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Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: a report from the Children's Oncology Group

Kathryn G. Roberts, Shalini C. Reshmi, Richard C. Harvey, I-Ming Chen, Kinnari Patel, Eileen Stonerock, Heather Jenkins, Yunfeng Dai, Marc Valentine, Zhaohui Gu, Yaqi Zhao, Jinghui Zhang, Debbie Payne-Turner, Meenakshi Devidas, Nyla A. Heerema, Andrew J. Carroll, Elizabeth A. Raetz, Michael J. Borowitz, Brent L. Wood, Leonard A. Mattano Jr., Kelly W. Maloney, William L. Carroll, Mignon L. Loh, Cheryl L. Willman, Julie M. Gastier-Foster, Charles G. Mullighan and Stephen P. Hunger

Key points

  • The prevalence of Ph-like ALL is lower in children with NCI standard-risk ALL compared to high-risk ALL.

  • Ph-like ALL in standard-risk patients harbor few targetable kinase fusions and have improved outcome compared to high-risk Ph-like ALL.

Abstract

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; BCR-ABL1-like ALL) in children with NCI high-risk (HR) ALL as defined by age and initial white blood cell count, or intermediate risk as defined by minimal residual disease response, is associated with poor outcome. Ph-like ALL is characterized by genetic alterations that activate cytokine receptor and kinase signaling and may be amenable to treatment with tyrosine kinase inhibitors (TKIs). The prevalence, outcome and potential for targeted therapy of Ph-like ALL in NCI standard-risk (SR) ALL is less clear. We retrospectively analyzed a cohort of 1023 SR childhood B-ALL consecutively enrolled on the Children's Oncology Group AALL0331 clinical trial. The Ph-like ALL gene expression profile was identified in 206 patients, 67 patients with either BCR-ABL1 (n=6) or ETV6-RUNX1 (n=61) were excluded from downstream analysis, leaving 139 of 1023 (13.6%) as Ph-like. Targeted RT-PCR assays and RNA-sequencing identified kinase-activating alterations in 38.8% of SR Ph-like cases, including CRLF2 rearrangements (29.5% of Ph-like), ABL-class fusions (1.4%), JAK2 fusions (1.4%), an NTRK3 fusion (0.7%) and other sequence mutations (IL7R, KRAS, NRAS; 5.6%). Patients with Ph-like ALL had inferior 7-year event-free survival compared to non Ph-like ALL (82.4±3.6% vs. 90.7±1.0%, P = .0022), with no difference in overall survival (93.2±2.4% vs. 95.8±0.7%, P = .14). These findings illustrate the significant differences in the spectrum of kinase alterations and clinical outcome of Ph-like ALL based on presenting clinical features, and establish that genomic alterations potentially targetable with approved kinase inhibitors are less frequent in SR than in HR ALL.

  • Submitted April 3, 2018.
  • Accepted June 20, 2018.