2  CMML

2.1 Risk Strtaification

2.1.1 IPSS-M

• Only for dysplastic CMML((WBC <13 × 109/L))

2.1.2 CPSS-Mol

• Both dysplastc and proliferative CMML
• Mayo Molecular, Groupe Francophone des Myelodysplasies, and molecular CPSS models

2.1.3 iCPSS

2.1.4 BLAST/BLAST-mol Tefferi et al. (2025)

• Mayo clinic dataset n=457
• MD Anderson dataset n=449 Validation
• University of Milan dataset n=202 Validation

2.1.4.0.1 Important questions

• There is subjectivity in identifying blasts and promonocytes (blast equivalents) included in this model, and clinicians should be vigilant to those cells misclassified as “reactive lymphocytes” or reported under “immature granulocytes” by automated cell counters
• Can BLAST and BLAST-mol confirm the benefit of HSCT in the intermediate- and high-risk groups and predict their survival posttransplant?
• Should patients with intermediate- and high-risk disease proceed with HSCT soon after diagnosis or wait till they show signs of disease progression?
• Patients with oligomonocytic CMML are currently included under CMML in the ICC/WHO criteria, but would they be better stratified using BLAST/BLAST-mol, IPSS-M, or CPSS-Mol?
• Can BLAST/BLAST-mol be applied to patients with CMUS?
• Can this new model identify patients with treatment-related CMML that are relatively “lower risk” and benefit from watchful waiting?
• Can BLAST/BLAST-mol be used in other MDS/MPN overlap syndromes that share similar mutational profiles such as MDS/MPN with neutrophilia (atypical chronic myeloid leukemia) and MDS/MPN, not otherwise specified?

2.1.5 CMML risk stratification model

• https://cmml-container-app.happystone-1ba2e890.swedencentral.azurecontainerapps.io/

2.2 Treatment of CMML

2.2.1 Erythropoiesis-stimulating or maturation agents

2.2.2 Hydroxyurea

2.2.3 Hypomethylating agents (HMAs)

• HMAs (azacitidine, decitabine, decitabine/cedazuridine) are the only Food and Drug Administration–approved therapies in CMML and do not affect mutational burden or clonal evolution(Merlevede et al. 2016)
• A phase 3 trial failed to show superiority of azacitidine in improving event-free survival (death, AML transformation, or progression) compared with hydroxyurea in proliferative CMML, due to toxicity(Itzykson et al. 2023). Patients treated with hydroxyurea had numerically longer median overall survival (21.9 months) compared with those treated with azacitidine (18.4 months, P = .67)

2.2.4 Thrombopoietin receptor agonists

2.2.5 JAK inhibitors

2.2.6 Acute myeloid leukemia (AML)-like therapy (eg, intensive chemotherapy or HMA + venetoclax)

2.3 Clinical trials in CMML

2.3.1 Lenzilumab

2.3.2 CMML INTERCEPT study

2.3.3 STX-0712

• A CyTAC targeting the GPCR CCR2, which is a selective marker expressed at high levels on pathogenic monocytes. Pathogenic monocytes expressing CCR2 have been shown to be the key drivers in some hematological malignancies. STX-0712 targets and eliminates pathogenic monocytes.

• (Turunen et al. 2024; Leach et al. 2024)ASH abstract

• Target single- or dual-tumor antigens with heterobivalent small molecule CyTACs • Pair CyTACs with proprietary ADCC-enhanced, ADC, or bispecific platform antibodies. • Enable potent and selective killing of hematologic and solid tumor cells

2.4 Allogeneic stem cell transplant in CMML

• Allogeneic hematopoietic stem cell transplantation (HSCT) is the only treatment modality with curative potential in CMML, but may decrease life expectancy if used early in patients with lower-risk disease(Robin et al. 2022)

Itzykson, Raphael, Valeria Santini, Sylvain Thepot, et al. 2023. “Decitabine Versus Hydroxyurea for Advanced Proliferative Chronic Myelomonocytic Leukemia: Results of a Randomized Phase III Trial Within the EMSCO Network.” Journal of Clinical Oncology 41 (10): 1888–97. https://doi.org/10.1200/jco.22.00437.

Leach, Craig, Laura Bertoldi, Sofia Carbajosa, et al. 2024. “Ex-Vivo Evaluation of Stx-0712, a CCR2 Cytotoxicity Targeting Chimera (CCR2-CyTAC) for the Treatment of Acute Myeloid Leukemia.” Blood 144 (Supplement 1): 1380–80. https://doi.org/10.1182/blood-2024-209323.

Merlevede, Jane, Nathalie Droin, Tingting Qin, et al. 2016. “Mutation Allele Burden Remains Unchanged in Chronic Myelomonocytic Leukaemia Responding to Hypomethylating Agents.” Nature Communications 7 (1). https://doi.org/10.1038/ncomms10767.

Robin, Marie, Liesbeth C. de Wreede, Eric Padron, et al. 2022. “Role of Allogeneic Transplantation in Chronic Myelomonocytic Leukemia: An International Collaborative Analysis.” Blood 140 (12): 1408–18. https://doi.org/10.1182/blood.2021015173.

Tefferi, Ayalew, Saubia Fathima, Maymona Abdelmagid, et al. 2025. “BLAST: A Globally Applicable and Molecularly Versatile Survival Model for Chronic Myelomonocytic Leukemia.” Blood Journal, ahead of print, May 7. https://doi.org/10.1182/blood.2024027170.

Turunen, Brandon, Craig Leach, Matthew Smith, et al. 2024. “Preclinical Evaluation of Stx-0712, a CCR2 Cytotoxicity Targeting Chimera (CCR2-CyTAC) for the Treatment of Chronic Myelomonocytic Leukemia.” Blood 144 (Supplement 1): 2771–71. https://doi.org/10.1182/blood-2024-209024.