Treatment with an investigational oral form of azacitidine, CC-486, improved overall survival in older patients with newly diagnosed acute myeloid leukemia (AML) who were in remission following standard induction chemotherapy with or without consolidation therapy, according to a phase III study presented by Wei et al at the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract LBA-3). The drug was found to be safe, and researchers say the results are the first to validate the role of maintenance therapy in AML.

"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.”

— Andrew H. Wei, MBBS, FRACP, FRCPA, PhD

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“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,” said lead study author Andrew H. Wei, MBBS, FRACP, FRCPA, PhD, of the Alfred Hospital, Melbourne, in a press release from ASH. “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.”

Based on these findings, Dr Wei said it is reasonable to expect that this therapy will become an integral part of treatment for older people with AML in remission and may help them to defer the need for further AML therapy. Currently, in the postremission period after induction and consolidation, management is either observation or stem cell transplant, the latter of which is complex and not viable for everyone. 

CC-486 has multiple potential mechanisms of action, including remodeling the epigenetic program in leukemic blasts. The oral route of administration, which allows for extended duration dosing (14 days each cycle) over a prolonged period of time (approximately 30% of patients are still on therapy after 2 years), may be an important factor in explaining the drug’s effectiveness, said Dr. Wei.  

QUAZAR AML-001

A total of 472 patients with AML aged 55 to 86 years with either intermediate- or poor-risk cytogenetics were enrolled in the QUAZAR AML-001 trial between May 2013 and October 2017 across 148 centers in 23 countries. To be included, patients had to achieve a complete response or complete response with incomplete count recovery after induction chemotherapy (with or without consolidation) and not be candidates for hematopoietic stem cell transplant. Within 4 months of attaining any complete response, patients were randomly assigned to receive either 300 mg of CC-486 or placebo once daily for 14 days of a 28-day cycle plus best supportive care until disease relapse. 

Researchers tracked overall survival—the study’s primary endpoint—as well as relapse-free survival, safety and tolerability, and health-related quality of life.

Findings

After a median follow-up of 41.2 months, there was a 31% lower risk of death among patients receiving CC-486 compared with those on placebo; median overall survival was 24.7 months vs 14.8 months. The risk of relapse was also lower in those who received CC-486—10.2 months vs 4.8 months for placebo. Minimal residual disease was also eradicated more frequently in patients receiving the drug.

Another finding, according to Dr. Wei, was that treatment benefits remained consistent across broad subgroups of patients, including the number of prior [chemotherapy] cycles received, the presence of any measurable residual disease, poor cytogenetic risk, or patients aged ≥ 65 years. Self-reported quality of life did not change across treatment groups.

There were more gastrointestinal events among patients receiving CC-486—including nausea, vomiting, and diarrhea—but most of these events occurred in the first two cycles and patients remained on therapy with supportive care. The most common grade 3–4 adverse events were neutropenia, thrombocytopenia, and anemia. Serious adverse events were infrequent, consisting mainly of infections, which occurred in 17% of patients in the CC-486 arm and 8% of patients in the control arm. Despite these side effects, patients in the treatment group underwent more cycles of treatment than those on placebo (median exposure of 12 vs 6 cycles). Additionally, those who were on placebo were more likely to receive posttrial treatments, including chemotherapy and stem cell transplantation. 

“The QUAZAR [study] 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,” said Dr. Wei.

Disclosure: The QUAZAR trial was funded by Celgene. For full disclosures of the study authors, visit ash.confex.com.