CML-558 Genetic Alterations in Chronic Myeloid Leukemia Patients With Tyrosine Kinase Inhibitors Resistance From Guatemala Through Next-Generation Sequencing

• Published in: Clinical lymphoma, myeloma and leukemia myeloma and leukemia, 2024-09, Vol.24, p.S375-S375
• Main Authors: Oliva, Anai, Alvarado, Vera, Fuentes-Merlos, Isabel, Castellanos, Marian, Chopox, Liseth, Arrivillaga-Cano, Eduardo, Villegas, Mauricio
• Format: Article
• Language: English
• Subjects: ABL1; ASXL1; CML; NGS; TKIresistance
• ISSN: 2152-2650
• DOI: 10.1016/S2152-2650(24)01320-X

BCR::ABL1-positive patients with chronic myeloid leukemia (CML) are treated with tyrosine kinase inhibitors (TKIs) to reduce the transcript copy-number, achieving a major molecular response (MMR). However, genetic alterations in ABL1 and other genes may be associated with resistance, making it important to characterize genetic abnormalities in these patients. The study aims to determine the existence of additional genetic alterations in BCR::ABL1-positive CML patients with TKI resistance in Guatemala. From 2021 to 2023, we selected 45 CML, BCR::ABL1-positive patients from various national hospitals. All patients showed failure in molecular response according to the 2020 European LeukemiaNet recommendations. Using next-generation sequencing (NGS), we analyzed 30 myeloid malignancy-related genes. Variant classification was based on Association for Molecular Pathology, American Society of Clinical Oncology, College of American Pathologists, and ClinVar. Out of 45 patients, the median age at diagnosis was 34 years. Of these, 22 (49%) were male and 23 (51%) were female. The types of BCR::ABL1 transcripts were e14a2 (37.8%), e13a2 (33.3%), e14a2/e13a2 (4.5%), and unspecified (24.4%). Of these patients, 40% reached MMR at some point of the therapy, but 60% never achieved this response. At the time of NGS testing, RNA levels ranged from 1.68% IS to BCR::ABL1>ABL1. We detected 42 variants in 23 (51.1%) patients. Eighteen (40%) had pathogenic variants in one or multiple genes, whereas only 5 had variants of uncertain significance. Out of these, we identified 31 pathogenic variants in 4 genes. The most frequent variants were found in ABL1 (15/31), ASXL1 (13/31), RUNX1 (2/31), and DNMT3A (1/31). All ABL1 variants were missense variations occurring in the kinase domain, whereas ASXL1 were frameshift variants located within exon 13. RUNX1 exhibited splice donor and missense alterations both in exon 4. The only DNMT3A alteration was nonsense in exon 15. Despite the limited number of patients, our results showed that 51.1% of our patients presented a variant in ABL1 or other myeloid-related genes, highlighting the importance of performing an extended analysis in CML patients with TKI resistance.