CMML Is in the Eye of the Be_Who_ Lder: Interrogating the Newly Proposed Entity of Oligomonocytic Chronic Myelomonocytic Leukemia (O-CMML): MDS or CMML?
Authors: Komrokji Rami S. , Komrokji Zena , Al Ali Najla H. , Xie Zhuoer , Chan Onyee , Kuykendall Andrew T. , Jabbour Joseph E. , Walker Alison R. , Lancet Jeffrey E , Sallman David , Padron Eric 
Published: December 2024

Background:
The new WHO and ICC 2022 proposed lowering the threshold for diagnosis of CMML to an absolute monocyte count (AMC) ≥ 0.5 × 109/L as long as monocyte is ≥ 10% of differential with supporting evidence of clonality, dysplasia, classical monocytosis, and/or cytopenia. This proposal may influence standard clinical practice, complicate eligibility for clinical trials and response assessments. There are limited data on the molecular architecture and clinical outcomes in this clinical subgroup of CMML patients with 0.5-1.0 × 109/L AMC.
Methods:
We reviewed 2 large separate comprehensively molecularly annotated cohorts of MDS and CMML. We identified all patients (pts) among the MDS database who met the new definition of CMML (formerly oligomonocytic CMML (O-CMML)) and would be classified by WHO/ICC 2022 as CMML but were not included in the CMML database which used historical &gt; 1.0 x109/L AMC (WHO 2017 criteria). We compared baseline characteristics, genomic landscape, and outcomes among 4 cohorts: MDS, O-CMML (AMC 0.500-1.0× 109/L), dysplastic CMML (D-CMML) (AMC &gt; 1.0 ×109/Land WBC &lt;13 ×109/L) and proliferative CMML (P-CMML) (AMC &gt; 1.0 ×109/L and WBC &gt;13 ×109/L).
Results:
Among 1861 MDS pts, 468 patients (25%) met the new proposed criteria for O-CMML and re-classified accordingly. In a separate cohort, we identified 576 CMML pts (WHO 2017 definition) (307 D-CMML and 269 P-CMML). The baseline characteristics between the 4 groups were compared. MDS pts were younger compared to O-CMML and CMML. The mean bone marrow myeloblasts were higher among MDS pts while mean Hgb and platelets were higher among CMML pts compared to MDS and O-CMML. The control CMML cohort (WHO 2017 criteria) was classified as CMML-1 in 82% and P-CMML in 47%. Both O-CMML and MDS pts were “higher risk” by IPSS-M compared to D-CMML and P- CMML.
The genomic landscape of O-CMML was more comparable to MDS than D-CMML, or P-CMML. TET-2 mutation was observed in 19%, 30%, 66%, 57% among MDS, O-CMML, D-CMML, P-CMML, respectively (P &lt;.005). ASXL1 was mutated in 21%, 21%,33%, and 53% respectively (P &lt; .005). SRSF2 mutation rate was 11%, 14%, 42% and 42% respectively (P &lt;.005). CBL, NRAS, RUNX-1, SETBP1 were more commonly observed in CMML compared to MDS and O-CMML, more so in P-CMML. On the other hand, DNMT3A and TP53 genes were more commonly mutated among MDS and O-CMML compared to CMML. TP53 mutation was observed in 23%, 18%, 3% and 4% among MDS, O-CMML, D-CMML, P-CMML, respectively (P &lt;.005). Interestingly SF3B1 mutation was observed among 29% of O-CMML compared to 16% in MDS, 8% in D-CMML and 5% in P-CMML (p&lt; .005).
The rate of AML transformation was 30%, 20%, 20% and 28% respectively for MDS, O-CMML, D-CMML and P-CMML (p&lt;.005). Thirteen out of 468 O-CMML pts progressed to overt CMML compared to 4 out of 1393 MDS pts.
After adjusting for IPSS-M risk category, the hazard ratio for OS compared to MDS was 1.2 (95% CI 1.03-1.4) for O-CMML (p .018), 1.3 (95% CI 1.07-1.58) (p=.008) for D-CMML and 1.87 (95% CI 1.57-2.4) (P=.005) for P-CMML. Among pts with SF3B1 mutation (n=400) MDS and O-CMML pts had better OS than CMML pts.
Conclusions
Twenty-five percent of MDS pts will be reclassified as O-CMML if the new WHO/ICC 2022 CMML criteria were applied. The genomic landscape of O-CMML is closer to the molecular phenotype of MDS compared to CMML, while the clinical features and outcomes of O-CMML overlap between MDS and CMML. SF3B1 mutations are enriched among O-CMML pts, displaying outcome similar to MDS-SF3B1 rather than CMML-SF3B1.