Clinical and molecular characteristics of clonal monocytosis with and without cytopenia(s)

Clonal monocytosis of undetermined significance (CMUS) and clonal cytopenia with monocytosis of undetermined significance (CCMUS) are recently defined precursor states, with unclear progression rates to myeloid neoplasms (MN), including chronic myelomonocytic leukemia (CMML). We evaluated a cohort of 958 patients with sustained monocytosis ( ≥ 0.5 ×10⁹/L, ≥10%) and stringently excluded MN. Among 958 patients, 74 met criteria for CMUS (n = 10) and CCMUS (n = 64), respectively. These patients were compared with a cohort with oligo monocytic-CMML (OM-CMML; n = 47). CMUS patients were younger (median age: 63 years), whereas CCMUS demonstrated lower BM blast %, in comparison to OM-CMML (median blast %: 1 vs. 2). OM-CMML was enriched for TET2 (60% vs. 32%, p = 0.012), ASXL1 (40% vs. 9%, p < 0.001), and SRSF2 (45% vs. 8%, p < 0.001) mutations, while CMUS/CCMUS had higher rates of DNMT3A (36% vs. 9%, p < 0.001) and PPM1D (12% vs. 0, p = 0.029) mutations. Mutation burden and VAF for most mutations (except SRSF2) were significantly higher in OM-CMML. DNMT3A mutations in CMUS/CCMUS often involved the methyltransferase (MT) domain, and MT domain mutations and co-mutations were associated with progression of CCMUS to CMML. With a median follow-up of 31 months, there were no progression events in CMUS patients, while 13% of CCMUS patients progressed to MN, mainly CMML (7/8). Median OS was inferior in OM-CMML (71 months) compared to CMUS/CCMUS (not reached), p < 0.001. Our findings demonstrate that CMUS and CCMUS represent biologically distinct clonal states with variable progression risk and highlight the importance of integrating morphologic and genomic data to refine classification.