According to research presented as a late-breaking abstract at the 2019 ASH Annual Meeting, treatment with CC-486, an oral formulation of the hypomethylating agent azacitidine, improved overall survival (OS) and relapse-free survival (RFS) when used as maintenance therapy in patients with acute myeloid leukemia (AML) who were in remission after induction chemotherapy.
These efficacy results suggest that CC-486 could represent a new standard in this setting, lead investigator Andrew H. Wei, MBBS, PhD, from the Alfred Hospital and Monash University in Melbourne, Australia, said during a press briefing. "The QUAZAR trial shows that, rather than observing patients and waiting for them to relapse, we can now actively engage in trying to reduce relapse risk and improve survival in the postremission phase," he explained.
The randomized, double-blind, placebo-controlled phase III QUAZAR AML-001 trial included patients with de novo or secondary AML who had achieved a first complete remission (CR) or CR with incomplete count recovery (CRi) after induction chemotherapy, with or without consolidation chemotherapy. Participants also had intermediate- or poor-risk cytogenetics, had an Eastern Cooperative Oncology Group (ECOG) performance status score of â‰¤3, and were not considered candidates for hematopoietic cell transplantation (HCT).
Patients were randomized to receive either once-daily CC-486 300 mg (n=238) or placebo (n=234), administered on days 1-14 of 28-day cycles. Randomization occurred within 4 months of patients achieving CR/CRi. Treatment continued until presence of >15% blasts, unacceptable toxicity, or HCT.
Median age across both treatment groups was 68 years (range = 55-86 years), with 91% of patients presenting with de novo AML. In addition, 86% had intermediate-risk cytogenetics. Most participants (81%) had achieved CR following induction, while 19% achieved CRi. Most patients (78% in the CC-486 group and 82% in the placebo group) received consolidation therapy, and similar portions of each cohort had achieved measurable residual disease (MRD) negativity (56% and 47%, respectively).
After a median follow-up of 41.2 months, the median exposures to CC-486 and placebo were 12 cycles (range = 1-80) and 6 cycles (range = 1-73), respectively.
Compared with placebo, treatment with CC-486 was associated with significantly longer overall survival (OS): 24.7 months versus 14.8 months, respectively (hazard ratio [HR] = 0.69; 95% CI 0.55-0.86; p=0.0009). Median relapse-free survival (RFS) also was prolonged with CC-486 (10.2 months vs. 4.8 months; HR=0.65; 95% CI 0.52-0.81; p=0.0001).
These benefits were seen across prespecified subgroups, Dr. Wei reported, including those with MRD, poor cytogenetic-risk disease, or â‰¥65 years. The researchers also noted that there was no significant difference in health-related quality of life between oral azacitidine and placebo.
According to the researchers, the manageable safety profile of CC-486 in this study was consistent with that observed with injectable azacitidine. Grade 1 or 2 gastrointestinal (GI) events were the most common adverse events (AEs) related to CC-486 and observed in the placebo arm and were mostly reported during the first two treatment cycles. These events included:
- nausea: 64% with CC-486 and 23% with placebo
- vomiting: 59% and 10%
- diarrhea: 49% and 21%
Neutropenia was the most frequently reported hematologic AE, occurring in 45% of CC-486–treated patients and 26% of those who received placebo; neutropenia was grade 3 or 4 in 41% and 24%, respectively. Overall, serious AEs were reported in 34% and 25% of patients in the CC-486 and placebo groups, respectively, but Dr. Wei noted that discontinuations due to AEs were infrequent and there were no treatment-related deaths during follow-up.
"While several agents have been studied and shown to increase relapse-free duration [in AML], demonstration of a survival benefit has been elusive," Dr. Wei concluded. "CC-486 is the first therapy to provide statistically significant and clinically meaningful improvement in both overall survival and relapse-free survival, with or without consolidation."
He added that oral azacitidine may become an integral part of treatment for older people with AML in remission, but the implications of the study are limited by the comparison with pla-cebo, precluding direct comparisons between oral and injectable azacitidine, and by the increased use of approaches to AML other than intensive induction, such as hypomethylating agents plus venetoclax or mutation-targeted agents.
Study authors report relationships with Celgene, which sponsored the trial.
Wei AH, DÃ¶hner H, Pocock C, et al. The QUAZAR AML-001 Maintenance Trial: Results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia (AML) in first remission. Abstract #LBA-3. Presented at the 2019 ASH Annual Meeting, December 10, 2019; Orlando, FL.