Targetable kinase gene fusions in high-risk B-ALL: a study from the Children’s Oncology Group

Abstract

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed patients with childhood B-lineage ALL with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of whom were excluded from additional analyses because of the presence of <i>BCR</i>-<i>ABL1</i> (n = 46) or <i>ETV6</i>-<i>RUNX1</i> (n = 11). Among the remaining 284 patients (20.4%), overexpression and rearrangement of <i>CRLF2</i> (<i>IGH</i>-<i>CRLF2</i> or <i>P2RY8</i>-<i>CRLF2</i>) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway (<i>JAK1</i>, <i>JAK2</i>, <i>IL7R</i>) identified in 63 patients (50.8% of those with <i>CRLF2</i> rearrangement). Among the remaining patients, using reverse transcriptase polymerase chain reaction or transcriptome sequencing, we identified targetable ABL-class fusions (<i>ABL1</i>, <i>ABL2</i>, <i>CSF1R</i>, and <i>PDGFRB</i>) in 14.1%, <i>EPOR</i> rearrangements or <i>JAK2</i> fusions in 8.8%, alterations activating other JAK-STAT signaling genes (<i>IL7R</i>, <i>SH2B3</i>, <i>JAK1</i>) in 6.3% or other kinases (<i>FLT3</i>, <i>NTRK3</i>, <i>LYN</i>) in 4.6%, and mutations involving the Ras pathway (<i>KRAS</i>, <i>NRAS</i>, <i>NF1</i>, <i>PTPN11</i>) in 6% of those with Ph-like ALL. We identified 8 new rearrangement partners for 4 kinase genes previously reported to be rearranged in Ph-like ALL. The current findings provide support for the precision-medicine testing and treatment approach for Ph-like ALL implemented in Children's Oncology Group ALL trials.