A Phase II Study of Cladribine and Low Dose Cytarabine in Combination With Venetoclax, Alternating With Azacitidine and Venetoclax, in Patients With Higher-risk Myeloproliferative Chronic Myelomonocytic Leukemia or Higher-risk Myelodysplastic Syndromes With Excess Blasts

Eligibility Criteria

• 1. Age \>/= 18 years.
• 2. Diagnosis of MDS or CMML by WHO and:
• * MDS relapsed cohort (Cohort A): MDS with Int-2 or High risk IPSS and \>5% blasts with no response after 6 cycles of azacitidine, decitabine, guadecitabine, CC-486 or ASTX727 (decitabine/cedazuridine) or relapse or progression after any number of cycles
• * CMML relapsed cohort (Cohort B): CMML 1 or 2 with no response after 6 cycles of azacitidine, decitabine, guadecitabine, CC-486 or ASTX727 (decitabine/cedazuridine) or relapse or progression after any number of cycles
• * MDS HMA-naïve cohort (Cohort C): MDS with Int-2 or High risk by IPSS and \>10% blasts OR diagnosis
• * CMML HMA-naïve cohort (Cohort D): CMML-2; OR CMML-1 with at least one of the following high-risk features: extramedullary disease, splenomegaly of \>5cm below costal margin, platelets \<100x109/L, Hgb level \<10g/dL, WBC \>13x109/L, clonal cytogenetic abnormality (other than monosomy Y).
• 3. Eastern Cooperative Oncology Group (ECOG) performance status of \</= 2
• 4. Creatinine clearance \> 30 ml/min no end/stage renal disease (using Cockcroft-Gault)
• 5. Adequate hepatic function with total bilirubin 2x ULN, AST or ALT 2.5 xULN unless deemed to be due to underlying disease involvement.
• 6. Willing to adhere to and comply with all prohibitions and restrictions specified in the protocol.
• 7. Patient must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study.
• 8. White blood cell (WBC) count \<50,000/L. Hydroxyurea may be used to control leukocytosis prior to C1D1. Use of hydroxyurea beyond this point may be permitted as clinically indicated, on a case-by-case basis and after discussion with the PI.
• 9. English and Non-English speaking patients will be allowed
• 1. Uncontrolled infection not adequately responding to appropriate antibiotics
• 2. New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF \<50% by echocardiogram or multigated acquisition (MUGA) scan.
• 3. History of myocardial infarction within the last 6 months or unstable/uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias.
• 4. Female patients who are pregnant or lactating.
• 5. Patients with reproductive potential who are unwilling to following contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives \[birth control pills\], contraceptive injections, intrauterine devices \[IUD\], double-barrier method \[spermidical jelly or foam with condoms or diaphragm\], contraceptive patch, or surgical sterilization) throughout the study.
• 6. Female patients with reproductive potential who do not have a negative urine or blood beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening.
• 7. Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy.