One vs. 2 vs. ≥3 TET2 mutations in chronic myelomonocytic leukemia: co-mutation patterns and prognostic relevance in the context of contemporary prognostic models including BLAST-mol and CPSS-mol

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping myelodysplastic and myeloproliferative features [ 1 ]. TET2 is the most frequently mutated gene in CMML, present in ~60% of patients [ 2 ]. In a 2016 study in CMML [ 3 ], we reported a TET2 mutational frequency of 43% with 58 (52%) out of the 113 TET2 -mutated cases harboring ≥2 TET2 MUT ; the presence of TET2 MUT was associated with superior overall survival (OS) but significance was lost during multivariable analysis that was adjusted for adverse karyotype or the Mayo Molecular risk Model (MMM) [ 4 ]; furthermore, the results were not affected by the type or number of TET2 MUT [ 3 ]. In a subsequent multicenter study [ 5 ], we observed a significantly longer OS in the presence of ≥2 TET2 MUT , compared to that seen with one or no TET2 MUT . In a more recent study [ 6 ], we showed that the survival difference in patients harboring 0 vs. 1 vs. ≥2 TET2 MUT was apparent in both myelodysplastic (CMML-MD) and myeloproliferative (CMML-MP) CMML variants, with significance sustained during multivariable analysis that accounted for both the MMM [ 4 ] and CMML-specific molecular (CPSS-mol) [ 7 ] risk models. Other investigators have also associated ≥2 TET2 MUT with longer OS in CMML [ 8 ]. The objective of the current study was to obtain additional information on the relationship between the number of TET2 MUT and prognosis in CMML, in the context of contemporary risk models, including BLAST, BLAST-mol, and CPSS-mol [ 7 , 9 , 10 ].