Phenotypic subtypes of leukaemic transformation in chronic myelomonocytic leukaemia

Summary Chronic myelomonocytic leukaemia (CMML) is a haematological disorder with high risk of transformation to acute myeloid leukaemia (AML). To characterize the phenotypic and genomic patterns of CMML progression, we evaluated a cohort of 189 patients with AML evolving from CMML. We found that transformation occurs through distinct trajectories characterized by genomic profiles and clonal evolution: monocytic (Mo‐AML, 53%), immature myeloid (My‐AML, 43%) or erythroid (Ery‐AML, 2%). Mo‐AML, characterized by expansion of monoblasts and promonocytes (low CD34, CD117 expression; high CD14, CD33, CD56 and CD64 expression), were defined by SRSF2 , TET2 and RAS pathway mutation co‐dominance and were more likely to evolve from SRSF2‐TET2 co‐mutant CMML through emergence/expansion of RAS pathway mutant clones. Conversely, My‐AML, characterized by expansion of immature myeloid blasts (high frequency of CD34, CD38, CD117; low frequency of CD14, CD64 and CD56 expression) were less likely to exhibit SRSF2‐TET2 co‐mutations or RAS pathway mutations and had higher frequency of CEBPA mutations. Ery‐AML was defined by complex karyotypes and TP53 mutations. A trend towards improved OS and EFS with hypomethylating agent‐venetoclax combination was observed in My‐AML, but not Mo‐AML. These findings define distinct progression of CMML and set the basis for future studies evaluating the role of phenotype‐specific therapeutics.