Patients on maintenance therapy saw improved progression-free survival over placebo

Oral azacitidine (CC-486) maintenance therapy is associated with significantly longer overall and relapse-free survival, compared to placebo, in patients with acute myeloid leukemia (AML) who are in remission after chemotherapy, researchers found.

According to results of a phase III trial, median overall survival from the time of randomization was significantly longer with oral azacitidine than with placebo (24.7 months and 14.8 months, respectively), as was median relapse-free survival compared to placebo (10.2 months and 4.8 months, respectively).

The study, by A.H. Wei, MB, BS, PhD, Monash University, Melbourne, VIC, Australia, and colleagues was published in The New England Journal of Medicine.

While complete remission is achieved with standard induction chemotherapy in patients with AML who are older than 60 years of age, most are likely to relapse — about 80% to 90%. And, as pointed out by Wei and colleagues, longer durations of first remission are associated with better survival outcomes. Therefore, the authors wrote, prevention of early AML relapse is an important treatment goal.

Hematopoietic stem-cell transplant (HCST) is potentially curative for AML, but it inappropriate for many older patients. “For patients who are not candidates for HSCT, effective AML maintenance therapies are needed that can reduce the risk of relapse and prolong overall survival without causing undue adverse effects or compromising health-related quality of life,” the authors wrote.

In the phase 3, double-blind, placebo-controlled QUAZAR AML-001 trial, Wei and colleagues evaluated the hypomethylating agent oral azacitidine as AML maintenance therapy in patients 55 years of age or older in remission after induction chemotherapy who weren’t candidates for stem-cell transplant.

The trial was conducted at 148 sites in 23 countries and included 472 patients, 238 of whom were randomized to receive azacitidine (300 mg) and 234 of whom received placebo — both treatments were administered once daily for 14 days per 28-day cycle.

The primary end point was overall survival, while the secondary end points included relapse-free survival and health-related quality of life.

At a median follow-up of 41.2 months, the median overall survival from the time of randomization was 24.7 months in the azacitidine group compared to 14.8 months in the placebo group, while the estimated percentage of patients surviving at 1 year was 72.8% in the azacitidine group and 55.8% in the placebo group (a 17.0-point percentage point difference). The percentages at 2 years were 50.6% and 37.1%, for a difference of 13.5 percentage points.

Median relapse-free survival from the time of randomization was 10.2 months in the azacitidine compared to 4.8 months with placebo. The percentage of patients who relapse-free survival at 6 months was 67.4% in the azacitidine group and 45.2% in the placebo group, and 44.9% and 27.45 respectively at 1 year.

“Median relapse-free survival in the CC-486 group was more than twice that in the placebo group, which probably explains the superior overall survival with CC-486,” the authors observed.

As for adverse events, in both groups the most common adverse events in the period between the first dose and 28 days after the last dose were grade 1 and 2 gastrointestinal adverse events (including nausea, vomiting, and diarrhea). These occurred more frequently in the azacitidine group.

Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the azacitidine group and 24% of patients in the placebo group), thrombocytopenia (in 22% and 21%, respectively), and anemia (14% and 13%, respectively).

Health-related quality of life scores were similar in the two treatment groups.

“Despite demonstrable survival advantages with CC-486 maintenance therapy, the risk of eventual relapse and death from AML remains problematic,” wrote Wei and colleagues. “Whether CC-486 may benefit patients with AML when it is used in other clinical contexts requires further investigation. Results from an open-label phase 2 study suggest that CC-486 may provide effective maintenance therapy after HSCT, but larger, controlled trials are needed.”

The study authors also noted that determining which molecular characteristics might influence outcomes for patients on maintenance therapy may be useful in identifying the patients who are most likely to benefit from this method of treatment. “Although assessment of molecular abnormalities was not required for this trial, correlative samples were obtained for potential future analysis.”

  1. Patients with acute myeloid leukemia who are in remission after chemotherapy achieve longer overall survival with oral azacitidine maintenance therapy.

  2. These patients also achieve longer relapse-free survival.

Michael Bassett, Contributing Writer, BreakingMED™

The study was supported by Celgene; QUAZAR AML-001 ClinicalTrials.gov number, NCT01757535.

Wei reports grants/contracts: AbbVie, Amgen, AstraZeneca, Celgene, Novartis, Servier; Advisory board: Abbvie, Amgen, Astellas Pharma, AstraZeneca, Celgene, Genentech, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Macrogenics, Novartis, Pfizer, Servier; Consultant; Servier; Speaking engagement; AbbVie, Celgene, Novartis.

Cat ID: 116

Topic ID: 78,116,730,116,118,119,466,935,192,925