COG AAML1331 Trial: Arsenic Trioxide and All-Trans Retinoic Acid in Pediatric Patients With APL

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As reported in JAMA Oncology by Kutny et al, the Children’s Oncology Group (COG) AAML1331 trial has shown that treatment with arsenic trioxide and all-trans retinoic acid (ATRA) with no maintenance therapy produced high event-free and overall survival rates in pediatric patients with acute promyelocytic leukemia (APL).

Study Details 

In the study, 154 newly diagnosed patients aged 1 to 21 years were enrolled at sites in the United States, Canada, and Australia between June 2015 and May 2019. Patients were stratified as having standard-risk APL (white blood cell [WBC] count < 10,000/μL; n = 98) or high-risk APL (WBC count ≥ 10,000/μL; n = 56). All patients received ATRA and arsenic trioxide continuously during induction therapy and intermittently during four consolidation cycles. Those with high-risk APL also received four doses of idarubicin during induction therapy only. No maintenance therapy was administered; the duration of treatment was approximately 9 months. The primary outcome measure was 2-year event-free survival.

The study included a noninferiority analysis comparing outcomes to those in a historical control group of patients with APL from the COG AAML0631 study; in the latter study, treatment included consolidation therapy with two 5-week cycles of arsenic trioxide combined with an anthracycline, maintenance therapy, and prophylactic intrathecal cytarabine. Event-free survival rates in the current study were compared with 2-year rates from the AAML0631 study of 97% among patients with standard-risk APL, using a noninferiority margin of 10%, and 83% among those with high-risk APL, using a noninferiority margin of 14.5%.

Key Findings

Median follow-up was 24.7 months (range = 0–49.5 months) for patients with standard-risk APL and 22.8 months (range = 0–47.7 months) for patients with high-risk APL.

Among standard-risk patients, 2-year event-free survival was 98.0% (90% confidence interval [CI] = 93.4%–99.3%), thus meeting the noninferiority criterion. Overall survival at 2 years was 99.0% (90% CI = 94.8%–99.8%). Among high-risk patients, 2-year event-free survival was 96.4% (90% CI = 88.2%–98.8%), thus meeting the noninferiority criterion. Overall survival at 2 years was 100% (90% CI = 93.0%–100%).

Three patients experienced APL relapse, with a cumulative 2-year incidence of 2.1% (1.1% for those with standard-risk APL and 3.9% for those with high-risk APL).

Early death during induction therapy occurred in one standard-risk patient and none of the high-risk patients.

The number of days hospitalized was lower among patients in the AAML1331 study vs the AAML0631 study; eg, the median number of days hospitalized during consolidation cycle 4 was 0 (range = 0–21 days) vs 13 (range = 0–34 days, P < .001).

The investigators concluded, “In this nonrandomized, noninferiority trial, pediatric patients with standard-risk APL who received treatment with a chemotherapy-free ATRA and arsenic trioxide regimen experienced positive outcomes. Patients with high-risk APL also had positive outcomes when treated with a novel ATRA and arsenic trioxide–based regimen that included four doses of idarubicin during induction therapy only and no maintenance therapy. The 2-year event-free survival estimates were noninferior to the historical comparator group, and advantages of the regimen included shorter treatment duration, lower exposure to anthracycline and intrathecal chemotherapy, and fewer days hospitalized.”

Matthew A. Kutny, MD, of the Division of Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by grants from the National Institutes of Health and St. Baldrick’s Foundation. For full disclosures of the study authors, visit

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