An investigational oral form of azacitidine (CC-486) as maintenance therapy induced a statistically significant improvement in overall survival (OS) compared with placebo in patients with newly diagnosed acute myeloid leukemia (AML) who achieved a complete response or complete response with incomplete hematologic recovery after treatment with induction chemotherapy.
In the phase 3 QUAZAR AML-001 clinical trial, at a median follow-up of 41.2 months, the OS was 24.7 months in patients assigned to CC-486 as maintenance therapy versus 14.8 months in patients randomized to placebo (hazard ratio, 0.69; P = .00009), announced Andrew H. Wei, MBBS, PhD, FRACP, FRCPA, Head, Leukaemia Research, the Alfred Hospital, Melbourne, Australia, at ASH 2019.
Relapse-free survival was also significantly prolonged in the CC-486 group, from a median of 4.8 months in the placebo arm to 10.2 months in the CC-486 arm (P = .0001).
The 5-year survival rate for patients with AML remains less than 30%. Standard treatment is intensive chemotherapy combining 7 days of cytarabine and 3 days of an anthracycline. “Although a lot of patients get into remission with this, unfortunately the vast majority of patients still relapse, particularly those in older age-groups,” said Dr Wei.
The only standard postremission therapy at present is hematopoietic stem-cell transplant (HSCT), which is not suitable for older patients with AML. To date, no maintenance therapy has been shown to improve OS.
“CC-486 is the first maintenance therapy to provide a statistically significant and clinically meaningful improvement in both overall and relapse-free survival across a broad range of patient subgroups with AML who are in remission after intensive chemotherapy with or without consolidation therapy,” Dr Wei said.
“Based on the positive results of this landmark clinical trial, we hope that maintenance therapy with CC-486 might represent a potential new therapeutic standard in patients aged 55 and older with AML in first remission,” he added.
CC-486 is a cytidine nucleoside analog that is thought to lead to DNA hypomethylation and cytotoxicity of hematopoietic cells in the bone marrow causing cell death.
The QUAZAR AML-001 study included 472 patients with de novo or secondary AML and intermediate- or poor-risk cytogenetics. Patients were randomized to 300 mg of oral CC-486 or to placebo once daily for 14 days in 28-day cycles until disease progression. The patients were not candidates for HSCT. Within 4 months, patients had achieved first complete response or complete response with incomplete blood count recovery after induction chemotherapy, with or without consolidation chemotherapy.
The median patient age was 68 years. In all, 91% of the patients enrolled in the study had de novo AML, and 86% and 14% of patients had intermediate-risk or poor-risk cytogenetics, respectively. After induction, 81% of the patients achieved complete response and 19% achieved complete response with incomplete hematologic recovery. A total of 80% of the patients had received consolidation chemotherapy.
The patients were assessed for the recurrence of bone marrow disease every 3 months during the study. If their disease remained in remission, patients could continue with the therapy until death or until the discontinuation of study procedures. If the bone marrow showed early relapse (ie, bone marrow blast count of 5%-15%), physicians were allowed to increase the duration of exposure to therapy from 14 days to 21 days. If they had an increase in bone marrow blasts of >15%, patients had to stop treatment and began survival follow-up.
Some 43% of the patients in the CC-486 arm had minimal residual disease (MRD) after chemotherapy, “which we assume is potentially an important source of relapse,” Dr Wei said. In the placebo arm, 50% of patients had MRD.
The 1-year relapse rate was 53% in the CC-486 arm and 71% in the patients assigned to placebo. Treatment with CC-486 resulted in benefits in OS and in relapse-free survival benefits, regardless of the baseline cytogenetic risk, the number of previous consolidation cycles received, and the response status.
Patients in the CC-486 arm received a median of 12 cycles of therapy compared with 6 cycles in the placebo arm.
Health-related quality of life was preserved in the CC-486 arm compared with the arm that received placebo. CC-486 had a manageable safety profile that was generally consistent with that of the injectable form of azacitidine.
The most common grade 3 or 4 adverse events with CC-486 were febrile neutropenia (30%), anemia (22%), neutropenia (17%), and thrombocytopenia (17%).