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

Primary Objectives:

• To determine the efficacy, safety and tolerability of the combination of cladribine, cytarabine and venetoclax in higher-risk MDS with excess blasts and higher-risk CMML.
• MDS relapsed cohort (Cohort A, N=20): 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, N=10): 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, N=20): MDS with Int-2 or High risk by IPSS and >10% blasts OR diagnosis
• CMML HMA-naïve cohort (Cohort D, N=10): 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).

Secondary Objectives:

• To evaluate responses by 2015 IWG MDS/MPN response criteria in patients with MDS/MPN and by 2023 IWG response criteria in all patients (Appendix).
• To assess overall survival (OS), duration of response, leukemia-free survival (LFS), and relapse-free survival (RFS).
• To evaluate proportion of transplant-candidate patients bridged to allogeneic stem-cell transplant.
• Correlative studies including correlation of response with disease subtype and genomic profile.
• To evaluate changes in clonal composition and VAF of identified mutations with therapy.

Inclusion criteria

• 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

Exclusion criteria

• Uncontrolled infection not adequately responding to appropriate antibiotics
• New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF <50% by echocardiogram or multigated acquisition (MUGA) scan.
• History of myocardial infarction within the last 6 months or unstable/uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias.
• Female patients who are pregnant or lactating.
• 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.
• Female patients with reproductive potential who do not have a negative urine or blood beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening.
• Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy.