In a study published by Magnum et al in JAMA Oncology, researchers reported on how two separate DNA changes appear to predict aggressive childhood leukemias when they occur in combination. The team evaluated tumor characteristics of more than 1,300 pediatric patients with B-cell acute lymphoblastic leukemia (ALL).
The research team utilized sophisticated genomic analysis techniques to evaluate both inherited and environmental genetic changes in children with B-cell ALL. They evaluated genomic information of patients across multiple states and countries. The study included cohorts of patients with leukemia who also had Down syndrome.
“We found a barely noticeable area of DNA, known as 22q11.22, to be missing in about 30% to 40% of pediatric patients with B-cell ALL,” said Joshua Schiffman, MD, co–senior author of the study, a pediatric cancer physician-scientist at Huntsman Cancer Institute, and Professor of Pediatrics at the University of Utah. “We began to wonder if something so small was missing so often, could this missing piece of DNA impact survival?”
That’s when the study team turned their attention to a much better-known gene in childhood leukemia called IKZF1.
“IKZF1 changes have puzzled doctors for some time,” explained study coauthor Luke Maese, DO, a pediatric oncologist at Huntsman Cancer Institute and Associate Professor of Pediatrics at the University of Utah who cares for children with leukemia at Intermountain Primary Children’s Hospital. “We have known for over a decade that IKZF1 changes predict a very poor outcome in some, but not all, patients.”
The study team began to investigate if this missing part of 22q11.22 could work together with IKZF1 changes to more reliably predict outcomes.
KEY POINTS
- Patients who already had an IKZF1 alteration had almost twice the risk of relapse if they also had a deletion in the 22q11.22 region.
- Patients with the double deletion also had worse outcomes compared with patients with IKZF1 alterations and wild-type 22q11.22 alleles in every cohort examined.
Effects of the “Double Deletion”
“Sure enough, we found that patients with both the 22q11.22 deletion and the IKZF1 changes—collectively known as a ‘double deletion’—had some of the worst outcomes in childhood leukemia,” said Dr. Schiffman. The team found that patients who already had an IKZF1 alteration had almost twice the risk of relapse if they also had a deletion in the 22q11.22 region.
Patients with the double deletion also had worse outcomes compared with patients with IKZF1 alterations and wild-type 22q11.22 alleles in every cohort examined (combined cohorts: 5-year event-free survival rates = 43.3% vs 68.5%, hazard ratio [HR] = 2.18; 95% confidence interval [CI] = 1.54–3.07, P < .001; 5-year overall survival rates = 66.9% vs 83.9%, HR = 2.05, 95% CI = 1.32–3.21, P = .001).
David Spencer Mangum, MD, co–lead author and Assistant Professor of Pediatric Hematology/Oncology at Nemours Children’s Health, commented: “Throughout all of my years in training, we never stopped trying to understand how this 22q11.22 deletion could impact children with leukemia. We gathered data from many different clinical trials to make sure this finding was real and reproducible. Our findings are significant because we found that the likelihood of relapse and death was consistent across multiple different cohorts of children with ALL, including children with Down syndrome.”
The research team hopes this finding can yield new insights into treatments for childhood leukemia. For example, the frequency of the 22q11.22 focal deletion indicates it may be important for leukemia development, and the combined association with worse outcomes means it could be a useful clinical prognostic marker in the future.
“[Children] with double-deleted leukemia may need more treatment—or bone marrow transplants right away—whereas [those] without double deletion may require less toxic chemotherapy to still achieve excellent outcomes. All of this needs to be further explored,” said Dr. Schiffman.
Disclosure: The study was funded by the National Institutes of Health/National Cancer Institute; the Pediatric Cancer Research Program funded by Intermountain Healthcare, Primary Children’s Hospital Foundation, and Department of Pediatrics at University of Utah; the Leukemia & Lymphoma Society Translational Research Program; the American Lebanese Syrian Associated Charities; and Huntsman Cancer Foundation. For full disclosures of the study authors, visit jamanetwork.com.
