Omacetaxine and Venetoclax for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Harboring Mutant RUNX1

This phase Ib/II trial best dose, possible benefits and/or side effects of omacetaxine and venetoclax in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has come back (recurrent) or does not respond to treatment (refractory) and have a genetic change RUNX1. Drugs used in chemotherapy, such as omacetaxine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving omacetaxine and venetoclax may help to control the disease.

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability and recommended phase 2 dose (RP2D) of omacetaxine in combination with venetoclax for patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome harboring a RUNX1 mutation. (Phase 1b) II. To determine the efficacy of omacetaxine in combination with venetoclax for patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome harboring a RUNX1 mutation. (Phase II)

SECONDARY OBJECTIVES:

I. To determine duration of response (DOR), event-free survival (EFS), and overall survival (OS).

II. To evaluate occurrence of minimal residual disease (MRD) negative status by multiparameter flow cytometry and molecular evaluation.

EXPLORATORY OBJECTIVE:

I. To investigate global gene expression profiles, deoxyribonucleic acid (DNA) methylation profiles, BH3 profiling and other potential prognostic markers to explore predictors of antitumor activity and/or resistance to treatment.

OUTLINE: This is a phase I, dose de-escalation study followed by a phase II study.

Patients receive omacetaxine subcutaneously (SC) twice daily (BID) on days 2-3 or 2-4, and venetoclax orally (PO) on days 1-7, 1-10 or 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days, then every 3 months for 3 years.

Eligibility Criteria:
Inclusion Criteria:

* Patients with a diagnosis of relapsed or refractory acute myeloid leukemia (AML) (or biphenotypic or bilineage leukemia including a myeloid component) or myelodysplastic syndrome
* For myelodysplastic syndrome (MDS) patients, patients must have no response, progression, or relapse following at least 4 cycles of azacytidine or decitabine; and/or intolerance defined as grade \>= 3 drug-related toxicity precluding continued therapy
* Age \>= 18 years
* Subjects must have documented RUNX1 gene mutation
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
* Creatinine \< 2 unless related to the disease
* Direct bilirubin \< 2x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement
* Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \< 3x ULN unless considered due to leukemic involvement
* In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 7 days for cytotoxic or non-cytotoxic (i.e. immunotherapy) agents. Oral hydroxyurea and/or cytarabine (up to 2 g/m\^2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the principal investigator (PI)
* Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug
* Willing and able to provide informed consent

Exclusion Criteria:

* Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British \[FAB\] class M3-AML)
* Patients with any concurrent uncontrolled clinically significant medical condition including active infection or psychiatric illness, which could place the patient at unacceptable risk of study treatment
* Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant (patients without active GVHD on chronic suppressive immunosuppression and/or phototherapy for chronic skin GVHD are permitted after discussion with the PI)
* Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications
* Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or known human immunodeficiency virus (HIV) infection
* Subject has a white blood cell count \> 25 x 10\^9/L. (Note: Hydroxyurea is permitted to meet this criterion.)
* Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception

  * Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide)