Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia.

PURPOSE

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.

MATERIALS AND METHODS

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 = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 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.

RESULTS

Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of -altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; 3.18 × 10). 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]; = 8.02 × 10; St Jude Children's Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; = .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]; = 2.19 × 10; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; = .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of in ALL, , and in high-hyperdiploid ALL and in -like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including and in high-hyperdiploid ALL.

CONCLUSION

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.