Genomic landscape of B-other acute lymphoblastic leukemia in an adult retrospective cohort with a focus on <i>BCR-ABL1</i>-like subtype

<i>BCR-ABL1</i>-like acute lymphoblastic leukemia (ALL) is a high-risk disease with a complex genomic background. Though extensively studied, data on the frequency and mutual associations of present mutations are still incomplete in adult patients. This retrospective study aims to map the genomic landscape of B-other ALL in a cohort of adult patients with a focus on the <i>BCR-ABL1</i>-like ALL subtype. We analyzed bone marrow and peripheral blood samples of adult B-other ALL patients treated consecutively at three major Czech teaching hospitals. Samples were analyzed by cytogenetic methods, gene expression profiling, multiplex ligation-dependent probe amplification (MLPA), and next-generation sequencing (NGS). Fifty-eight B-other ALL patients (not <i>BCR-ABL1</i>, <i>KMT2A</i>-rearranged, <i>ETV6-RUNX1</i>, <i>TCF3-PBX1</i>, or iAMP21) were included in the study. Median follow-up was 23.8 months. Samples from 33 patients were available for a gene expression analysis, 48.9% identified as <i>BCR-ABL1</i>-like ALL. Of the <i>BCR-ABL1</i>-like ALL cases, 18.8% harbored <i>IGH-CRLF2</i> and 12.5% <i>P2RY8-CRLF2</i> fusion gene. We observed a higher MRD failure rate in <i>BCR-ABL1</i>-like than in non-<i>BCR-ABL1</i>-like ALL patients after the induction treatment (50.0 vs. 13.3%, <i>p</i>=.05). There was a trend to worse progression-free and overall survival in the <i>BCR-ABL1</i>-like group, though not statistically significant. Deletions in <i>IKZF1</i> gene were found in 31.3% of <i>BCR-ABL1</i>-like cases. Patients with concurrent <i>IKZF1</i> and <i>CDKN2A/B, PAX5</i> or PAR1 region deletions (<i>IKZF1</i>^plus profile) had significantly worse progression-free survival than those with sole <i>IKZF1</i> deletion or <i>IKZF1</i> wild-type (<i>p</i>=.02). NGS analysis was performed in 54 patients and identified 99 short variants in <i>TP53, JAK2, NRAS, PAX5, CREBBP, NF1, FLT3, ATM, KRAS, RUNX1</i>, and other genes. Seventy-five of these gene variants have not yet been described in B-cell precursor ALL to date. This study widens existing knowledge of the <i>BCR-ABL1</i>-like and B-other ALL genomic landscape in the adult population, supports previous findings, and identifies a number of novel gene variants.