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 - (n = 46) or - (n = 11). Among the remaining 284 patients (20.4%), overexpression and rearrangement of (- or -) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway (, ,) identified in 63 patients (50.8% of those with rearrangement). Among the remaining patients, using reverse transcriptase polymerase chain reaction or transcriptome sequencing, we identified targetable ABL-class fusions (, ,, and ) in 14.1%, rearrangements or fusions in 8.8%, alterations activating other JAK-STAT signaling genes (, ,) in 6.3% or other kinases (, ,) in 4.6%, and mutations involving the Ras pathway (, ,, ) 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.

High prevalence of relapse in children with Philadelphia-like acute lymphoblastic leukemia despite risk-adapted treatment

“…3 In contrast, US studies have used a TaqMan Low Density Arrays (TLDA) based approach consisting of either eight or fifteen genes selected by Prediction Analysis for Microarrays (PAM) analysis. 7,8 While there is overlap, the HC model identifies a greater proportion of patients as having a BCR-ABL1-like signature, but this approach does not directly identify causative fusions.…”

Cytogenetics, Molecular Genetics and Epigenetics and Their Impact on The Management of Acute Lymphoblastic Leukemia

“…Nevertheless, novel therapies are needed to improve the outcome of patients with Ph-like ALL as this this subtype of ALL represents a disease where precision medicine testing, and treatment approach should be implemented [90,94,99]. Newly discovered genetic alterations that drive HR Ph-like ALL can now be targeted with TKIs and JAK inhibitors leading to clinical trials for this particular HR subset [100].…”

“…It has characteristic and distinct genetic mutations and rearrangements that are activated by a diverse array of cytokine receptor and tyrosine kinase signaling [87,89,[92][93][94]96]. The genetic lesions in adults with Ph-like ALL resembles that in children with Ph-like ALL but differs from the profile in the remaining patients with pre-B ALL [99].…”

“…When compared to other pre-B ALL subtypes, Ph-like ALL has the following characteristic features: (1) higher median leukocyte count at presentation, (2) higher median levels of MRD at the end of induction therapy, (3) inferior estimated event-free survival (EFS) at 5 years [58% versus (vs.) 84% in children, 41% vs. 83% in adolescents and 24% vs 63% in young adults], and (4) inferior estimated OS at 5 years [73% vs. 92% in children, 66% vs. 93% in adolescents and 26% vs 75% in young adults [88]. The various genetic abnormalities that are encountered in patients with Ph-like ALL and their targeted therapies are shown in Table 8 [19,[93][94][95][96][97] The investigational targeted therapies in Ph-like ALL are shown in Table 9 [89,98].…”

“…Unfortunately, Ph-like ALL is essentially heterogeneous and a HR subtype of ALL [19,[92][93][94][95]98]. It has characteristic and distinct genetic mutations and rearrangements that are activated by a diverse array of cytokine receptor and tyrosine kinase signaling [87,89,[92][93][94]96].…”