Low Incidence of ABL-Class And JAK-STAT Signaling Pathway Alterations In Uniformly Treated Pediatric And Adult B-Cell Acute Lymphoblastic Leukemia Patients Using MRD Risk-Directed Approach – A Population-Based Study

Abstract Background: ABL-class and JAK-STAT signaling pathway activating alterations have been associated with both poor post-induction minimal residual disease (MRD) response and inferior outcome in B-cell acute lymphoblastic leukemia (B-ALL). However, in most of the studies patients received non-uniform treatment. Methods: We performed population-based analysis of 160 (122 pediatric and 38 adult) Lithuanian BCR-ABL1-negative B-ALL patients who had been uniformly treated according to MRD-adapted NOPHO ALL-2008 protocol. Targeted RNA sequencing and FISH analysis was performed in cases without canonical B-ALL genomic alterations (high hyperdiploids and low hypodiploids included). Results: We identified ABL-class fusions in 3 (1.9%) B-ALL patients (exclusively in adults (p=0.032)). JAK-STAT pathway fusions were present in 4 (2.5%) cases. Of note, P2RY8-CRLF2 fusion was absent in both pediatric and adult B-ALL cases. Patients with ABL-class or JAK-STAT pathway fusions had poor MRD response and were assigned to the higher risk groups, had worse event-free survival (EFS) and overall survival (OS) compared to patients without these fusions. In multivariate analysis, positivity for ABL-class and JAK-STAT fusions was a risk factor for worse EFS (p=0.043) but not for OS (p=0.278) in adults. Conclusions: We show low overall frequency of ABL-class and JAK-STAT fusions and the absence of P2RY8-CRLF2 gene fusion in the Lithuanian BCR-ABL1 negative B-ALL cohort. Poor event-free survival in ABL-class / JAK-STAT fusion-positive adult patients despite MRD-directed therapy should be confirmed in future studies.