Next-Generation Sequencing Assays and Target Therapy Changing Outcomes in Childhood ALL

Hiroto Inaba, MD, PhD, with St. Jude Children’s Research Hospital and the chair of NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Panel for Pediatric Acute Lymphoblastic Leukemia, said “next-generation sequencing has identified multiple mutations that are drivers of ALL. However, there is still a great deal that is unknown.” 

Currently, effective molecular targeted therapy is limited to a small fraction (approximately 5%) of cases of ALL with known genetic alterations, such as ALL with BCR::ABL1 or ABL-class abnormalities. “Treating these forms of ALL with tyrosine kinase inhibitors, such as imatinib, dasatinib, and ponatinib, has significantly improved outcomes,” said Dr Inaba.

Immunotherapy of B-ALL includes the bispecific T-cell engager (blinatumomab), an antibody-drug conjugate, and chimeric antigen receptor (CAR) T cells. These are being tested in patients with relapsed/refractory ALL or infant ALL. 

Dr Inabe explained using these therapies in combination with or as a replacement for conventional chemotherapy has reduced adverse effects and improved outcomes in these patients. “Further understanding the functions of mutations that drive ALL will lead to increased options for molecular targeted therapy, and incorporating immunotherapy into the frontline setting, will reduce chemotherapy-related morbidity and mortality,” he said.

The advance of new therapeutic approaches is very rapid, and there is an urgent need to evaluate these approaches in larger patient populations, according to Dr Inabe. “If molecular targeted therapy and immunotherapy are optimized, I foresee a marked reduction in the use of conventional chemotherapy, as has already occurred for adults with BCR::ABL1 ALL, who are currently treated with a combination of a tyrosine kinase inhibitor and immunotherapy only,” he said.

The authors of the review wrote that future efforts need to focus on making these effective, but very expensive, new technologies and therapies available to children with ALL worldwide. “This is a very difficult issue as most children with ALL live and die in low- or middle-income countries,” said Dr Pieters. 

To make these therapies available where they are most needed, it will require individual countries to set up programs specifically for childhood ALL as part of routine care. “I wholeheartedly agree with the authors regarding the vital need to make costly, yet highly effective, new technologies and therapies accessible to children worldwide who are grappling with ALL. To achieve this ambitious goal, my experience has led me to believe that a multifaceted approach within individual countries is essential,” Dr Pui said.

This approach should include the active involvement of one or more dedicated cancer centers or national study groups, the support of philanthropic individuals and charitable organizations, and government agencies, according to Dr Pui.

Reference

Pieter R, Mullighan CG, & Hunger SP. Advancing diagnostics and therapy to reach universal cure in childhood ALL. J Clin Oncol. Published online October 11, 2023. doi:10.1200/JCO.23.01286 

This article originally appeared on Hematology Advisor