Targeted Next-Generation Sequencing Identifies Additional Mutations Other than BCR∷ABL in Chronic Myeloid Leukemia Patients: A Chinese Monocentric Retrospective Study

SIMPLE SUMMARY: TKI have vastly improved long-term outcomes for patients with CML, although it is still hard for a proportion of patients to obtain ideal molecular responses. Advances in NGS technology have enabled the incorporation of somatic mutation profiles in classification and prognostication. With an increased focus on achieving deep molecular responses, we try to explore the risk conferred by additional genomic lesions other than BCR∷ABL through NGS technology. We also figure out how clinical characteristics, distinct TKI options and risk scores influence the achieving of molecular responses. This research has the potential to lay the foundation for improved risk classification according to clinical and genomic risk and to enable more precise early identification of TKI. ABSTRACT: A proportion of patients with somatic variants show resistance or intolerance to TKI therapy, indicating additional mutations other than BCR∷ABL1 may lead to TKI treatment failure or disease progression. We retrospectively evaluated 151 CML patients receiving TKI therapy and performed next-generation sequencing (NGS) analysis of 22 CML patients at diagnosis to explore the mutation spectrum other than BCR∷ABL1 affecting the achievement of molecular responses. The most frequently mutated gene was ASXL1 (40.9%). NOTCH3 and RELN mutations were only carried by subjects failing to achieve a major molecular response (MMR) at 12 months. The distribution frequency of ASXL1 mutations was higher in the group that did not achieve MR(4.0) at 36 months (p = 0.023). The achievement of MR(4.5) at 12 months was adversely impacted by the presence of >2 gene mutations (p = 0.024). In the analysis of clinical characteristics, hemoglobin concentration (HB) and MMR were independent factors for deep molecular response (DMR), and initial 2GTKI therapy was better than 1GTKI in the achievement of molecular response. For the scoring system, we found the ELTS score was the best for predicting the efficacy of TKI therapy and the Socal score was the best for predicting mutations other than BCR∷ABL.