CML-288 Impact of ASXL1 Mutations on Prognosis of Chronic Phase Chronic Myeloid Leukemia

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Mutations in ABL1 are established risk factors for therapy resistance in chronic phase chronic myeloid leukemia (CML-CP). However, much less is known about the impact of other cancer-associated gene mutations. Study the prevalence and clinical impact of cancer-associated gene mutations in CML-CP. We screened our databases for CML-CP patients who were tested with a targeted next-generation sequencing panel that included 81 genes recurrently mutated in hematologic malignancies. Event-free survival (EFS) was measured from treatment initiation to the time of an event defined as loss of hematologic response, loss of major cytogenetic response (MCyR), lack of MCyR after 12 months, or transformation to accelerated/blast phase. Failure-free survival (FFS) was measured similarly, with the additional events of drug discontinuation due to adverse effects or no response. We subsequently performed univariate and multivariate analyses. The median age of patients was 60 years (18-80) and 46% were female. The most common first-line therapy was dasatinib (52%), followed by imatinib (19%), dasatinib + venetoclax (16%), and other TKIs (13%). The distribution of evaluable patients to low, intermediate, and high Sokal groups was 21%, 61%, and 18%, respectively. Cancer mutations were found in 23/68 patients (34%). The most common mutations involved ASXL1 (10/68 patients; 15%), DNMT3A (5/68 patients; 7%), and RUNX1 (3/68 patients; 4%). Mutations were also detected in ASXL2, CALR, EZH2, GNAS, IDH2, SF3B1, SMC3, SRSF2, STAG2, and SUZ12. Unlike mutations in other genes, patients with ASXL1 mutations had worse EFS compared to the no-mutation group (median of 33 vs. 88 months; P=0.002) and worse FFS (median of 14 vs. 58 months; P=0.04). There was no difference in overall survival by mutational status. In a multivariate analysis, mutated ASXL1 was independently associated with worse EFS (HR of 4.42; 95% CI 1.63-11.99). There was a non-statistically significant trend of lower molecular response rates and longer times to response (TTR) in ASXL1-mutated patients compared to wild-type (major molecular response rate of 78% vs. 82%; P=0.7 with median TTR of 17.5 vs. 9.2 months; P=0.5). Mutations in ASXL1 are associated with delayed responses and worse outcomes when detected in CML-CP.