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“Remarkable” results with a novel treatment regimen in pediatric acute promyelocytic leukemia (APL) have been reported by researchers at the National Cancer Institute (NCI).

Two-year event free survival (EFS) with the regimen was 98% and overall survival (OS) was 99% in patients with standard-risk APL, and the EFS was 96.4% and OS was 100% in patients with high-risk disease.

These are the best survival outcomes ever reported for high-risk pediatric APL, the team noted at a November 10 press briefing held at the NCI.

The finding “is a remarkable advance for children with APL and will be the new standard of care,” said briefing moderator Malcolm Smith, MD, PhD, atomoxetine over the counter associate branch chief for pediatric oncology at NCI.

The findings were published online November 11 in JAMA Oncology.

This work was the culmination of a series of trials sponsored by NCI through its Children’s Oncology Group research network to figure out the best way to use the novel treatment regimen, which is comprised of all-trans retinoic acid (ATRA) and arsenic trioxide, in the treatment of pediatric APL.

Both products have been around for years and are standard treatments for adult disease.

The new results suggest a that a minimalist approach is best, with ATRA/arsenic alone used for standard risk children. For children with high-risk disease (white blood cell counts 10,000/μL or higher), the team added just four doses of the traditional cytotoxic idarubicin during induction. There is no maintenance phase of treatment.  

“This was a long time in the making,” commented lead investigator Matthew Kutny, MD, a pediatric blood cancer specialist at the University of Alabama at Birmingham. “We are very excited about the results,” he added, emphasizing that this is “radically different from what we’ve seen with our prior APL studies,”

There was just one death during induction therapy, a remarkable finding in APL, he said.

Casting a Wide Net

The trial included 154 newly diagnosed APL patients up to 21 years old treated at 85 pediatric oncology centers throughout Canada, Australia, and the US

APL is rare, with only about 80 pediatric cases diagnosed in the US each year, so investigators had to throw a wide net, Kutny explained.

Children received oral ATRA and intravenous arsenic trioxide daily for at least 28 days during induction, then intermittently over four consolidation cycles, plus supportive care, including dexamethasone for differentiation syndrome.

The idarubicin for high-risk patients was to reduce white blood cell counts; no other traditional cytotoxics were used.

The one death was in the standard-risk group and was the result of sepsis. One standard-risk and two high-risk children relapsed at a median follow-up of almost 25 months.

Overall, treatment was well tolerated, with low rates of infections and febrile neutropenia. Grade 3 or higher adverse events occurred in less than 10% of children, and all during induction. “Patients tolerate this quite well,” Kutny said.

A Better Approach

The work was “the natural successor,” Kutny said, to a 2017 trial with 101 subjects.

That trial, also led by Kutny, had used a more involved and more toxic regimen, with ATRA alone for induction followed by consolidation with ATRA, arsenic, cytarabine, and anthracycline, and a maintenance regimen of ATRA, methotrexate, and mercaptopurine.

Survival outcomes for standard-risk patients were comparable to the new approach, but in that previous trial, the high-risk patients did worse, with a 2-year overall survival of 85.7%.

Treatment also took much longer with the maintenance phase, over 2 years vs just 9 months with the new regimen.

“We wanted to build upon” the 2017 results, and “felt we owed it to children” to find a less toxic approach, Kutny commented. The result “is a far less toxic treatment. It’s much shorter, and patients spend much less time in the hospital.” Adverse events “were far less with this regimen. [Children] did wonderful with it,” Kutny said.

The next step is to see if intravenous arsenic trioxide can be swapped out for an oral formulation, so children and their families can spend even less time in the hospital.

Subjects were a median age 14 years, and just over half were boys. The ATRA/arsenic combination works by blocking proteins that APL cells need to survive and grow.

A notorious poison like arsenic “can be a powerful medicine,” at the right dose, Kutny said. “Over time, we have figured out the exact dosing that would be effective in killing these types of leukemia cells without damaging other healthy tissues.”

The work was funded by the National Institutes of Health (Children’s Oncology Group) and the St. Baldrick’s Foundation. Kutny has disclosed no relevant financial relationships. Co-author Madhvi Rajpurkar, MD, reported personal fees from Novo Nordisk outside the submitted work.

JAMA Oncol. Published online November 11, 2021. Abstract

M. Alexander Otto is a physician assistant with a master’s degree in medical science, and an award-winning medical journalist who has worked for several major news outlets before joining Medscape. He is an MIT Knight Science Journalism fellow. Email: [email protected]

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