Molecular and prognostic correlates of cytogenetic abnormalities in chronic myelomonocytic leukemia: A Mayo Clinic-French Consortium Study

Abstract

Four hundred and nine patients with chronic myelomonocytic leukemia (CMML) were included in the international collaborative study (268 (66%) and 141 (34%) from Mayo clinic and French consortium respectively). Thirty percent displayed an abnormal karyotype, including; 72% sole, 16% two, and 11% complex abnormalities. The most common abnormalities included; +8 (23%), -Y (20%), -7/7q-(14%), 20q- (8%), +21 (8%), and der(3q) (8%). Patients with an abnormal karyotype were more likely to be elderly (P=0.03), be anemic (P=0.0009), have leukocytosis (P=0.02) with neutrophilia (P=0.03), demonstrate increased circulating immature myeloid cells (P=0.0003), peripheral blood blasts (P<0.0001), and bone marrow blasts (P<0.0001). ASXL1 (P=0.04) and SF3B1 (P=0.03) mutations clustered with an abnormal karyotype, whereas SRSF2 (P=0.02) mutations occurred more commonly with a normal karyotype. A step-wise survival analysis resulted in three distinct cytogenetic risk categories: high (complex and monosomal karyotypes), intermediate (all abnormalities not in the high or low risk groups) and low [normal, sole -Y and sole der (3q)] with median survivals of 3 [hazard ratio (HR)=8.1, 95% confidence interval (CI)=4.6-14.2], 20 (HR=1.7, 95% CI=1.2-2.3) and 41 months, respectively. In multivariable analysis, this particular cytogenetic risk stratification remained significant in the context of the Molecular Mayo Model (P<0.0001), MD Anderson prognostic model (P<0.0001), the GFM CMML model (P<0.0001) and was effective in predicting leukemic transformation (P=0.004).