Novel Drug Combination May Help Children With Acute Promyelocytic Leukemia Avoid Conventional Chemotherapy

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A clinical trial recently published by Kutny et al in JAMA Oncology found that the combination of all-trans retinoic acid and arsenic trioxide was highly effective in children with standard- and high-risk acute promyelocytic leukemia (APL). Nearly all patients in the trial survived for 2 years without experiencing a relapse. None of the children with standard-risk APL required conventional chemotherapy, and those with high-risk APL received just four doses of idarubicin.

“This is a remarkable achievement and will be the new standard of care,” said Malcolm A. Smith, MD, PhD, of the Cancer Therapy Evaluation Program at the National Cancer Institute, which funded the multi-institutional, nonrandomized phase III cooperative group trial. “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.”

“As a pediatrician and an oncologist, I've had to have difficult talks with families about what their child is facing and what type of therapy they're going to have to go through to be cured,” said Matthew Kutny, MD, of Children’s of Alabama and the University of Alabama at Birmingham, the study’s lead investigator. “So, being able to offer a therapy that is less intense and has fewer side effects, but at the same time has amazingly high survival rates, is a really good feeling.”

Study Background

APL accounts for 5% to 10% of acute myeloid leukemia diagnoses in children and adolescents. Symptoms of this blood and bone marrow cancer include excessive bleeding, easy bruising, low red blood cell count, fever, and fatigue. Previously, treatment for children with APL involved anthracyclines, which can damage the heart.

An earlier Children’s Oncology Group trial showed that children with APL who were treated with arsenic trioxide and all-trans retinoic acid, along with chemotherapy drugs that included anthracyclines, had high rates of 2-year event-free survival and low risk of relapse. The combination of all-trans retinoic acid and arsenic trioxide is currently the preferred initial treatment for adults with standard-risk APL. Adults with high-risk APL also receive some chemotherapy, as well as maintenance therapy.

Key Findings

In the current trial, children with standard- and high-risk APL had 2-year overall survival rates of 99% and 100%, respectively. The 2-year event-free survival rates were 98% and 96%, respectively. One child with standard-risk APL died early in treatment, and three children (one with standard-risk APL and two with high-risk APL) experienced a relapse.

Fewer than 10% of the children experienced severe side effects, which occurred only in the initial phase of treatment. Side effects included increased blood sugar, liver irritation, and bleeding. Some of the patients with high-risk APL developed mouth sores from the idarubicin treatment. A severe complication of APL is differentiation syndrome, which may cause life-threatening inflammation. Physicians were offered supportive care strategies to help participants manage this and other side effects.

Dr. Kutny pointed out that because there was no need for maintenance therapy, the length of time the children were undergoing treatment was reduced from more than 2years to approximately 9 months. More follow-up will be needed, he said, to determine the long-term effects of treating children with all-trans retinoic acid and arsenic trioxide.

“Arsenic is often associated with being a poison, but it can also be a powerful medicine,” Dr. Kutny noted. “Arsenic trioxide has been used in traditional Chinese medicine for millennia. The difference between a medication and a poison is really the dose. 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.”

Arsenic trioxide works cooperatively with all-trans retinoic acid to block the action of proteins needed by leukemia cells to survive and grow. Dr. Kutny noted that the Children’s Oncology Group is currently investigating ways to deliver arsenic trioxide in an oral form, which would make it easier for children to take.

Disclosure: The trial was funded by the National Cancer Institute. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.