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

Abstract

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; --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 - (n = 6) or - (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 rearrangements (29.5% of Ph-like),-class fusions (1.4%), fusions (1.4%), an fusion (0.7%), and other sequence mutations (, ,; 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%, = .0022), with no difference in overall survival (93.2 ± 2.4% vs 95.8 ± 0.7%, = .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.

BCR‐ABL1‐like B‐lymphoblastic leukemia/lymphoma: Review of the entity and detection methodologies

“…The incidence increases across the age spectrum, occurring in approximately 10%‐20% of childhood cases of B‐ALL and reaching 20%‐30% in adults, potentially higher in Hispanic and Native American populations. Among children, BCR‐ABL1 ‐like ALL is seen primarily among NCI high‐risk patients, although NCI standard risk patients with BCR‐ABL1 ‐like ALL have inferior event‐free survival compared to their non‐ BCR‐ABL1 ‐like counterparts . Adults with BCR‐ABL1 ‐like ALL have significantly worse overall and event‐free survival, with a 5‐year survival of approximately 23% …”

“…At our institution, we utilize the LDA gene expression assay as a screening test in the first step of a diagnostic algorithm. Depending on the results of the LDA screening assay, reflex testing may be performed, including FISH to identify rearrangements in high‐incidence genes, a RNA gene fusion panel, and a multiplex next‐generation sequencing panel that evaluates a large number of genes known to be associated with BCR‐ABL1 ‐like ALL . By using the LDA assay as an initial screening step, we comprehensively identify and characterize cases of BCR‐ABL1 ‐like ALL, yet avoid performing more costly studies in the large majority of patients who are negative by the LDA assay.…”

“…Genetic abnormalities associated with BCR-ABL1-like ALL converge on activation of kinase signaling pathways: Those involved in the JAK/ STAT pathway, ABL-class genes, and others that lead to increased kinase signaling such as IKZF1, FGFR1, and RAS ( Figure 1). 6,[8][9][10] These abnormalities are not mutually exclusive and more than one alteration can be identified in a single case. Some of the more common rearrangements and mutations are described here.…”

“…6,14 The remaining BCR-ABL1-like ALL cases that lack these common gene fusions instead harbor a wide variety of rare gene fu- uates a large number of genes known to be associated with BCR-ABL1-like ALL. 9,10,19 By using the LDA assay as an initial screening step, we comprehensively identify and characterize cases of BCR-ABL1-like ALL, yet avoid performing more costly studies in the large majority of patients who are negative by the LDA assay.…”

“…There are some instances in which there is duplication of the CRLF2 locus-usually secondary to duplication of the X or Y chromosome-without rearrangement. Whether or not these cases should also be included in BCR-ABL1-like ALL is controversial 6,8,10,[12][13][14].…”