ATRA and Arsenic Trioxide May Be Even Better Than ATRA and Chemotherapy in Treating Low-to-Intermediate Risk Acute Promyelocytic Leukemia 

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All-trans retinoic acid (ATRA) plus arsenic trioxide bested the already high remission rates achieved by ATRA with chemotherapy, the standard of care for acute promyelocytic leukemia, in a phase III multicenter trial among patients with low-to-intermediate risk acute promyelocytic leukemia. “Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P = .12),” according to the results published in The New England Journal of Medicine. These results led researchers from the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) and the German–Austrian Acute Myeloid Leukemia Study Group and Study Alliance Leukemia to conclude, “ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk [acute promyelocytic leukemia].”

Eligibility requirements for the study included age between 18 to 71 years and low-to-intermediate risk acute promyelocytic leukemia based on a white-cell count ≤ 10×109 per liter. “Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA,” the authors explained. 

Study Results

The study “was designed to show that ATRA-arsenic trioxide was not inferior to ATRA-chemotherapy with respect to the event-free survival rate at 2 years,” the authors noted. Results showed that 2-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group. This represented a difference of 11% (95% confidence interval [CI] = 2–22). “Since the lower bound of the 95% confidence interval for the difference in event-free survival rates was not lower than -5%, the noninferiority of ATRA–arsenic trioxide was confirmed (P < .001). Furthermore, the log-rank test for the difference in event-free survival curves indicated the superiority of ATRA-arsenic trioxide (P = 0.02),” the authors explained.

The 2-year overall survival probability was 99% in the ATRA–arsenic trioxide vs 91% in the ATRA-chemotherapy group (P = 0.02). The median follow-up was 34.4 months.

ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections than ATRA-chemotherapy, but more patients in the ATRA-arsenic trioxide group had grade 3 or 4 hepatic events. In addition, prolongation of the QTc interval occurred in 12 patients in the ATRA-arsenic trioxide group, but no patients in the ATRA-chemotherapy group. 

“The present study suggests that APL is curable without conventional chemotherapy. Although longer follow-up will be needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic trioxide act synergistically to eradicate [acute promyelocytic leukemia],” the authors averred.

“No pharmaceutical company was involved in the design of the study, data collection or analysis, or the writing of the manuscript,” the researchers noted. “Arsenic trioxide was donated for this investigation by Cephalon Europe and, since 2011, by Teva Pharmaceutical Industries.” ■

Lo-Coco F, et al: N Engl J Med 369:111-121, 2013.