taking CC-486 had a 31% lower risk of death than those taking placebo.

Older patients with acute myeloid leukemia (AML) who achieved remission with chemotherapy saw significant improvements in both relapse-free and overall survival (OS) with Celgene’s investigational oral azacitidine, CC-486, a result that investigators say finally validates the role of maintenance therapy in this disease.

Phase 3 findings from the QUAZAR trial, presented Tuesday at the 61st American Society of Hematology Annual Meeting and Exposition in Orlando, Florida, showed the therapy brought OS improvements across a range of subgroups, including with or without consolidation, and those older and younger than age 65.

AML is a common form of adult leukemia and tends to strike seniors, with fewer than 30% of those who develop this cancer surviving for 5 years. The 472 study patients reflected this: they ranged from 55 to 86 years of age (mean age, 68). Participants had to achieve a complete response (CR) or CR with incomplete recovery count (iCR) after induction chemotherapy. They could not be candidates for a bone marrow transplant. With 4 months of CR, they were randomized 1:1 to receive 300 mg of CC-486 or placebo for 14 days of a 28-day cycle until relapse.

After a median follow-up of 41.2 months, investigators reported the following results:

  • The primary end point, OS, was 24.7 months for the study drug group vs 14.8 months for placebo, for a 31% lower risk of death; hazard ratio (HR) 0.69 (95% CI, 0.55-0.86, P = .0009).
  • Risk of relapse was 35% lower among those taking CC-486: 10.2 months for those on the study drug vs 4.8 months on placebo; HR 0.65 (95% CI, 0.52-0.81, P = .0001).
  • Patients on CC-486 were more likely to attain undetectable minimal residual disease.
  • Serious adverse events (AEs) were reported for 34% of the CC-486 group and 25% of the placebo arm, with the most common AE in both groups being neutropenia or gastrointestinal events.
  • Treatment discontinuation due to AEs was infrequent.
  • CC-486 did not adversely impact quality-of-life compared with placebo.

Because AML is not considered a curable disease, investigators believe the findings offer the opportunity for prevention of progression instead of waiting for a relapse to treat the disease.

“The AML community has been trying to validate the role of maintenance therapies to extend initial treatment responses for many decades and—until now—without without success,” lead study author Andrew H. Wei, MBBS, PhD, of Alfred Hospital, Melbourne, Australia, said in a statement. “While several agents have been studied and shown to increase relapse-free duration, demonstration of a survival benefit has been elusive.”

Robert Brodsky, MD, director of the Division of Hematology at Johns Hopkins, said CC-486 could offer a maintenance therapy for AML patients who really have not had a good option. For AML patients, “It’s pretty easy to get into remission, but it’s very short-lived—there’s never any consolidation that’s really been effective,” he said.

A viable maintenance option in AML could bring significant savings to the healthcare system, especially Medicare. An analysis of the cost burden of AML presented at the 2017 ASH meeting found that relapse brings frequent and costly hospitalizations; the least expensive episode from low-intensity chemotherapy was $53,081; the one with the highest cost was a bone marrow transplant at $329,621.

Brodsky and Wei both said having an oral drug for maintenance is beneficial and convenient for patients. The drug is a cytidine nucleoside analogue that contributes to hypomethylation, or modification of DNA, and cytotoxicity of hematopoietic cells in the bone marrow, leading to cell death. Renal toxicities have been reported in the intravenous version of azacitidine in the treatment for myelodysplastic syndrome, but this was among the AEs reported in QUAZAR-AML-001.

Wei said he anticipates that CC-486 will become “a fundamental building block” of more effective drug combinations in AML, perhaps with venetoclax.

When Celgene announced topline results for QUAZAR AML-001 earlier this year, company officials said regulatory filings would occur in the first half of 2020. Celgene funded the study.


Wei AH, Dohner H, Pocock C, et al. The QUAZAR AML-001 maintenance trial: results of a phase 3 international, randomized, double-bline, placebo-controlled study of CC-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia (AML) n first remission. Presented at the 61st American Society of Hematology Annual Meeting and Exposition, Orlando, Florida; December 7-10; Abstract LBA-3.

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