While the combinations of all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO; ATRA+ATO) and of ATRA+ATO plus gemtuzumab ozogamicin (GO; ATRA+ATO+GO) have yielded good clinical outcomes for patients with low-risk acute promyelocytic leukemia (APL), patients with high-risk APL remain a therapeutic challenge and experience significant rates of mortality and relapse. In a recent study of treatment options, Jeffrey E. Lancet, MD, and colleagues found that induction therapy with the three-drug ATRA+ATO+GO regimen was both feasible and safe for these high-risk patients.
Dr. Lancet presented the results of the phase II study at the 2015 ASCO Annual Meeting. The study was designed by SWOG investigators to validate the safety and efficacy of this combination in high-risk APL. Primary objectives were assessment of early (6-week) death rate and assessment of three-year continuous complete remission (CCR).
Investigators enrolled 73 adults with newly-diagnosed high-risk APL into the study. Patients had a median age of 46.5 years and 52 percent were female. Induction therapy consisted of 45 mg/m2 ATRA per day on day 1 until complete remission, 0.15 mg/kg ATO per day on day 10 until complete remission, and 9 mg/m2 GO on day 1.
Patients in complete remission received consolidation with two cycles of ATO, followed by ATRA plus daunorubicin for two cycles, followed by two cycles of GO. Subsequent maintenance therapy consisted of ATRA plus 6-mercaptopurine plus methotrexate for up to one year.
Sixty-two (85%) patients completed induction therapy as planned and 48 patients (66%) completed all planned consolidation. Thirty-two patients (44%) completed maintenance therapy. The “lower-than-expected” rate of completion of all planned therapy suggests that consolidation and/or maintenance therapy may be “overly toxic,” Dr. Lancet and colleagues explained.
Following treatment initiation:
- Eight of the 73 patients (11%) died within six weeks
- Three patients (4%) voluntarily withdrew from the study
Importantly, the early mortality rate was below the investigators predefined target rate (15%); the lower early mortality rate also supported rejection of the null hypothesis, which assumed a 30 percent early death rate.
On the safety side, the most common treatment-related grade 3 or 4 adverse events (AEs) during induction included febrile neutropenia (33%), aspartate aminotransferase/alanine aminotransferase elevation (12%), hypoxia/differentiation syndrome (11%), hyperglycemia (11%), headache (11%), and prolonged QTc (11%).
Among the 59 patients receiving consolidation, the most common grade 3-4 AEs again included febrile neutropenia (52%) and headache (14%), as well as fatigue (14%) and nausea (12%).
“The combination of ATO+ATRA+GO appears safe and well-tolerated in patients with high-risk APL,” Dr. Lancet and colleagues conclude, adding that the CCR analysis is ongoing.
Lancet JE, Othus M, DeAngelo DJ, et al. Safety and tolerability of the combination of ATRA + arsenic trioxide (ATO) + gemtuzumab ozogamicin (GO) in high-risk acute promyelocytic leukemia (APL): Initial report of the SWOG/Alliance/ECOG S0535 trial. Abstract #7016. Presented at the 2015 American Society of Clinical Oncology Annual Meeting, Chicago, IL, May 31, 2015.