• Age 18 and older.

• CMML diagnosis according to ICC 2022 criteria.

• Intermediate-2 or high risk according to the molecular CMML Prognostic Scoring System (CPSS-mol) at study entry. In patients treated with HY at screening, the white blood count (WBC) prior to introduction of HY will be used to compute CPSS-mol. In patients with failed or missing cytogenetics or genetics at screening, cytogenetics and genetics at CMML diagnosis will be used to compute CPSS-mol.

• No prior treatment with hypomethylaing agents, including Azacitidine, decitabine, SGI-110, AST7227 or CC-486 for CMML or any antecedent condition, including antecedent MDS or auto-immune disease. Prior treatment with Erythropoiesis Stimulating Agents (ESA) is allowed with a \> 15 days washout from ESAs. Prior treatment with hydroxyurea (HY) is acceptable. No washout is necessary for those patients but pre-HY WBC will be taken in consideration for CPSS-mol computation.

• Performance status 0-2 on the Eastern Cooperative Oncology Group (ECOG) Scale.

• Adequate organ function including the following:

‣ total bilirubin \< 2 times upper limit of normal (ULN) (except moderate unconjugated hyperbilirubinemia due to intra medullary hemolysis or due to Gilbert syndrome),

⁃ alanine transaminase (ALT) and aspartate transaminase (AST) \< 3 times ULN,

⁃ Creatinine clearance \> 30 mL/min as estimated by the CKD-EPI equation.

• Signed Informed Consent Form (ICF).

• Negative pregnancy and adequate contraception (including in male patients) if relevant.

• A FCBP (female of childbearing potential) for this study is defined as a sexually mature woman who: (1) has not undergone a hysterectomy or bilateral oophorectomy; or (2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).

• A FCBP participating in the study must:

⁃ Have had 2 negative pregnancy tests as verified by the investigator prior to starting investigational medicinal product (IMP) (unless the screening pregnancy test was done within 72 hours of Cycle 1 Day 1). She must have had agreed to ongoing pregnancy testing during the course of the study and after end of treatment.

⁃ If sexually active, agree to use, and be able to comply with, highly effective contraception\*\* without interruption, 5 weeks prior to starting IMP, during treatment with IMP (including dose interruptions), and for 3 months after the last dose of IMP.

∙ Highly effective contraception is defined in this protocol as the following (information also appears in the ICF): Hormonal contraception (eg, birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation (tying your tubes), or a partner with a vasectomy.

• Male subjects must have agreed to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (eg, polyurethane), during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions, and for at least 3 months after the last dose of IMP, even if he had undergone a successful vasectomy.

• Affiliation to a health insurance system.