1. DiGiulio, Sarah

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A new clinical trial from the Children's Oncology Group found that, for children with acute promyelocytic leukemia (APL), drug combination therapy and much less intensive chemotherapy yielded very good 2-year survival rates. Researchers deem the all-trans retinoic acid (ATRA) and arsenic trioxide combination the new standard of care for these patients.

Matthew Kutny, MD. M... - Click to enlarge in new windowMatthew Kutny, MD. Matthew Kutny, MD

"The results of the AAML1331 clinical trial provide a new standard of care for children with both standard-risk and high-risk APL," Malcolm A. Smith, MD, PhD, Associate Branch Chief for Pediatric Oncology in the Cancer Therapy Evaluation Program at the National Cancer Institute (NCI), told Oncology Times. "Pediatric oncologists treating children with APL can now use a highly effective regimen with fewer side effects and shorter duration of treatment."


For the NCI-funded trial, 154 children between the ages of 1 and 22 who were newly diagnosed with standard- or high-risk APL were given oral ATRA, along with IV arsenic trioxide, daily for at least 28 days. Children with high-risk APL also received 4 doses of the anthracycline idarubicin chemotherapy during the initial phase of treatment. And children treated on the trial also completed 4 consolidation cycles with ATRA and arsenic trioxide treatments for a total treatment duration of approximately 9 months.


Children with standard- and high-risk APL had 2-year overall survival rates of 99 percent and 100 percent, respectively. The 2-year event-free survival rates were 98 percent and 96 percent, 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 (JAMA Oncol 2021; doi: 10.1001/jamaoncol.2021.5206).


"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," Smith noted in a statement from NCI. Fewer than 10 percent of the children in the trial experienced severe side effects (including bleeding and inflammatory complications from APL), which occurred only in the initial phase of treatment. Other more common and mild side effects included increased blood sugar and liver irritation. In an interview, the study's lead investigator, Matthew Kutny, MD, Associate Professor in the Department of Pediatrics in the Division of Hematology and Oncology at the University of Alabama at Birmingham and Children's of Alabama, further explained why these results are so promising.


1 What led the Children's Oncology Group to try this drug combination in children with APL?

"The primary goal of this Children's Oncology Group clinical trial (AAML1331) was to achieve excellent cure rates for children with APL with fewer side effects from the treatment. ATRA and arsenic trioxide are established targeted therapies for APL, but the previous standard treatment regimens for children with APL also included intensive cycles of conventional chemotherapy that can cause many side effects in children. Reports of clinical trials in adults indicated that ATRA plus arsenic trioxide without conventional chemotherapy was highly effective for adults with APL, and the AAML1331 clinical trial extended this result to children with both standard-risk and high-risk APL.


"The tested treatment regimens with no conventional chemotherapy for standard-risk patients and with only a few doses of an anthracycline for high-risk patients were studied to establish better and less toxic treatments for children with APL."


2 Can you elaborate on the benefits of this drug combination for these patients?

"Standard treatment for children with APL has evolved from only intensive chemotherapy, to a combination of intensive chemotherapy and ATRA plus arsenic trioxide, to the new standard defined by results of the Children's Oncology Group AAML1331 study, in which standard-risk patients are treated with only ATRA plus arsenic trioxide and high-risk patients are additionally treated with a few doses of a chemotherapy agent.


"The intensive chemotherapy previously used was associated with acute side effects such as severe myelosuppression and infection risk, as well as long-term side effects such as cardiac toxicity related to anthracycline use. These acute and long-term side effects and complications are avoided with the ATRA plus arsenic trioxide combination.


"Patients also benefit from a shorter duration of therapy (now approximately 9 months compared to over 2 years with prior regimens). This new regimen also eliminates intrathecal chemotherapy (which is administered into the cerebrospinal fluid by lumbar puncture) for most patients, with the exception of those who demonstrate disease or bleeding in the central nervous system. Less intrathecal therapy and fewer sedated lumbar puncture procedures is a great benefit to young patients."


3 What's the bottom-line message about this work and any next steps?

"APL in children is a highly curable disease through the use of ATRA plus arsenic trioxide for standard-risk patients-with a few doses of anthracycline added for high-risk patients and through careful attention to early monitoring and intervention for treatment-associated differentiation syndrome and APL-associated coagulopathy.


"The treatment used on this clinical trial was highly effective and well-tolerated, but the arsenic trioxide is an intravenous infusion that requires numerous visits to a hospital or clinic. Investigators in the Children's Oncology Group, supported by the National Cancer Institute and St Baldrick's Foundation, hope to test a new oral formulation of arsenic trioxide to use with ATRA (also an orally administered agent) that will significantly decrease the burden of care for patients and their families."