Clinical, molecular, and prognostic correlates of number, type, and functional localization of TET2 mutations in chronic myelomonocytic leukemia (CMML)—a study of 1084 patients

Loss-of-function TET2 mutations ( TET2 MT ) are frequent early clonal events in myeloid neoplasms and are thought to confer a fitness advantage to hematopoietic precursors. This large, multi-institutional study ( n = 1084), investigated the TET2 mutational landscape and prognostic implications of the number, type, and location of TET2 MT and the epistatic relationship with other somatic events in chronic myelomonocytic leukemia (CMML). Nine hundred and forty-two TET2 MT were identified in 604 (56%) patients, of which 710 (75%) were predicted to be truncating (involving the catalytic domain). Three hundred and sixteen (29%) patients had ≥1 TET2 MT , with 28%, 1%, and 0.2% harboring 2, 3, and 5 mutations, respectively. In comparison to TET2 WT , TET2 MT patients were older in age, more likely to have dysplastic CMML, a higher number of co-occurring mutations, and lower-risk stratification. Importantly, TET2 MT were associated with a survival advantage (49 vs. 30 months, p < 0.0001), especially in the context of multiple TET2 MT (≥2; 57 months, p < 0.001), and truncating TET2 MT (51 months, p < 0.001). In addition, the adverse prognostic impact of ASXL1 MT was partially mitigated by concurrent TET2 MT , with the ASXL1 WT / TET2 MT genotype having better outcomes and resulting in further risk stratification of ASXL1 inclusive CMML prognostic models, in comparison to ASXL1 MT alone.