• Patients need to have a confirmed diagnosis of AML, or MDS/AML with 10% to 19% blasts, per the International Consensus Classification 2022 or the WHO 2022 classification.23,24

• Patients .18 years with R/R AML or R/R MDS/AML, other than acute promyelocytic leukemia (APL), with no available standard treatment options.

• Relapsed or refractory disease defined by standard criteria as follows:

• a. Relapsed: Bone marrow blasts .5%, reappearance of blasts in the blood, or development of extramedullary disease following achievement of CR/CRi/MLFS b. Refractory: Failure to achieve CR/CRi/MLFS following initial treatment, with evidence of persistent leukemia by blood and/or bone marrow evaluation with blasts .5% c. Appropriate prior therapy in order for patient to be deemed relapsed or refractory include any of the following: i. At least 1 cycle of purine analogue containing intensive induction chemotherapy regimen, e.g., FLAG-Ida, CLIA or CLAG-M or similar regimens with or without venetoclax.25,26 ii. At least 1 cycle of intensive induction chemotherapy with venetoclax, e.g., 7 + 3 or CPX-351 with venetoclax or similar regimens iii. At least 2 cycles of intensive induction chemotherapy such as 7 + 3 or 5 + 2 or similar regimens without venetoclax iv. 2 cycles of BCL2 inhibitor with HMA/LDAC +/- other agents v. 4 cycles of HMA-based regimen without BCL2 inhibitor

• \- Younger/fit patients (\<60 years) in first relapse following intensive chemotherapy, will only be eligible if the first remission (CR1) duration was .12 months.

• d. Patients relapsing with persistent or new TP53 mutation will be eligible irrespective of CR1 duration. e. Older/unfit patients who relapse on HMA + venetoclax based maintenance regimen will be eligible irrespective of CR1 duration.

• ECOG PS 0 to 1

• Patients relapsing after allo-SCT may be eligible if they have recovered from all transplant related toxicities and are off all immunosuppression, with no more than grade 1 chronic GVHD. Physiologic ( greplacement h) dose of steroids (.10 mg prednisone or equivalent) may be acceptable. Patients must be off all immunosuppression, including calcineurin inhibitors, for at least 2 weeks or 5 half-lives, whichever is longer, prior to enrollment on study.

• Patients with actionable mutations with available FDA-approved therapies, e.g., FLT3, IDH1/2 inhibitors may be enrolled after they have exhausted appropriate lines of FDA approved treatment options.

• Patients with antecedent hematological disorder (AHD), e.g., aplastic anemia, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or myeloproliferative disorder or neoplasm (MPD or MPN) who have previously received a regimen appropriate for AML for the antecedent hematological disorder, as described above, and have progressed to AML, will be eligible for the dose escalation and salvage dose expansion cohorts. This is due to recognized poor outcomes in such patients with treated secondary AML.27,28

• Adequate hepatic function (total bilirubin . 1.5 x upper limit of normal (ULN), and AST and/or ALT . 2 x ULN). Patients with Gilbert disease will be eligible with total bilirubin . 4.5 mg/dL.

• Adequate renal function with creatinine clearance . 60 mL/min calculated by the Cockcroft- Gault formula or MDRD equation or measured by 24-hour urine collection.

⁃ The effects of these agents on the developing human fetus are unknown. For this reason, and because other therapeutic agents used in this trial may be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 90 days after last treatment.

⁃ a. This includes all female patients between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following: i. Postmenopausal (no menses in greater than or equal to 12 consecutive months).

⁃ ii. History of hysterectomy or bilateral salpingo-oophorectomy. iii. Ovarian failure (follicle-stimulating hormone and estradiol in menopausal range, who have received whole pelvic radiation therapy).

⁃ iv. History of bilateral tubal ligation or another surgical sterilization procedure.

⁃ b. Approved methods of birth control are as follows: Hormonal contraception (i.e., birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), tubal ligation or hysterectomy, subject/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

⁃ c. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of treatment.

⁃ Ability to understand and the willingness to sign a written informed consent document.