Emapalumab With Post-Transplant Cyclophosphamide, Tacrolimus and Mycophenolate Mofetil for the Prevention of Graft-versus-Host Disease After Donor Reduced-Intensity Hematopoietic Cell Transplant

Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative

  * Assent, when appropriate, will be obtained per institutional guidelines
* Age: ≥ 18 years and ≤ 75 years

  * Note: Patients \> 70 years of age must have Karnofsky performance status ≥ 80% and HCT-comorbidity index (CI) ≤ 2
* Karnofsky performance status ≥ 70%
* Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in complete remission with bone marrow (BM) blast of \< 5%. AML must be negative for minimal residual disease (MRD-)
* Planned to undergo reduced-intensity conditioning (RIC) with either fludarabine/melphalan (Flu/Mel) or busulfan/fludarabine (Bu/Flu) regimens prior to an allogeneic HCT using a mobilized peripheral blood stem cell (PBMC) graft from an 8/8 match related/unrelated donor (A, B, C, DR by high resolution typing)
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless has Gilbert's disease)
* Aspartate aminotransferase (AST) ≤ 3.0 x ULN
* Alanine aminotransferase (ALT) ≤ 3.0 x ULN
* Creatinine clearance of ≥ 60 mL/min per 24-hour urine test or the Cockcroft-Gault formula
* Left ventricular ejection fraction (LVEF) ≥ 50%

  * Note: To be performed within 30 days prior to day 1 of protocol therapy
* Bazett's correction formula (QTcB) ≤ 480 ms
* If able to perform pulmonary function tests: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) (diffusion capacity) ≥ 50% of predicted (corrected for hemoglobin).
* If unable to perform pulmonary function tests: Oxygen (O2) saturation \> 92% on room air
* Seronegative for HIV antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative) OR

  * If seropositive for HIV, HCV or HBV, nucleic acid quantitation must be performed. Viral load must be undetectable
* Meets other institutional and federal requirements for infectious disease titer requirements

  * Note Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy
* QuantiFERON-TB Gold+

  * Administer tuberculosis prophylaxis to patients at risk for tuberculosis, or known to have a positive purified protein derivative (PPD) test result, or positive interferon gamma (IFNγ) release assay
* Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

  * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 180 days post-HCT

  * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)

Exclusion Criteria:

* Prior allogeneic HCT
* Other cancer therapies (chemotherapy, radiation, biologics) are not allowed within two weeks of starting HCT conditioning; however targeted agents for underlying hematologic malignancies may be continued up to one day before conditioning, including, but not limited to:

  * FLT3 inhibitors
  * IDH1/2 inhibitors
  * Menin inhibitors
  * ABL-BCR inhibitors
  * BCL-2 inhibitors
  * Hydroxyurea
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
* Psychological issues, no appropriate caregivers identified, or non-compliant to medication
* Clinically significant uncontrolled illness
* Active uncontrolled infections (bacterial, viral, fungal). Infections are considered controlled if appropriate therapy has been initiated and, at the time of screening, no signs of infection are present
* Other active malignancy
* Females only: Pregnant or breastfeeding
* Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)