Children with acute promyelocytic leukemia (APL) can be safely and effectively managed with the combination of arsenic trioxide and all-trans retinoic acid (ATRA) without maintenance therapy, according to a report from the Children’s Oncology Group AAML1331 Trial published in JAMA Oncology. The combination also significantly reduced the use of chemotherapy.

The multicountry nonrandomized, noninferiority trial enrolled 154 children, aged 1 to 21 years, with newly diagnosed APL at 85 pediatric oncology centers in Australia, Canada and the US from 2015 to 2019. They were followed till October 31, 2020.

All patients had newly diagnosed APL and were categorized into standard-risk APL (white blood cell count less than 10,000/μL) and high-risk APL (white blood cell count 10,000/μL or higher) cohorts. Ninety-eight patients (~64%) had standard-risk APL, and 56 patients (36.4%) had high-risk APL.

Patients were administered arsenic trioxide (intravenous) and ATRA (oral) combination during induction therapy and also intermittently during four consolidation cycles. High-risk APL patients were also given four doses of idarubicin only during induction therapy. The main outcome measure was event-free survival at two years after diagnosis. The predetermined noninferiority criteria were a margin of 10% in standard-risk APL patients and 14.5% in the high-risk APL children.

The event-free survival rates at 2 years in children at standard-risk APL was 98%, while in the high-risk APL patients, the rate was 96.4%%. The overall survival rates at two years were 99% and 100% in the standard-risk and high-risk patients respectively. These rates were noninferior to the rates of 97% and 82.9%, respectively in a predecessor comparator trial (AAML0631), wherein patients were also treated with chemotherapy. In the present trial (AAML1331), the average length of hospitalization was 4 days compared to 13 days in the AAML0631 study.

Overall mortality rate in the present trial was 0.6% compared to 4% in the AAML0631 trial. Three patients suffered a relapse of the disease; one in the standard risk group and the remaining two in the high-risk APL group. None of the patients in the standard-risk group needed conventional chemotherapy, while only four doses of idarubicin were required for patients in the high-risk group. According to the authors, as no maintenance therapy was administered, the duration of treatment was reduced from two years to around nine months. Severe adverse effects were reported by less than 10% and were noted only in the induction period.

The strategy of using the combination of ATRA and arsenic trioxide without maintenance therapy is an effective treatment for adults with standard-risk APL. This study has now shown that it is also safe and beneficial in pediatric APL patients as evident by the overall survival rates of 99% and 100% in the two patient categories. These outcomes were comparable to the historical experience with a more intensive standard treatment regimen.

The combination also had added advantages such as shorter duration of treatment, less exposure to cytotoxic anthracycline and intrathecal chemotherapy with fewer adverse effects and shorter length of hospital stay. So, will this approach become a new standard of care for pediatric patients with APL?

Reference

1. Kutny MA, et al. Assessment of arsenic trioxide and all-trans retinoic acid for the treatment of pediatric acute promyelocytic leukemia: A report from the Childrens Oncology Group AAML1331 Trial. JAMA Oncol. 2021 Nov 11. doi: 10.1001/jamaoncol.2021.5206.