[ICKSH 2025] ‘High-risk pediatric AML needs precision, not more chemotherapy’

High-risk pediatric acute myeloid leukemia (HR-AML) remains one of the most challenging hematologic malignancies in children, with long-term survival still lagging behind despite decades of therapeutic development.

While overall outcomes in pediatric AML have improved to 65–70 percent, relapse and treatment-related toxicities continue to pose significant hurdles, particularly in the high-risk population.

At the 2025 International Conference of the Korean Society of Hematology (ICKSH), Professor Todd Cooper of the University of Washington delivered a presentation addressing how clinical strategies must evolve to improve outcomes in HR-AML. His lecture centered on novel classification systems, targeted therapies, and collaborative clinical trial networks.

“The future of high-risk pediatric AML treatment lies not in intensifying chemotherapy but in precision medicine and international collaboration,” Cooper emphasized.

He described how the Children’s Oncology Group (COG) AAML1831 trial is pioneering a molecularly defined risk stratification model.

This new framework goes beyond traditional markers like FLT3, NPM1, and CEBPA mutations, integrating broad molecular panels, immunophenotyping, and FISH/microarray data.

As a result, patients are now categorized into more refined subgroups—Low Risk 1, Low Risk 2, and High Risk—with the high-risk group expanding from 30 percent to 41 percent, reflecting improved classification accuracy.

“The goal is not only to predict risk more precisely, but to match patients to therapies that target the biology of their disease,” Cooper said. “This is how we begin to break the plateau in survival we’ve seen over the last decade.”

Cooper pointed out that conventional chemotherapy has reached a saturation point in terms of intensity.

The cumulative doses of anthracyclines and cytarabine have led to concerning rates of cardiotoxicity and infection without corresponding survival gains.

“Our toxicity ceiling is real,” he noted. “The last major advance in survival was with the addition of gemtuzumab ozogamicin in AAML0531—since then, we’ve been stuck.”

New therapies are providing hope. Cooper highlighted the Menin inhibitor ziftomenib, which targets shared leukemogenic pathways in KMT2A, NUP98, and MLLT10 rearranged leukemias.

Ziftomenib is currently being evaluated in the APAL2020K trial under the global PedAL Initiative.

He also referenced the use of venetoclax, a BCL-2 inhibitor already effective in adults, now being studied in relapsed pediatric AML populations.

In parallel, immunotherapy is advancing rapidly. Cooper discussed next-generation CAR-T therapies targeting antigens like CD123, CLEC2A, and LAMP5, which are associated with poor prognosis or rare fusion-driven subtypes such as CBFA2T3-GLIS2 and KMT2A-MLLT3.

Platforms developed at Seattle Children’s and Fred Hutchinson Cancer Center are expected to enter the clinic as early as 2025, with targets such as FOLR1, MSLN, and CLEC2A.

One of the most ambitious undertakings described was the Leukemia & Lymphoma Society's PedAL Initiative—an international collaborative platform for molecular profiling and trial matching.

“This is an incredibly important and ambitious initiative, and we’ve made huge progress in surmounting many of these [barriers] with the help of LLS and Dare to Dream,” Cooper said. The platform seeks to enroll relapsed or refractory patients into early-phase trials based on their unique genomic profiles, overcoming the regulatory and logistical hurdles that have historically stymied pediatric drug development.

Cooper concluded with a firm message.

“We can’t solve this by pushing more chemo,” he said. “We need smarter, more targeted tools—and we need to work together to build the systems to deliver them.”