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

Prior treatment

• 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.
• Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy.

Other illness

• Uncontrolled infection not adequately responding to appropriate antibiotics
• History of myocardial infarction within the last 6 months or unstable/uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias.

Lab values

• New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF \<50% by echocardiogram or multigated acquisition (MUGA) scan.

Other

• Female patients who are pregnant or lactating.
• Female patients with reproductive potential who do not have a negative urine or blood beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening.

• Age \>/= 18 years.
• Diagnosis of MDS or CMML by WHO and:
  • MDS relapsed cohort (Cohort A): MDS with IPSS-R score \>3.5 and \>5% blasts with no response after 6 cycles of azacitidine, decitabine, guadecitabine 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 or ASTX727 (decitabine/cedazuridine) or relapse or progression after any number of cycles
  • MDS HMA-naïve cohort (Cohort C): MDS with IPSS-R score \>3.5 and \>/= 10% blasts
  • 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 or by sonographic volumetric assessment, platelets \<100x109/L, Hgb level \<10g/dL, WBC \>13x109/L, clonal cytogenetic abnormality (other than monosomy Y) or high risk mutations (ASXL1, RUNX1, SETBP1, BRAF, NRAS, KRAS, PTPN11, NF1, CBL).
  • MDS/MPN relapsed cohort (Cohort E): MDS/MPN-NOS, MDS/MPN with neutrophilia (atypical CML) or MDS/MPN-RS-T with \>5% blasts with no response after 6 cycles of azacitidine, decitabine, guadecitabine or ASTX727 (decitabine/cedazuridine) or relapse or progression after any number of cycles
  • MDS/MPN HMA-naïve cohort (Cohort F): MDS/MPN-NOS or MDS/MPN with neutrophilia (atypical CML) with
  • \>/=10% blasts or
  • with \>5% blasts at least one of the following high-risk features: splenomegaly \>5cm below costal margin, WBC \>13x109/L, high risk cytogenetic or molecular features (ASXL1, SETBP1, i(17q), TP53) or
  • who might not be deemed to benefit from HMA therapy due to proliferative or extramedullary disease.
• Eastern Cooperative Oncology Group (ECOG) performance status of \</= 2
• Creatinine clearance \> 30 ml/min no end/stage renal disease (using Cockcroft-Gault)
• Adequate hepatic function with total bilirubin 2x ULN, AST or ALT 2.5 xULN unless deemed to be due to underlying disease involvement.
• Willing to adhere to and comply with all prohibitions and restrictions specified in the protocol.
• 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.
• English and Non-English speaking patients will be allowed