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ORLANDO -- Overall survival (OS) in acute myelogenous leukemia (AML) improved by almost 10 months in patients who received the oral azacitidine agent CC-486 as maintenance therapy after attaining complete response, a randomized trial showed.

Patients assigned to CC-486 had median OS of 24.7 months as compared with 14.8 months for patients who received best supportive care (BSC) as maintenance. Median relapse-free survival (RFS) more than doubled from 4.8 months with BSC to 10.2 months with CC-486. Significantly more patients remained relapse free at 12 months with CC-486.

The safety profile of CC-486 was similar to what is observed with injectable azacitidine, reported Andrew H. Wei, MBBS, PhD, of the Alfred Hospital in Melbourne, Australia, at the American Society of Hematology (ASH) annual meeting.

"CC-486 is the first maintenance therapy to provide statistically significant and clinically meaningful improvements in both overall survival and relapse-free survival in a broad range of older patients with AML in remission following induction chemotherapy with or without consolidation," Wei said during an ASH press briefing. "Overall survival benefits with CC-486 were observed across subgroups of patients defined by prespecified baseline characteristics."

"CC-486 did not adversely impact overall health-related quality of life," he added.

The study will have a practice-changing impact on treatment of older patients with poor-risk AML when CC-486 becomes available, predicted Robert Brodsky, MD, of Johns Hopkins in Baltimore.

"These were all patients with poor-risk AML, over the age of 55 and intermediate- or poor-risk cytogenetics, in first complete remission," said Brodsky. "It isn't hard to get most patients in this group into remission. The problem is keeping them in remission."

Wei reported findings from an international phase III , which addressed the remission issue in the management of AML.

"Standard treatment with intensive induction chemotherapy induces complete remission in 60-80% of patients 60 or younger and in 40-60% of older patients," he said. "The majority of patients who attain a complete remission will eventually relapse, and relapse in the primary obstacle to long-term survival. The goals of AML maintenance therapy are to decrease the likelihood of disease relapse and prolong overall survival without causing undue toxicity or compromising health-related quality of life."

"To date, no AML maintenance therapy has shown clear improvements in overall survival," he stated.

CC-486 has demonstrated clinical activity in patients with hematologic malignancies, Wei continued. An oral formulation of azacitidine allows for extended drug exposure during each treatment cycle, prolonging therapeutic activity. Investigators hypothesized that prolonged treatment with CC-486 would be effective as postremission maintenance in AML.

The study included 472 patients ages ≥55 (range 55-86) with de novo or secondary AML in first complete remission after induction chemotherapy and ineligible for stem-cell transplantation. The study population had a median age of 68, 91% had de novo AML, 81% had intermediate-risk cytogenetics, 14% had high-risk cytogenetics, 81% had CR after induction therapy, and 14% had CR with incomplete hematologic recovery (CRi). Additionally, 80% of the patients had received consolidation therapy.

The patients were randomized to CC-486 or placebo, dosed once-daily for 14 days, followed by a 14-day break, plus BSC. The 28-day cycles were repeated until loss of remission (>15% blasts), unacceptable toxicity, or eligibility for transplantation. The trial had a primary endpoint of OS.

After a median follow-up of 41.2 months, data analysis showed that CC-486 maintenance reduced the mortality hazard by 31% versus placebo (95% CI 0.55-0.86). The 5.3-month difference in RFS represented a 35% reduction in the hazard ratio in favor of CC-486 (95% CI 0.52-0.81). Wei said patients derived similar benefits from CC-486 regardless of baseline characteristics: age, cytogenetic risk, AML type (de novo or secondary), number of cycles of consolidation therapy received, and CR/CRi status.

The most common adverse events associated with CC-486 were gastrointestinal (GI) and hematologic in nature. GI events included nausea (65%, 3% grade 3/4), vomiting (60%, 3%), diarrhea (50%, 5%), and constipation (39%, 1%). Hematologic events included neutropenia (45%, 41%), thrombocytopenia (34%, 23%), and anemia (20%, 14%). Serious adverse events occurred in 34% of the CC-486 group and 25% of placebo-treated patients.

"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 Wei. "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."

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