Drug Combination Used in Adults Can Benefit Children With Acute Promyelocytic Leukemia

All-trans retinoic acid and arsenic trioxide used together can let children avoid treatment with convention chemotherapy, which has more adverse effects.

A combination of all-trans retinoic acid (ATRA) and arsenic trioxide can be used effectively in children with standard- and high-risk acute promyelocytic leukemia (APL) and let children with standard risk avoid treatment with conventional chemotherapy. The findings were published in JAMA Oncology.

ATRA/arsenic trioxide therapy is the preferred regimen for adults with APL. Use of this combination therapy “has been associated with substantial improvements in outcomes, and APL is now the most curable subtype of acute myeloid leukemia,” according to the authors.

The AAML1331 trial was conducted by the Children’s Oncology Group. A previous study (AAML0631) evaluated patients with newly diagnosed APL. Those patients received consolidation therapy and two 5-week cycles of arsenic trioxide and an anthracycline dose. AAML1331 evaluated a chemotherapy-free regimen, with the goal of examining 2-year event-free survival (EFS) and comparing it with the 2-year EFS in AAML0631.

Enrollment began on June 29, 2015, and data were collected until October 31, 2020. The final analysis included 154 children with a median age of 14.4 years; 52.6% were male. The majority (63.6%) had standard-risk APL and 36.4% had high-risk APL. Ultimately, 8 patients withdrew.

During induction therapy, the death rate was 0.6% in the AAML1331 study compared with 4.0% in the AAML0631 study (P = .08) for all patients. The death rates were 1.0% vs 0% (P = .16) for standard-risk APL and 0% vs 11.4% (P = .02) for high-risk APL in the AALM1331 and AAML0631 studies, respectively.

In AAML1331, the 2-year overall survival rates were 99.0% (90% CI, 94.8%-99.8%) for patients with standard-risk APL and 100% (90% CI, 93.0%-100%) for patients with high-risk APL. The EFS rates were noninferior to those in the AAML0631 study. The 2-year EFS rates in AAML1331 were 98.0% (90% CI, 93.4%-99.3%) for standard-risk APL and 96.4% (90% CI, 88.2%-98.8%) for high-risk APL.

“This is a remarkable achievement and will be the new standard of care,” Malcolm A. Smith, MD, PhD, of the Cancer Therapy Evaluation Program at the National Cancer Institute, which funded the trial, said in a statement. “Twenty years ago, these patients would have been treated with intensive chemotherapy, including drugs that lead to heart problems later in life. By comparison, all-trans retinoic acid and arsenic trioxide have fewer acute or long-term side effects.”

The ATRA/arsenic trioxide therapy was well tolerated. Patients in AALM1331 had fewer days of hospitalization compared with AAML0631 (median 0 days [range, 0-21] vs 13 days [range, 0-34]; P < .001). The authors noted that rates of febrile neutropenia and infection were low for the combination therapy.

While the authors noted the study’s sample of less than 200 patients was a limitation, APL is a rare disease and this study was considered large for the disease. Although the outcomes were positive, receiving numerous doses of arsenic trioxide, which is given intravenously and typically requires administration in a health care facility, can be a major stress for patients and families.

“Thus, the next steps in optimizing APL therapy will be to minimize the burden of care by evaluating emerging oral forms of arsenic and to ensure that these oral treatments can safely and successfully replace intravenous arsenic trioxide,” the authors wrote.


Kutny MA, Alonzo TA, Abla O, et al. 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. JAMA Oncol. Published online November 11, 2021. doi:10.1001/jamaoncol.2021.5206