Advancements in genomics are transforming the clinical management of chronic myeloid leukemia (CML) toward precision medicine. The impact of somatic mutations on treatment outcomes is still under debate. We studied the association of somatic mutations in epigenetic modifier genes and activated signaling/myeloid transcription factors (AS/MTFs) with disease progression and treatment failure in patients with CML after tyrosine kinase inhibitor (TKI) therapy. A total of 394 CML samples were sequenced, including 254 samples collected at initial diagnosis and 140 samples taken during follow-up. Single-molecule molecular inversion probe (smMIP)-based next-generation sequencing (NGS) was conducted targeting recurrently mutated loci in 40 genes, with a limit of detection of 0.2%. Seventy mutations were detected in 57 diagnostic samples (22.4%), whereas 64 mutations were detected in 39 of the follow-up samples (27.9%). Carrying any mutation at initial diagnosis was associated with worse outcomes after TKI therapy, particularly in AS/MTF genes. Patients having these mutations at initial diagnosis and treated with imatinib showed higher risks of treatment failure (hazard ratio, 2.53; 95% confidence interval, 1.13-5.66; P = .0239). The adverse prognostic impact of the mutations was not clear for patients treated with second-generation TKIs. The multivariate analysis affirmed that mutations in AS/MTF genes independently serve as adverse prognostic factors for molecular response, failure-free survival, and progression risk. Additionally, there was an observable nonsignificant trend indicating a heightened risk of progression to advanced disease and worse overall survival. In conclusion, mutations in the AS/MTF genes using smMIP-based NGS can help identify patients with a potential risk of both treatment failure and progression and may help upfront TKI selection.

Department of Computer Science University of Toronto Toronto ON Canada

Department of Internal Medicine Center for Hematologic Malignancies National Cancer Center Goyang Republic of Korea

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Masaryk University Brno Czech Republic

Department of Internal Medicine Inje University Ilsan Paik Hospital Goyang Republic of Korea

Department of Molecular Genetics University of Toronto Toronto ON Canada

Division of Hematology and Oncology Department of Internal Medicine Soon Chun Hyang University Seoul Hospital Seoul Republic of Korea

Division of Medical Oncology and Hematology Princess Margaret Cancer Centre Toronto ON Canada

Faculty of Medicine University of Toronto Toronto ON Canada

Fundaleu Buenos Aires Argentina

Genome Diagnostics and Cancer Cytogenetics Laboratories Department of Laboratory Medicine and Pathobiology Faculty of Medicine University of Toronto Toronto Canada

Hematology and Hemotherapy Center University of Campinas Campinas Brazil

Malignant Hematology Tissue Bank Princess Margaret Cancer Centre Toronto ON Canada

National Health Insurance Service Ilsan Hospital Ilsan Republic of Korea

Ontario Institute for Cancer Research Toronto ON Canada

The Donnelly Centre for Cellular and Biomolecular Research Donnelly Centre for Cellular and Biomolecular Research Toronto ON Canada

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