Impact of ASXL1 at diagnosis in patients with CML receiving frontline potent TKIs: high risk of kinase domain mutations

Shanmuganathan, N; Saunders, V; Yeung, DT; Kenyon, RR; Wadham, C; Braley, J; Fernandes, A; Maqsood, M; Shahrin, N; Lin, M; Toubia, J; McConnell, J; Kaczorowski, D; Ross, DM; Yong, ASM; Chee, L; Shortt, J; Viiala, N; Kok, CH; Hughes, TP; Branford, S

Author(s): Shanmuganathan, N; Saunders, V; Yeung, DT; Kenyon, RR; Wadham, C; Braley, J; Fernandes, A; Maqsood, M; Shahrin, N; Lin, M; Toubia, J; McConnell, J; Kaczorowski, D; Ross, DM; Yong, ASM; Chee, L; Shortt, J; Viiala, N; Kok, CH; Hughes, TP; Branford, S;
Details: Publication Year 2025-12-04,Volume 146,Issue #23,Page 2821-2832
Journal Title: Blood
Publication Type: Research article
Abstract: Genomic profiling in patients with chronic-phase chronic myeloid leukemia (CP-CML) demonstrated somatic variants in blood cancer-related gene variants (CGVs) and rearrangements associated with the formation of the Philadelphia chromosome (Ph-associated rearrangements) at diagnosis, collectively termed additional genetic abnormalities (AGAs). AGAs had a negative impact on failure-free survival (FFS) and molecular response in imatinib-treated patients. We investigated whether treatment with more potent therapies could overcome the negative impact of AGAs at diagnosis. Targeted RNA-based next-generation sequencing was performed on diagnostic samples of 315 patients consecutively enrolled in 4 clinical trials of frontline potent tyrosine kinase inhibitors (TKIs) in CP-CML. AGAs were present in 34% of patients at diagnosis, including 20% harboring CGVs and 18% with Ph-associated rearrangements (4% had both). Although the negative impact of Ph-associated rearrangements was overcome by more potent inhibitors, patients with CGVs continued to experience inferior outcomes. This result was largely attributable to patients with ASXL1 variants, observed in 7% overall. Patients harboring ASXL1 variants also had inferior outcomes compared with those with wild-type ASXL1 in terms of 12-month major molecular response (55% vs 83%; P = .001), 2-year FFS (61% vs 91%; P < .001), and notably, the development of treatment-emergent BCR::ABL1 kinase domain mutations at 2 years (35% vs 1%; P < .001). In multivariable models, both CGVs and ASXL1 variants were predictors of each outcome. Treatment with frontline potent TKIs overcame the negative impact of Ph-associated rearrangements observed with frontline imatinib. However, inferior outcomes were still associated with the presence of CGVs. The acquisition of TKI-resistant BCR::ABL1 mutations was almost exclusively associated with mutated ASXL1 at diagnosis.
Keywords: Humans; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/genetics/diagnosis; *Protein Kinase Inhibitors/therapeutic use; Male; Middle Aged; Female; *Mutation; Adult; *Repressor Proteins/genetics; Aged; Fusion Proteins, bcr-abl/genetics; Young Adult; Aged, 80 and over
Department(s): Haematology
Publisher's Version: https://doi.org/10.1182/blood.2025030259
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-10-02 01:41:49

Last Modified: 2026-01-23 03:46:46