CMML is in the eye of the be-WHO-lder: interrogating the newly proposed entity of oligomonocytic CMML: MDS or CMML?

The World Health Organization and international consensus 2022 classifications have proposed lowering the absolute monocyte count threshold to ≥ 0.5 × 109/L for the diagnosis of chronic myelomonocytic leukemia (CMML). This was based on reports describing patients with oligomonocytic CMML (O-CMML) (0.5 × 109/L to 1.0 × 109/L) as a CMML variant. We identified patients among the myelodysplastic syndrome (MDS) database with O-CMML who meet the new criteria for CMML and compared them to MDS and CMML (≥1.0 × 109/L). Among 1861 patients with MDS, 468 (25%) were O-CMML meeting new CMML criteria. The genomic landscape of O-CMML was more comparable to MDS. Classical CMML somatic mutations (TET-2, ASXL-1 and SRSF2) frequencies were closer to MDS. Proliferative CMML (P-CMML) mutations were less common. DNMT3A and TP53 mutations were more commonly observed in MDS and O-CMML compared to CMML. SF3B1 SM was observed in 29% of O-CMML compared to 16% in MDS, 8% dysplastic CMML (D-CMML) and 5% P-CMML (P < .005). Thirteen patients (2.8%) progressed from O-CMML to CMML. The rate of acute myeloid leukemia transformation was less than MDS and P-CMML. The hazard ratio for overall survival was 1.2 (95% confidence interval [CI], 1.03-1.4; P = .018) for O-CMML, 1.3 (95% CI, 1.07-1.58; P = .008) for D-CMML and 1.87 for P-CMML (95% CI, 1.57-2.4; P = .005) compared to MDS after adjusting for molecular international prognostic scoring system. Although O-CMML may be a unique entity, the current classification does not enrich CMML-like variants by all clinical measures. A comprehensive analysis of clinical, molecular and immunophenotype is needed for better classification.