Ziftomenib for the Treatment of Patients with Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, and Myelodysplastic Syndrome Following Donor Hematopoietic Cell Transplant

Inclusion Criteria

• Age ≥ 18 years
• Pathologically confirmed diagnosis of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) or myelodysplastic syndrome (MDS)
• For participants with AML or ALL, disease status of complete remission (CR) or complete remission with incomplete count recovery (CRi) at screening. * Complete remission (CR): ** No circulating blasts in peripheral blood and < 5% blasts in bone marrow ** No extramedullary disease ** Platelet count ≥ 100 x 10^9/L and/or absolute neutrophil count ≥ 1000/uL * Complete remission with incomplete count recovery (CRi) ** No circulating blasts in peripheral blood and < 5% blasts in bone marrow ** No extramedullary disease ** Platelet count < 100 x 10^9/L and/or absolute neutrophil count < 1000/uL
• For participants with MDS, disease status no circulating blasts and <10% blasts in the bone marrow at screening
• Presence of at least one of the following molecular mutations: * KMT2A rearrangement ** Eligibility and enrollment will be based on local mutational testing ** The presence of a KMT2A rearrangement (excluding partial tandem duplication [PTD]) at the time of initial diagnosis or any other time thereafter is sufficient ** Participants may receive additional treatment for AML between consent and transplant * NPM1 mutation ** Eligibility and enrollment will be based on local mutational testing ** For participants being transplanted in complete remission 1 (CR1), the presence of a NPM1 mutation after 2 cycles of chemotherapy (e.g., induction + 1 cycle of consolidation, or 2 cycles of hypomethylating agent-based therapy, etc.) is necessary for the purposes of eligibility ** For participants being transplanted in ≥ complete remission 2 (CR2) or beyond, the presence of a NPM1 mutation at the time of consent is not necessary for eligibility and its presence at the time of initial diagnosis or any other time thereafter is sufficient ** Participants may receive additional treatment for disease between consent and transplant * NUP98 gene fusions ** Eligibility and enrollment will be based on local mutational testing ** The presence of a NUP98 gene fusion at the time of initial diagnosis or any other time thereafter is sufficient ** Participants may receive additional treatment for disease between consent and transplant * UBTF tandem duplications ** Eligibility and enrollment will be based on local mutational testing ** The presence of a UBTF8 tandem duplication at the time of initial diagnosis or any other time thereafter is sufficient ** Participants may receive additional treatment for disease between consent and transplant
• Treatment with a menin inhibitor prior to transplant is permitted. However, patients who experienced disease relapse or progression while being treated with a menin inhibitor prior to transplant are ineligible
• Will undergo first allogeneic HCT for their malignancy
• Transplantation will be performed with the use of conventional myeloablative (MAC) or reduced intensity conditioning (RIC)
• HCT Donor will be one of the following: * 5/6 or 6/6 (histocompatibility antigen [HLA]-A, B, DR) matched related donor * 7/8 or 8/8 (HLA-A, B, DR, C) matched unrelated donor. Matching in the unrelated setting must be at the allele level. * Haploidentical related donor, defined as ≥ 3/6 (HLA-A, B, DR) matched * ≥ 4/6 (HLA-A, B, DR) umbilical cord blood (UCB). Matching in the UCB setting is at the antigen level. Recipients may receive either one or two UCB units. In the case of 2 UCB units, both units must have been at least 4/6 matched with the recipient
• Any non-investigational GVHD prophylaxis regimen is allowed
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) and alkaline phosphatase < 3 x institutional upper limit of normal (ULN)
• Total bilirubin < 1.5 x institutional ULN (with the exception of subjects with a history of Gilbert’s syndrome, for which the total bilirubin must be < 5 x ULN)
• Calculated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula)
• Left ventricular ejection fraction (LVEF) must be ≥ 50%, as measured by multigated acquisition (MUGA) scan or echocardiogram
• Female patients of childbearing potential must have a negative pregnancy test, as measured by serum or urine testing
• The effects of ziftomenib on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during the entire study treatment period and through 6 months after the last dose of treatment
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• History of other malignancy(ies) unless * The participant has been disease-free for at least 2 years and is deemed by the investigator to be at low risk of recurrence of that malignancy, or * The cancer has been deemed indolent with no progression over the last 2 years, and deemed by the investigator to be at low risk for further progression during the course of study and follow-up * The only prior malignancy was cervical cancer in situ and/or basal cell or squamous cell carcinoma of the skin
• Known diagnosis of active hepatitis B or hepatitis C
• Current or history of congestive heart failure New York Heart Association (NHYA) class 3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF < 50%, as measured by MUGA scan or echocardiogram)
• Current or history of ventricular or life-threatening arrhythmias or diagnosis of long-QT syndrome
• Systemic uncontrolled infection
• Known dysphagia, short-gut syndrome, gastroparesis, or other condition(s) that limits the ingestion or gastrointestinal absorption of drugs administered orally
• Uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg)
• QTc interval (i.e., Friderica's correction [QTcF]) ≥ 480 ms or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) at screening
• Uncontrolled intercurrent illness that would limit compliance with study requirements
• Persons who are pregnant or lactating