Outcome Modeling With Crlf2, Ikzf1, Jak And Minimal Residual Disease Study In Pediatric Acute Lymphoblastic Leukemia: A Children'S Oncology Group

As controversy exists regarding the prognostic significance of genomic rearrangements ofCRLF2 in pediatric B-precursor ALL classified as standard/intermediate-risk (SR) or high-risk(HR), we assessed the prognostic significance of CRLF2 mRNA expression, CRLF2 genomiclesions (IGH@-CRLF2, P2RY8-CRLF2, CRLF2 F232C), deletion/mutation in genes frequentlyassociated with high CRLF2 expression (IKZF1, JAK, IL7R) and minimal residual disease(MRD) in 1,061 pediatric ALL patients (499 HR and 562 SR) on COG Trials P9905/P9906.While very high CRLF2 expression was found in 17.5% of cases (19% of HR, 16.2% of SR),only 51.4% of high CRLF2-expressors had CRLF2 genomic lesions. The mechanism underlyingelevated CRLF2 expression in cases lacking known genomic lesions remains to be determined.All CRLF2 genomic lesions and virtually all JAK mutations were found in high CRLF2-expressors, while IKZF1 deletions/mutations were distributed across the full cohort. Inmultivariate analyses, NCI risk group, MRD, high CRLF2 expression (each P<.001), and IKZF1lesions (P=.037) were associated with relapse-free survival (RFS). Within HR ALL, only MRD(P<.001) and CRLF2 expression (P<.001) predicted a poorer RFS; no difference was seenbetween cases with or without CRLF2 genomic lesions. Thus, high CRLF2 expression isassociated with a very poor outcome in high, but not standard-risk ALL. This study is registeredat NCT00005596, www.ClinicalTrials.gov and NCT00005603, www.ClinicalTrials.gov.