Impact of ASXL1 at diagnosis in patients with CML receiving frontline potent TKIs: high risk of kinase domain mutations
- Author(s)
- Shanmuganathan, N; Yeung, DT; Wadham, C; Fernandes, A; Maqsood, M; Shahrin, N; Saunders, VA; Kenyon, R; Lin, M; Toubia, J; McConnell, J; Kaczorowski, D; Ross, DM; Yong, ASM; Chee, L; Shortt, J; Viiala, N; Braley, JA; Kok, CH; Hughes, TP; Branford, S;
- Journal Title
- Blood
- Publication Type
- Online publication before print
- Abstract
- Genomic profiling in chronic-phase chronic myeloid leukemia (CP-CML) patients demonstrated somatic variants in blood cancer-related genes (CGVs) and rearrangements associated with the formation of the Philadelphia-chromosome (Ph-associated rearrangements) at diagnosis, collectively termed additional genetic abnormalities (AGA). AGAs had a negative impact on failure-free survival 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 (NGS) was performed on diagnostic samples of 315 patients consecutively enrolled in four clinical trials of frontline potent tyrosine kinase inhibitors (TKIs) in CP-CML. AGAs were present in 34% of patients at diagnosis, including 20% with CGVs and 18% with Ph-associated rearrangements (4% had both). While the negative impact of Ph-associated rearrangements was overcome by more potent inhibitors, patients with CGVs continued to have inferior outcomes. This was largely attributable to patients with ASXL1 variants, observed in 7% overall. Comparing patients with ASXL1 variants to ASXL1 wildtype: 12-month major molecular response 55% versus 83% (P=0.001); 2-year failure-free survival 61% versus 91% (P<0.001); and notably, development of treatment emergent BCR::ABL1 kinase domain mutations at 2 years, 35% versus 1% (P<0.001). In multivariable models, CGVs and ASXL1 variants were predictors of each of these outcomes. 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.
- 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: 2025-10-02 01:43:42