Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia

When all-trans retinoic acid (ATRA) is used with chemotherapy as the standard of care for acute promyelocytic leukemia (APL), remission rates can reach 95%, and cure rates typically exceed 80%. Arsenic trioxide with or without ATRA has also been shown to be effective in the treatment of APL; synergy of arsenic trioxide and ATRA has been shown at both the biologic and clinical levels. As well, pilot studies of the treatment of arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity.

Researchers recently conducted a prospective, randomized, open-label, phase 3 multicenter Europe-based noninferiority trial [N Engl J Med. 2013;369(2):111-121] that compared the efficacy and toxicity of standard ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients 18 to 71 years of age with newly diagnosed, low-to-intermediate-risk APL. Low-to-medium risk was defined as having a white-cell count ≤10×10⁹ per liter.

The trial 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. Patients were randomly assigned to receive ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA–idarubicin induction therapy followed by 3 cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA.

The primary study end point was event-free survival at 2 years after diagnosis, with treatment failure defined as any of the following: no achievement of hematologic complete remission after induction therapy, no achievement of molecular complete remission after 3 consolidation courses, molecular relapse, hematologic relapse, or death. Secondary end points included the rate of hematologic complete remission after induction, the probability of overall survival, the cumulative incidence of relapse, toxic effects, and the kinetics of minimal residual disease.

There were 162 prespecified patients enrolled in the study between October 2007 and September 2010. The present analysis was performed in November 2012, with a median follow-up of 34.4 months (range, 0.5-55.8). Hematologic complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group (100%) and in 75 of the 79 patients (95%) in the ATRA–chemotherapy group. Median time to hematologic complete remission was 32 days (range, 22-68) in the ATRA–arsenic trioxide group and 35 days (range, 26-63) in the ATRA–chemotherapy group.

Two-year event-free survival rate was 97% in the ATRA–arsenic trioxide group (72 of 74 patients), compared with 86% in the ATRA–chemotherapy group (65 of 76 patients) (difference, 11 percentage points; 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). The log-rank test for the difference in event-free survival curves indicated the superiority of ATRA–arsenic trioxide (P=.02). In the per-protocol population, event-free survival rates were 97% in the ATRA–arsenic trioxide group (64 of 66 patients) versus 85% in the ATRA–chemotherapy group (61 of 72 patients) (difference, 12 percentage points; 95% CI, 2-23; P<.001 for noninferiority).

The 2-year overall survival probability was 99% (95% CI, 96%-100%) in the ATRA–arsenic trioxide group and 91% (95% CI, 85%-97%) in the ATRA–chemotherapy group (P=.02). The 2-year disease-free survival rate was 97% (95% CI, 94%-100%) in the ATRA–arsenic trioxide group and 90% (95% CI, 84-97) in the ATRA–chemotherapy group. The 2-year cumulative incidence of relapse was 1% (95% CI, 0%-4%) in the ATRA–arsenic trioxide group and 6% (95% CI, 0-11) in the ATRA–chemotherapy group.