Medical Technology

“Remarkable” Results in Pediatric Acute Promyelocytic Leukemia

“Remarkable” results from a new treatment strategy for the acute promyelocytic leukemia of children (APL) have been reported by researchers from the National Cancer Institute (NCI).

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

They are among the highest survival rates ever recorded for high-risk infants with APL. This was noted by the team at a press briefing held at NCI on the 10th of November.

This breakthrough is a significant advancement for children with APL, and will be the standard of care,” stated Malcolm Smith (MD, PhD), briefing moderator, associate branch chief pediatric oncology at NCI.

The results were published online November 11, in JAMA Oncology..

This work was the culmination of a series of studies funded by NCI through its Children’s Oncology Group research network to determine the best method to utilize the new treatment regimen, consisting of all-trans retinoic acid (ATRA) and arsenic trioxide, in the treatment of pediatric APL.

These medicines have been used for many years as routine treatments for adult ailments.

New results suggest that a simple approach is the best. Standard risk children can be treated using ATRA/arsenic alone. The study used four doses of the traditional chemotherapy or idarubicin for children with high-risk illnesses (white blood cells 10,000/mL or greater). There is no maintenance phase.

“This was an extended 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, insisting that this is “radically different from what we’ve seen with our prior APL studies,”

There was one death in the treatment induction, which is a remarkable finding in APL, he said.

Casting a Wide Net

The study included the participation of 154 APL patients diagnosed up to 21 years old who were treated in 85 pediatric cancer centers in Canada, Australia and the US.

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

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

Idarubicin was prescribed to high-risk patients to lower the white blood cell count. There was no other cytotoxics of the traditional variety were required.

The one death was in the standard risk group and was caused by sepsis. At a median follow up of close to 25 months, one standard-risk child and two high-risk kids both relapsed.

Overall, treatment was well tolerated with low rates of infections and febrile neutropenia. Induction was successful in less than 10% of children who experienced grade 3 or higher adverse reactions. “Patients can tolerate this quite well,” Kutny said.

A Better Approach

The trial was “the natural follow-up,” Kutny said, to the 2017 trial with 101 subjects.

This trial, also conducted by Kutny who was also the leader, had employed an extensive and toxic regimen, including ATRA as an induction drug, followed by a consolidation regimen that included ATRA, arsenic, cytarabine and anthracycline and a maintenance regimen consisting of ATRA, methotrexate and mercaptopurine.

The survival rates of standard-risk patients were similar to the new strategy. However in the previous study high-risk patients had a lower survival rate with a two-year overall survival rate of 85.7 percent.

The treatment was also longer during the maintenance phase, spanning over 2 years vs just 9 months under the new regimen.

Kutny said that “we wanted to build upon” 2017’s results and “felt it was owed to children” to find a less toxic approach. The result was “far less harmful.” It’s shorter, and patients spend much less time in hospitals.” Adverse events “were significantly less with this regimen. Kutny said that the kids performed admirably with it.

The next step is to determine whether arsenic trioxide that is administered intravenously can be replaced with an oral formulation, so that children and their families can spend less time in the hospital.

The median age of the subjects was 14 years. The majority of them were males. The ATRA/arsenic combination blocks proteins that APL cells require to live and develop.

Arsenic, a notorious poison “can be a potent medicine,” at the right dose, Kutny said. “We have been able to determine the right dose that would kill the leukemia cells of these kinds without causing damage to other healthy tissues,” Kutny said.

The research was funded by the National Institutes of Health (Children’s Oncology Group) as well as the St. Baldrick’s Foundation. Kutny has not disclosed any financial relationships with any financial institutions. Co-author Madhvi Rajpurkar, MD, disclosed personal expenses from Novo Nordisk outside the submitted work.

JAMA Oncol. Published online November 11 2021. Abstract

M. Alexander Otto, a physician assistant who holds a master’s degree in medical sciences, is an award-winning journalist who was employed by many major news outlets before joining Medscape. He is a MIT Knight Science Journalism fellow. Email: [email protected]

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