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.