Azacitidine Combined With Venetoclax in Patients With Higher-risk Chronic Myelomonocytic Leukemia (AVENHIR)

Inclusion Criteria: 1. Age 18 and older. 2. CMML diagnosis according to ICC 2022 criteria. 3. 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. 4. 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. 5. Performance status 0-2 on the Eastern Cooperative Oncology Group (ECOG) Scale. 6. 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. 7. Signed Informed Consent Form (ICF). 8. 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. 9. Affiliation to a health insurance system. Exclusion Criteria: 1. Myeloproliferative / myelodysplastic syndrome other than CMML. 2. Bone marrow or peripheral blood blasts (including promonocytes) ≥ 20%. If both local and central review are available and discrepant, the central review will be used. 3. CMML with t(5;12) or PDGFRbeta rearrangement that may be treated with imatinib. 4. Unavailable CPSS-mol at inclusion (WBC prior to HY used to compute CPSS-mol at inclusion in HY-exposed patients) or with a CPSS-mol low or intermediate-1 at study entry. 5. Pregnant or breastfeeding. 6. Serious concomitant systemic disorder, including auto-immune or auto-inflammatory disease requiring \> 20 mg/d prednisone equivalent, active bacterial, fungal or viral infection that in the opinion of the investigator, would compromise the safety of the patient and/or his/her ability to complete the study. 7. Medical condition requiring therapies with CYP3A strong or moderate inducing or inhibiting activity at screening. All strong or moderate CYP3A inducers should be discontinued 7 days prior to the first dose of study drug. All strong or moderate CYP3A inhibitors should be discontinued 3 days prior to the first dose of study drug. A sample list of CYP3A4 inhibitors and inducers is provided in Appendix F. 8. Prior malignancy (except in situ cervix carcinoma, limited basal cell carcinoma, asymptomatic prostatic cancer not requiring treatment, or other tumors if not active during the last 2 years). 9. Known positive test for human immunodeficiency virus (HIV). Note that HIV testing is not required at Screening. 10. Malabsorption syndrome or other condition that precludes an enteral route of administration. 11. Previous therapy with a hypomethylating agent including azacitidine, decitabine, SGI-110, AST7227 or CC-486 for CMML or any antecedent condition, including antecedent MDS or auto-immune disease. 12. Previous therapy with a BH3 mimetic. 13. Antecedent allogeneic stem cell transplantation (HSCT) for CMML or an antecedent of hematological malignancy. Those never transplanted but eligible for HSCT are eligible for the trial. 14. Subjects referred to in Articles L1121-5 to L1121-8-1 and L1122-1-2 of the Public Health Code.