In a study reported in the Journal of Clinical Oncology, Chang et al identified potential genomic determinants of relapse risk in pediatric acute lymphoblastic leukemia (ALL).
As stated by the investigators, “Although cure rates for childhood ALL exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk disease.”
Study Details
The study involved genome and transcriptome sequencing of diagnostic and remission samples of children with standard-risk disease (n = 1,381) or high-risk B-cell ALL with favorable cytogenetic features (n = 115) enrolled in Children’s Oncology Group (COG) trials. A case-control analysis included 439 patients who relapsed and 1,057 who remained in complete remission for ≥ 5 years. Associations were assessed in a validation cohort from two St. Jude Children’s Research Hospital studies.
Key Findings
Genomic subtype was associated with relapse. For example, relapse occurred in approximately 50% of cases of PAX5-altered ALL in the COG cohort (odds ratio [OR] = 3.31, 95% confidence interval [CI] = 2.17–5.03, P = 3.18 x 10-8).
Among patients with high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with a reduced risk of relapse in the COG cohort (OR = 0.27, 95% CI = 0.17–0.42, P = 8.02 x 10-10) and in the St. Jude validation cohort (OR = 0.22, 95% CI = 0.05–0.80, P = .009). Disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with an increased risk of relapse in the COG cohort (OR = 7.16, 95% CI = 2.63–21.51, P = 2.19 x 10-5) and in the St. Jude validation cohort (OR = 21.32, 95% CI = 3.62–119.30, P = .0004).
Genomic alterations were associated with an increased risk of relapse in a subtype-dependent manner in the COG cohort, including alterations of: INO80 in ETV6::RUNX1 ALL (OR = 2.23, 95% CI = 1.20–4.04, P = .01); IKZF1 (OR = 1.80, 95% CI = 1.34–2.40, P = .00008), with significant effects within multiple subtypes including hyperdiploid ALL (OR = 3.23, 95% CI = 2.00–5.20, P = 2.14 x 10-6); and CREBBP in high-hyperdiploid ALL (OR = 2.22, 95% CI = 1.45–3.40, P = .0003).
Genomic alterations were also associated with the increased risk of elevated minimal residual disease, including NRAS alterations (OR = 2.32, 95% CI = 1.54–3.51, P = 4.9 x 10-5) and CREBBP alterations in high-hyperdiploid ALL without double trisomy (OR = 3.11, 95% CI = 1.53–6.49, P = .0002).
The investigators concluded: “Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.”
Mignon L. Loh, MD, of the Department of Pediatrics and the Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, University of Washington, Seattle, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.
