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Genetic Profile, Treatment Response, and Outcomes of BCR::ABL1-Positive Mixed-Phenotype Acute Leukemia: A Study From the BCR::ABL1 Pathology Group.

Qiudan Shen·Xiaoyan Huang·Xiaoqiong Wang·Wen Shuai·Hong Fang·Ellias Jabbour·Weina Chen·Mehrnoosh Tashakori·Mahsa Khanlari·Xiaojun Wu·Lina Shao·Ling Zhang·Siba El Hussein·Sergej Konoplev·Joseph D Khoury·Guilin Tang·Wei Wang·Sa A Wang·L Jeffrey Medeiros·Shimin Hu
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Abstract

Mixed-phenotype acute leukemia (MPAL) with BCR::ABL1 fusion is rare, and its clinicopathological features, genetic landscape, therapeutic response, and patient outcomes remain incompletely defined, as does its relationship to blast-phase chronic myeloid leukemia. In this multicenter study of 44 patients, 86.4% had B/myeloid MPAL, 72.7% showed lymphoid predominance, 40.9% had complex karyotypes, and 68.3% harbored somatic mutations, most commonly RUNX1 mutations (46.3%). RUNX1 mutations frequently co-occurred with acute myeloid leukemia (AML)-associated alterations, whereas DNMT3A, TET2, and BCORL1 mutations were restricted to RUNX1-mutated cases. In contrast, acute lymphoblastic leukemia (ALL)-associated alterations (IKZF1 mutation/deletion and ETV6 mutations) were confined to RUNX1-wild-type patients. TP53 and signaling pathway mutations (NRAS, KRAS, PTPN11, and FLT3) were not detected. Forty-two patients received induction chemotherapy and/or immunotherapy combined with tyrosine kinase inhibitors: 74.2% of lymphoid-predominant patients and 63.6% of myeloid-predominant patients received ALL- and AML-type therapies, respectively. Ten patients relapsed, and 2 had primary refractory disease; some exhibited a dynamic shift in predominant lineage immunophenotype, chromosomal alterations, and somatic mutations at the relapse or refractory stage. The overall remission rate was 86.8%, with no significant differences across ALL-, AML-, or hybrid-type regimens. After a median follow-up of 24.2 months, the median overall survival was 52.5 months. Complex karyotype was associated with inferior overall survival compared with cases lacking additional chromosomal alterations (P = .02), whereas RUNX1 mutations were not. No significant differences in genetic profiles, treatment response, or outcomes were observed between patients with and without chronic myeloid leukemia-like features. This study provides a comprehensive genomic and clinical characterization of BCR::ABL1-positive MPAL, supporting improved risk stratification and future therapeutic strategies.

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AdolescentAdultAgedAged, 80 and overChildFemaleHumansMaleMiddle AgedYoung AdultCore Binding Factor Alpha 2 SubunitFusion Proteins, bcr-ablGenetic ProfileLeukemia, Biphenotypic, AcuteMutationPhenotypeTreatment OutcomeBCR::ABL1RUNX1blast phasechronic myeloid leukemiamixed-phenotype acute leukemiaJournal ArticleMulticenter Study

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Qiudan Shen, Xiaoyan Huang, Xiaoqiong Wang, Wen Shuai, Hong Fang, Ellias Jabbour, Weina Chen, Mehrnoosh Tashakori, Mahsa Khanlari, Xiaojun Wu, Lina Shao, Ling Zhang, Siba El Hussein, Sergej Konoplev, Joseph D Khoury, Guilin Tang, Wei Wang, Sa A Wang, L Jeffrey Medeiros, Shimin Hu. 2026-05-21. Genetic Profile, Treatment Response, and Outcomes of BCR::ABL1-Positive Mixed-Phenotype Acute Leukemia: A Study From the BCR::ABL1 Pathology Group.. https://doi.org/10.1016/j.modpat.2026.101016

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