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

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.