Prognostic interaction between ASXL1 and TET2 mutations in chronic myelomonocytic leukemia

Mutations involving epigenetic regulators (TET2 similar to 60% and ASXL1 similar to 40%) and splicing components (SRSF2 similar to 50%) are frequent in chronic myelomonocytic leukemia (CMML). On a 27-gene targeted capture panel performed on 175 CMML patients (66% males, median age 70 years), common mutations included: TET2 46%, ASXL1 47%, SRSF2 45% and SETBP1 19%. A total of 172 (98%) patients had at least one mutation, 21 (12%) had 2, 24 (14%) had 3 and 30 (17%) had 43 mutations. In a univariate analysis, the presence of ASXL1 mutations (P = 0.02) and the absence of TET2 mutations (P = 0.03), adversely impacted survival; while the number of concurrent mutations had no impact (P = 0.3). In a multivariable analysis that included hemoglobin, platelet count, absolute monocyte count and circulating immature myeloid cells (Mayo model), the presence of ASXL1 mutations (P = 0.01) and absence of TET2 mutations (P = 0.003) retained prognostic significance. Patients were stratified into four categories: ASXL1wt/TET2wt (n = 56), ASXL1mut/TET2wt (n = 31), ASXL1mut/TET2mut (n = 50) and ASXL1wt/TET2mut (n = 38). Survival data demonstrated a significant difference in favor of ASXL1wt/TET2mut (38 months; P = 0.016), compared with those with ASXL1wt/TET2wt (19 months), ASXL1mut/TET2wt (21 months) and ASXL1mut/TET2mut (16 months) (P = 0.3). We confirm the negative prognostic impact imparted by ASXL1 mutations and suggest a favorable impact from TET2 mutations in the absence of ASXL1 mutations.