Abstract
BackgroundABL-class and JAK-STAT signaling pathway activating alterations have been associated with both a poor post-induction minimal residual disease (MRD) response and an inferior outcome in B-cell acute lymphoblastic leukemia (B-ALL). However, in most of the studies patients received non-uniform treatment.MethodsWe performed a 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-directed NOPHO ALL-2008 protocol. Targeted RNA sequencing and FISH analysis were performed in cases without canonical B-ALL genomic alterations (high hyperdiploids and low hypodiploids included).ResultsWe identified ABL-class fusions in 3/160 (1.9%) B-ALL patients, and exclusively in adults (p = 0.003). JAK-STAT pathway fusions were present in 4/160 (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 a poor MRD response and were assigned to the higher risk groups, and had an inferior event-free survival (EFS) / overall survival (OS) compared to patients without these fusions. In a multivariate analysis, positivity for ABL-class and JAK-STAT fusions was a risk factor for worse EFS (p = 0.046) but not for OS (p = 0.278) in adults.ConclusionsWe report a 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. Future (larger) studies are warranted to confirm an inferior event-free survival of ABL-class/JAK-STAT fusion-positive adult patients in MRD-directed protocols.
Highlights
ABL-class and JAK-STAT signaling pathway activating alterations have been associated with both a poor post-induction minimal residual disease (MRD) response and an inferior outcome in B-cell acute lymphoblastic leukemia (B-Acute lymphoblastic leukemia (ALL))
Study population Overall, one hundred and sixty 1–65 year-old patients representing over 95% of the BCR-ABL1 negative B-cell acute lymphoblastic leukemia (B-ALL) patient population in Lithuania during the July 2008 – December 2017 period were included into this study (Table 1)
Our findings demonstrate the additional advantage of RNA sequencing (RNA-Seq) diagnostic method in B-ALL patients who are negative for canonical B-ALL fusions by fluorescence in situ hybridization (FISH) analysis
Summary
ABL-class and JAK-STAT signaling pathway activating alterations have been associated with both a poor post-induction minimal residual disease (MRD) response and an inferior outcome in B-cell acute lymphoblastic leukemia (B-ALL). Gene expression profiling (GEP) of patients negative for canonical B-ALL alterations identified a subgroup of cases characterized by a similar expression profile to those harboring t(9;22) (q34;q11)/BCR-ABL1 (Philadelphia chromosome-like (Ph-like) or BCR-ABL1like B-ALL) [4, 5]. Whole transcriptome/exome sequencing and fluorescence in situ hybridization (FISH) analysis of Ph-like BALL samples revealed high frequency of genomic alterations disrupting the normal function of kinase and cytokine receptor signaling pathways of which ABL-class kinase and JAK-STAT signaling pathway genes were the most commonly affected [6]. ABL-class gene and JAKSTAT pathway alterations are associated with high postinduction MRD levels, an increased relapse rate and inferior outcome. High expression levels of the CRLF2 gene and IKZF1 gene deletions are common in the Ph-like B-ALL subgroup resulting in a worse outcome in some series [5, 17]
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