Atypical chronic myeloid leukemia (aCML) is an aggressive myeloid neoplasm with overlapping features of myelodysplastic syndromes (prominent granulocytic dysplasia) and myeloproliferative neoplasms (neutrophilic leukocytosis). We studied 25 molecularly-annotated and World Health Organization defined aCML patients; median age 70 years, 84% males. Cytogenetic abnormalities were seen in 36% and gene mutations in 100%. Mutational frequencies were, ASXL1 28%, TET2 16%, NRAS 16%, SETBP1 12%, RUNX1 12%, ETNK1 8%, and PTPN11 4%. Fifteen patients (60%) had >1 mutation, while 9 (36%) had ≥3. The median overall survival (OS) was 10.8 months and at last follow up (median 11 months), 17 (68%) deaths and 2 (8%) leukemic transformations were documented. On univariate analysis, survival was adversely impacted by advanced age (P =.02), low hemoglobin (P =.01), red blood cell transfusion dependence (P =.03), high white blood cell count (P =.02), TET2 (P =.03), NRAS (P =.04), PTPN11 (P =.02) mutations and the presence of ≥3 gene mutations (P =.006); ASXL1, SETBP1, and ETNK1 mutations did not impact OS. In multivariable analysis, advanced age (P =.003) [age >67: HR 10.1, 95% CI 1.3-119], low hemoglobin (P =.008) [HB< 10 gm/dL: HR 8.2, 95% CI 1.6-23.2] and TET2 mutations (P =.01) [HR 8.8, 95% CI 1.6-47.7] retained prognostic significance. We then used age >67 years, hemoglobin <10 gm/dL and the presence of TET2 mutations (each counted as one risk factor) to create a hazard ratio weighted prognostic model; effectively stratifying patients into two risk categories, low (0-1 risk factor) and high (≥2 risk factors), with median OS of 18 and 7 months, respectively.
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