Cladribine Venetoclax in Monocytic AML

Inclusion Criteria: A subject will be eligible for study participation if they meet the following criteria within 28 days prior to the first day of treatment. Historical records are permitted per investigator discretion. Subject must have confirmation of non-acute promyelocytic leukemia (APL) Acute Myeloid Leukemia (AML) with a monocytic or monoblastic phenotype or a Ras pathway mutation. 1. The subject's AML must be relapsed after or refractory to prior treatment with hypomethylating agent (HMA) and venetoclax combination. Note: other prior line(s) of therapy including stem cell transplant (SCT) are allowed, but HMA/Ven must be one of the preceding treatments. Subjects who have progressed to AML after prior treatment with HMA/Ven for high grade Chronic Myelomonocytic Leukemia (CMML) or Myelodysplastic Syndrome (MDS) are also eligible. 2. Age ≥ 18 years 3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 4. Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 60 mL/min, calculated using the formula CKD-EPI Creatinine Equation (2021). 5. Adequate liver function, as demonstrated by: * Aspartate aminotransferase (AST) ≤ 3.0 x ULN\* * Alanine aminotransferase (ALT) ≤ 3.0 x ULN\* * Total bilirubin ≤ 1.5 x ULN, unless considered to be due to leukemic organ involvement or Gilbert's syndrome\* \*In subjects with Gilbert's syndrome, bilirubin needs to be ≤ 4 x ULN 6. Non-sterile male subjects must use contraceptive methods with partner(s) at least prior to beginning study drug administration and continuing up to 90 days after the last dose of study drug. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug. No contraception is required if male subjects are surgically sterile (vasectomy with medical assessment confirming surgical success) or if the male subject has a female partner who is postmenopausal or permanently sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy). 7. Female subjects must be either: * Postmenopausal: defined as age \> 60 years with no menses for 12 or more months without an alternative medical cause; OR * Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy); OR * If subject is of childbearing potential, use of contraception is required while on study treatment and for 6 months after the last dose. 8. Subject must voluntarily sign an informed consent, approved by the Institutional Research Board (IRB), prior to the initiation of any research-related screening or study procedures. Exclusion Criteria: 1. Subject has received prior treatment with cladribine for AML. 2. Subject has a white blood cell count \> 25 x 109/L. Note: hydroxyurea and/or leukapheresis are permitted to meet this criterion. 3. Subject has known active central nervous system (CNS) involvement of AML. 4. Subject exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal). Uncontrolled is defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment. Patients on antibiotics, antivirals, or antifungals with controlled systemic symptoms will not be excluded. 5. Subject has any clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study, including but not limited to: * New York Heart Association heart failure \> class 2 * Renal, neurologic, psychiatric, endocrine, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia. 6. Subject has a QTc interval \> 470 msec. 7. Subject has a history of other malignancies within 2 years prior to study entry, with the following exceptions: * Adequately treated in situ carcinoma of the breast or cervix * Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin * Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent * Prostate cancer not requiring therapy beyond hormonal therapy 8. Subject is pregnant or breastfeeding. 9. Subject is known to be positive for HIV. HIV testing is not required. 10. Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load. Hepatitis B or C testing is not required, and subjects with serologic evidence of prior vaccination to HBV may participate.