Oral azacitidine improves overall survival in patients with AML in remission

In a phase 3, randomised, placebo-controlled trial, a new oral formulation of azacitidine, called CC-486, significantly improved overall survival in patients with newly diagnosed acute myeloid leukaemia (AML) in remission after standard induction chemotherapy, with or without consolidation therapy. CC-486 had a favourable safety profile.

Dr Andrew Wei (Alfred Hospital, Australia) presented the results of the QUAZAR AML-001 trial in the late-breaking session [1]. The study attempted to address the deficit of maintenance therapy options available to older AML patients who have achieved remission after initial chemotherapy and want to defer any further aggressive treatment, such as stem cell transplantation. AML patients with either intermediate-risk or poor-risk cytogenetics (n=472; age range 55-86 years) were enrolled if they had (1) achieved a complete response after induction chemotherapy, with or without consolidation, and (2) if they were ineligible for a haematopoietic stem cell transplant. Patients were randomised to receive either 300 mg of CC-486 (n=238) or placebo (n=234) once daily for 14 days of a 28-day cycle plus best supportive care until disease relapse.

At a median follow-up of 41.2 months, the primary endpoint of overall survival was met: 31% fewer patients in the CC-486 arm had died versus those on placebo (HR 0.69; 95% CI 0.55-0.86; P=0.009; see Figure). Median overall survival was 24.7 months versus 14.8 months for CC-486 and placebo, respectively. The risk of relapse was also significantly lower in those who received the medication (10.2 months in the CC-486 arm versus 4.8 months for placebo; HR 0.65; 95% CI 0.52-0.81; P=0.0001). Complete molecular response with no evidence of minimal residual disease was also frequently observed in patients receiving the drug. Notably, benefits in the CC-486 arm were observed in patients with high-risk characteristics, including the number and duration of prior therapies, the presence of any measurable residual disease, poor cytogenetic risk, or patients ≥65 years. Self-reported quality of life did not change across treatment groups.

The most common grade 3-4 adverse events were neutropenia, thrombocytopenia, and anaemia. More gastrointestinal complaints were observed in the CC-486 arm (i.e. nausea, vomiting, and diarrhoea); however, these events typically occurred in the first 2 cycles and were easily resolved with standard supportive care. Serious adverse events were mostly infections, which occurred in 17% of patients in the CC-486 arm and 8% of patients in the placebo arm.

Dr Wei concluded: “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 success. While several agents have been studied and shown to increase relapse-free duration, demonstration of a survival benefit has been elusive. CC-486 is the first therapy to provide statistically significant and clinically meaningful improvement in both overall survival and relapse-free survival in patients with AML in remission following induction chemotherapy, with or without consolidation.”

Figure: QUAZAR AML-001 primary endpoint: overall survival from randomisationCI, confidence interval; HR, hazard ratio. Median follow-up: 41.2 months.

1. Wei A, et al. LBA-3, ASH 2019, 7-10 December, Orlando, USA.

Posted on 5 March 202030 March 2021