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Maintenance CC-486 extends OS for patients with AML in remission after induction chemotherapy
ORLANDO — The oral hypomethylating agent CC-486 provided statistically significant and clinically meaningful improvements in OS and RFS for patients with acute myeloid leukemia in remission after induction chemotherapy, according to results of the randomized phase 3 QUAZAR AML-001 study presented during the late-breaking abstract session at ASH Annual Meeting and Exposition.
CC-486 (Celgene) is the first maintenance therapy to demonstrate this type of benefit in a broad range of patients with AML in remission after induction chemotherapy, regardless of whether they received consolidation chemotherapy.
The agent represents a new potential standard therapy for this patient population, Andrew H. Wei, MBBS, FRACP, FRCPA, PhD, head of leukemia research at Alfred Hospital in Melbourne, Australia, told Healio.
“After people have completed intensive chemotherapy, rather than just having them be monitored and waiting for relapse, they now have the option of doing something positive against their disease,” Wei said in an interview. “It is very exciting to think that, by taking a tablet that is relatively well-tolerated, we can help reduce relapse risk and improve survival.”
Older patients with AML often respond to intensive induction chemotherapy, but responses typically do not last long and OS remains poor.
The only standard post-remission therapy is hematopoietic stem cell transplant; however, it is not feasible for most older patients to receive this treatment, and no other AML maintenance therapy has conferred significant OS benefit.
Wei and colleagues hypothesized that prolonged treatment with CC-486 (Celgene) — a bioavailable oral formulation of injectable azacitidine, with its own distinct pharmacokinetic/pharmacodynamic profile — could be effective in this setting. In prior studies, the agent demonstrated clinical activity against hematologic malignances.
The international, double-blind, placebo-controlled QUAZAR AML-001 study evaluated CC-486 as maintenance therapy for patients aged 55 years or older with AML in first remission after induction chemotherapy.
The study included 472 patients (median age, 68 years; range, 55-86) with de novo AML (91%) or secondary AML, intermediate-risk (86%) or poor-risk (14%) cytogenetics, and ECOG performance status of 3 or less.
All patients achieved first complete remission (81%) or complete remission with incomplete count recovery (19%) after induction chemotherapy — with or without consolidation chemotherapy — and were not candidates for HSCT. They also needed to have adequate bone marrow recovery after prior chemotherapy.
Most patients (80%) had received consolidation therapy; 45% received one consolidation cycle and 31% received two cycles.
Randomization occurred between May 2013 and October 2017, when all patients were within 4 months of remission.
Researchers randomly assigned patients to 300 mg CC-486 (n = 238) or placebo (n = 234) once daily on days 1 to 14 of each 28-day treatment cycle.
Patients who remained in remission continued on treatment until death or discontinuation. Study protocol allowed a 21-day dosing schedule for patients who experienced AML relapse with 5% to 15% blasts in blood or bone marrow while on the study. Those with blasts greater than 15% had to stop treatment.
Treatment groups were balanced with regard to baseline characteristics.
OS served as the primary endpoint. Secondary endpoints included RFS, health-related quality of life and safety.
Researchers collected samples for exploratory translational endpoints, which included measurable residual disease.
Median exposure was 12 cycles (range, 1-80) for CC-486 and six cycles (range, 1-73) for placebo.
Median follow-up was 41.2 months.
Patients assigned CC-486 achieved significantly longer median OS (24.7 months vs. 14.8 months; HR = 0.69; 95% CI, 0.55-0.86) and RFS (10.2 months vs. 4.8 months; HR = 0.65; 95% CI, 0.52-0.81). The 1-year relapse rate was 53% in the CC-486 group and 71% in the placebo group.
Researchers observed the benefits with CC-486 regardless of patients’ baseline cytogenetic risk, the number of prior consolidation cycles they received, and complete remission vs. complete remission with incomplete count recovery.
CC-486 exhibitied a manageable safety profile consistent with that of injectable azacitidine, and the agent did not worsen overall health-related quality of life compared with placebo.
The most common adverse events reported with CC-486 and placebo were gastrointestinal events. These included nausea (65% for CC-486 vs. 24% for placebo), vomiting (60% vs. 10%) and diarrhea (50% vs. 22%). Most were grade 1 or grade 2.
The most common grade 3 to grade 4 adverse events were neutropenia (41% for CC-486 vs. 24% for placebo), thrombocytopenia (23% vs. 22%) and anemia (14% vs. 13%).
Rates of serious adverse events were low in both groups. Infections occurred among 17% of patients assigned CC-486 and 8% of those assigned placebo. GI events were the most common adverse events to lead to treatment discontinuation (5% for CC-486 vs. 0.4% for placebo).
Wei said he is hopeful the results of this trial will lead to regulatory approval of CC-486 for use in the maintenance setting. However, there may be opportunities for other patients to benefit.
“This is just the first step,” he said. “Having an oral form of azacitadine gives us enormous potential for utilizing this agent in many other AML settings.”
One example includes frontline treatment of elderly patients, who account for two-third of AML cases.
“Although these patients are currently receiving azacitadine, imagine a future where we can utilize an oral medication instead of azacitadine given 7 days a month over the long term,” he said. “This also could become a fundamental building block for new combinations that hopefully will have transformative potential for patients.” – by Mark Leiser
Reference: Wei AH, et al. Abstract LBA-3. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Wei reports research funding or honoraria from, board of directors or consultant/advisory roles with, speakers bureau roles with AbbVie, Amgen, Astellas, AstraZeneca, Celgene, Genentech, Janssen, MacroGenics, Novartis, Pfizer and Servier. He also is a former employee of Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax (Venclexta; AbbVie, Genentech). Please see the abstract for all other authors’ relevant financial disclosures.