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Blood. 2018 Aug 23;132(8):815-824. doi: 10.1182/blood-2018-04-841676. Epub 2018 Jul 11.

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

Author information

1
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN.
2
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH.
3
Department of Pathology, The Ohio State University, Columbus, OH.
4
Department of Pathology, University of New Mexico Cancer Center, Albuquerque, NM.
5
Department of Biostatistics, University of Florida, Gainesville, FL.
6
Department of Cytogenetics and.
7
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN.
8
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.
9
Department of Pediatrics, NYU Langone Health, New York, NY.
10
Department of Pathology, Johns Hopkins University, Baltimore, MD.
11
Department of Pathology, Seattle Children's Hospital, Seattle, WA.
12
HARP Pharma Consulting, Mystic, CT.
13
Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital, Aurora CO.
14
Department of Pediatrics and Perlmutter Cancer Center, NYU Langone Health, New York, NY.
15
Department of Pediatrics, UCSF Benioff Children's Hospital and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA; and.
16
Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Abstract

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; BCR-ABL1-like ALL) in children with National Cancer Institute (NCI) intermediate- or high-risk (HR) ALL 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. The prevalence, outcome, and potential for targeted therapy of Ph-like ALL in standard-risk (SR) ALL is less clear. We retrospectively analyzed a cohort of 1023 SR childhood B-ALL consecutively enrolled in the Children's Oncology Group AALL0331 clinical trial. The Ph-like ALL gene expression profile was identified in 206 patients, and 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 reverse transcription polymerase chain reaction 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 with 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.

PMID:
29997224
PMCID:
PMC6107876
[Available on 2019-08-23]
DOI:
10.1182/blood-2018-04-841676

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