Relationship of CRLF2 expression and outcome in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL): A report from the Children’s Oncology Group.

Abstract

9505 Background: We previously reported a highly significant association between over-expression of CRLF2 (cytokine receptor-like factor 2) and poor clinical outcomes in 207 uniformly-treated children with high-risk B-ALL (Blood 115:5312, 2010). To validate and extend these studies to standard risk cases we studied 896 B-ALL patients from COG P9905. Eligible patients included 344 with NCI high-risk (HR) features and 552 with standard-risk (SR) features. Methods: Quantitative RT-PCR assays were used to determine CRLF2 expression in the diagnostic leukemic cells. Averages of duplicate assays were used to establish ΔCt values relative to a control gene (EEF2). Using the ΔCt threshold determined from our prior studies, 117/896 B-ALL samples had elevated CRLF2 expression. These 117 samples and other 35 samples below the threshold were tested for genomic rearrangements of CRLF2 to detect the P2RY8-CRLF2 fusion or CRLF2 F232C mutations. Studies to detect the IGH@-CRLF2 translocation, IKZF1 (IKAROS) deletions, and JAK mutations are ongoing. Outcomes were evaluated using relapse-free survival (RFS) and other known risk factors. Results: CRLF2 overexpression was associated with a poorer outcome in HR, but not in SR, B-ALL. Among the 246 HR cases lacking detectable end-induction minimal residual disease, CRLF2 expression levels could further distinguish those B-ALL patients who had a very good (>80%) vs. poor (<40%) RFS (Hazard Ratio = 2.59; P=0.002). While P2RY8/CRLF2 fusions were seen only in high CRLF2-expressors, 6/17 CRLF2 F232C mutations were among low CRLF2 expressors. Down syndrome ALL cases had a relatively good outcome regardless of CRLF2 expression levels or NIH risk status. Conclusions: Elevated CRLF2 expression predicts a significantly poorer outcome in HR, but not SR, B-ALL and can be used with other prognostic factors to improve ALL risk classification. Standard-risk RFS High-risk RFS N Hazard ratio P N Hazard ratio P All cases (n=896) 552 – – 344 – – High CRLF2 81 1.20 .510 36 1.84 .019 Down syndrome (DS) 35 1.25 .571 5 0.94 .952 Genomic abnormalities 99 53 P2RY8 fusion 37 1.00 .988 14 1.64 .034 F232C mutation 15 – – 2 – –