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Original Investigation
November 11, 2021

Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia: A Report From the Children’s Oncology Group AAML1331 Trial

Author Affiliations
  • 1Division of Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham
  • 2Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles
  • 3Division of Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada
  • 4Pediatric Hematology/Oncology, Wayne State University, Detroit, Michigan
  • 5Children’s Oncology Group, Monrovia, California
  • 6Division of Laboratory Medicine, University of Minnesota Medical Center–Fairview, Minneapolis
  • 7Department of Pathology, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 8Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, Ohio
  • 9Division of Behavioral Medicine/Neuropsychology, Children’s National Medical Center, Washington, District of Columbia
  • 10Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 11Division of Hematology/Oncology, Children’s Mercy Hospital and Clinics, Kansas City, Missouri
  • 12Division of Pediatric Hematology/Oncology, Nemours/Alfred I. DuPont Hospital for Children, Wilmington, Delaware
  • 13Division of Hematology/Oncology, Benioff Children’s Hospital Oakland, Oakland, California
  • 14Division of Pediatric Hematology/Oncology, Atlantic Health System, Goryeb Children’s Hospital, Morristown, New Jersey
JAMA Oncol. Published online November 11, 2021. doi:10.1001/jamaoncol.2021.5206
Key Points

Question  Is treatment with arsenic trioxide and all-trans retinoic acid (ATRA) without maintenance chemotherapy safe and noninferior to a historically used chemotherapy regimen in maintaining event-free survival among pediatric patients with newly diagnosed acute promyelocytic leukemia (APL)?

Findings  In this nonrandomized, noninferiority trial of 154 pediatric patients with APL who received ATRA and arsenic trioxide therapy, 2-year event-free survival rates among those with standard-risk and high-risk APL were 98% and 96%, respectively, which were noninferior to the rates observed in the historical control group.

Meaning  This trial suggests that pediatric patients with APL could be safely treated with ATRA and arsenic trioxide while either eliminating or substantially reducing the use of cytotoxic chemotherapy among those with standard-risk or high-risk APL, respectively.

Abstract

Importance  All-trans retinoic acid (ATRA) and arsenic trioxide therapy without the use of maintenance therapy has been found to be beneficial for the treatment of adults with standard-risk acute promyelocytic leukemia (APL). However, it is unclear whether similar regimens are safe and beneficial for the treatment of high-risk APL or pediatric patients with standard-risk APL.

Objective  To assess whether treatment with an ATRA and arsenic trioxide–based regimen is safe and allows for the elimination or substantial reduction of chemotherapy use among pediatric patients with standard-risk or high-risk APL, respectively.

Design, Setting, and Participants  The Children’s Oncology Group AAML1331 study is a nonrandomized, noninferiority trial that examined survival outcomes among 154 pediatric patients with APL compared with a historical control group of patients with APL from the AAML0631 study. Patients aged 1 to 21 years were enrolled at 85 pediatric oncology centers (members of the Children’s Oncology Group) in Australia, Canada, and the US from June 29, 2015, to May 7, 2019, with follow-up until October 31, 2020. All patients had newly diagnosed APL and were stratified into standard-risk APL (white blood cell count <10 000/μL) and high-risk APL (white blood cell count ≥10 000/μL) cohorts.

Interventions  All patients received ATRA and arsenic trioxide continuously during induction therapy and intermittently during 4 consolidation cycles. Patients with high-risk APL received 4 doses of idarubicin during induction therapy only. The duration of therapy was approximately 9 months, and no maintenance therapy was administered.

Main Outcomes and Measures  Event-free survival (EFS) at 2 years after diagnosis.

Results  Among 154 patients (median age, 14.4 years [range, 1.1-21.7 years]; 81 male participants [52.6%]) included in the analysis, 98 patients (63.6%) had standard-risk APL, and 56 patients (36.4%) had high-risk APL. The median follow-up duration 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. Patients with standard-risk APL had a 2-year EFS rate of 98.0% and an overall survival rate of 99.0%; adverse events included 1 early death during induction therapy and 1 relapse. Patients with high-risk APL had a 2-year EFS rate of 96.4% and an overall survival rate of 100%; adverse events included 2 relapses and 0 deaths. These outcomes met predefined noninferiority criteria (noninferiority margin of 10% among those with standard-risk APL and 14.5% among those with high-risk APL).

Conclusions and Relevance  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 4 doses of idarubicin during induction therapy only and no maintenance therapy. The 2-year EFS 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.

Trial Registration  ClinicalTrials.gov Identifier: NCT02339740

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