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Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia

MP2PRT
MP2PRT

Journal of Clinical Oncology. Volume 42, Issue 29, p.3491-3503, 9 August 2024 10.1200/JCO.23.02238

Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease. To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n 5 1,381) or high-risk B-ALL with favorable cytogenetic features (n 5 115) enrolled on Children’s Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years. Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of PAX5-altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; P 5 3.18 3 10–8). Within high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with favorable outcome (OR, 0.27 [95% CI, 0.17 to 0.42]; P 5 8.02 3 10–10; St Jude Children’s Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; P 5 .009), and disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with relapse (OR, 7.16 [95% CI, 2.63 to 21.51]; P 5 2.19 3 10–5; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; P 5 .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6:: RUNX1 ALL, IKZF1, and CREBBP in high-hyperdiploid ALL and FHIT in BCR::ABL1-like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including NRAS and CREBBP in high-hyperdiploid ALL. 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.

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