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Children with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) plus arsenic trioxide -- without maintenance therapy -- were able to achieve outcomes similar to the historical experience with a more intensive standard regimen, a single-arm noninferiority trial found.

In Children's Oncology Group AAML1331, the 2-year overall survival rates with ATRA/arsenic trioxide induction and consolidation were 99% (90% CI 94.8-99.8) for patients with standard-risk APL and 100% (90% CI 93.0-100) among those with high-risk APL, who also received idarubicin during induction, reported Matthew Kutny, MD, of the University of Alabama at Birmingham, and colleagues.

Event-free survival (EFS) rates at 2 years for the standard- and high-risk groups were 98% (90% CI 93.4-99.3) and 96.4% (90% CI 88.2-98.8), respectively, according to the findings in .

These 2-year EFS rates were noninferior to those in a preceding comparator trial, , that reported rates of 97% and 82.9% among standard- and high-risk APL patients treated with ATRA/arsenic trioxide plus chemotherapy, including anthracyclines.

"Numerically we can actually see that high-risk patients -- approximately a third of our APL patients -- had an improvement in their cure rates," said Kutny during a press briefing. "In that predecessor trial, with all of that intensive treatment, and 2 and a half years of therapy, their EFS was 83% while in our study it was 96%. That's a big achievement."

"This is a far less toxic treatment," Kutny added. "It is much shorter, patients spent much less time in the hospital, and they had similar-to-improved cure rates."

In AAML1331, children spent a median 4 days (range 0-21) hospitalized during cycle 4, for example, as compared to 13 days (range 0-34 days) in the AAML0631 study.

"It really does change the standard of care for these children," said Malcolm Smith, MD, PhD, of the Cancer Therapy Evaluation Program at the National Cancer Institute, which funded trial.

"Going back to the 1980s, only one in four children were alive and free of their leukemia 5 years from diagnosis," Smith noted. "Having these agents that lack the harsh toxicities of conventional leukemia, and having survival rates that are well above 90% is a remarkable advance."

"In general, this represented what we hope is the future for many childhood cancers," said Kutny. "That we can move away from the more toxic and intense treatments toward a more targeted approach."

The 154 patients in AAML1331 had a median age of 14.4 years (range 1.1-21.7) and all had newly diagnosed APL. They were enrolled at 85 pediatric oncology centers in the U.S., Canada, and Australia from 2015 to 2019. Patients were stratified into standard-risk (n=98; white blood cell count <10,000/μL) and high-risk (n=56; white blood cell count ≥10,000 μL) groups.

Patients were given oral ATRA, along with intravenous arsenic trioxide, daily for at least 28 days. Children with high-risk APL were enrolled in a separate arm of the study and also received idarubicin during induction. No patients received maintenance therapy (reducing treatment duration from more than 2 years to about 9 months). Median follow-up duration was 24.7 months for the standard-risk group and 22.8 months for the high-risk group.

Kutny noted that a significant result in AAML1331 was the low early death rate compared with AAML0631.

Historically, 5-10% percent of children with APL die early during induction because of complications of the disease itself (APL coagulopathy and differentiation syndrome), he said. But in the current study, the overall death rate during induction therapy was just 0.6% compared with 4.0% in AAML0631. Between trials, rates were 1.0% and 0%, respectively, for the standard-risk groups, and 0% and 11.4% for the high-risk groups.

Kutny explained that the AAML1331 study initiated arsenic trioxide on day 1 to rapidly reverse APL coagulopathy and included 14 days of dexamethasone therapy to prevent differentiation syndrome.

In terms of adverse events, "they were far less in intensity and number with this regimen compared with historical experience," Kutny said. "The higher-intensity ones were really only seen in the induction period when patients were dealing with the other complications of the disease itself. When the patients went out into the additional consolidation cycles, [the treatment] was very well tolerated."

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