Inclusion Criteria:
* Age ≥18 years.
* Patients with a history of a hematologic malignancy with a planned myeloablative conditioning (MAC) peripheral blood allogeneic HCT.
a. Note: Patients with acute leukemia must be in morphologic complete remission with or without hematologic recovery with ≤5% blasts in the bone marrow. Patients with Chronic Myelomonocytic Leukemia (CMML) must have a white blood cell (WBC) count ≤10,000 cells/µL and ≤5% blasts in the marrow. Patients with ≥5% blasts due to a regenerating marrow must contact the protocol chairs for review. Patients with a diagnosis of myelofibrosis require sponsor approval before enrolling.
* Patients must be receiving an allograft from a suitable HLA-matched sibling or (7/8 or 8/8) unrelated donor according to transplant center's guidelines (for selection of appropriate donor).
* The following laboratory values obtained ≤14 days prior to registration/randomization:
1. Total bilirubin ≤1.5 x ULN or total bilirubin ≤3.0 x the Upper Limit of Normal (ULN) in the presence of Gilbert's syndrome. If total bilirubin is abnormal (≥1.5 x ULN), assess direct bilirubin. NOTE: Patients with Gilbert Syndrome and elevated baseline unconjugated (indirect) bilirubin up to 3.0 mg/dL are eligible. Gilbert syndrome should be confirmed by the presence of UGT1A1\*28 variant.
2. Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤2.5 x ULN).
3. Calculated creatinine clearance ≥30 mL/min using the Cockcroft-Gault formula below:
Creatinine clearance for males = (140 - age)(weight in kg) /(72)(serum creatinine in mg⁄dL) Creatinine clearance for females = (140 - age)(weight in kg) (0.85) /(72)(serum creatinine in mg⁄dL)
* Negative serum pregnancy test done ≤7 days prior to registration/randomization, for persons of childbearing potential only.
* Sexually active patients and their partners must use an effective method of contraception associated with a low failure rate prior to study entry and for the duration of study participation and for at least 3 months after the last dose of study drug.
a. Note: The following are considered effective contraceptives: oral contraceptive pill; condom plus spermicide; diaphragm plus spermicide; patient or partner surgically sterile; patient or partner more than 12 months postmenopausal; or injectable or implantable agent/device. Male patients should refrain from sperm donation and female patients should refrain from breastfeeding throughout this period.
* Ability to understand and provide written informed consent at the time of initial study enrollment. Participants who later lose decisional capacity may remain on study with consent from a legally authorized representative (LAR), as applicable.
* Willingness to provide mandatory blood and bone marrow aspirate specimens for correlative research.
* Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
Exclusion Criteria:
* Any of the following because this study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effect on the developing fetus and newborn are unknown:
1. Pregnant persons.
2. Nursing persons.
3. Persons of childbearing potential, and persons able to father a child, who are unwilling to employ adequate contraception.
* Any of the following current or prior therapies:
1. Patients receiving a cord blood transplant.
2. Patients undergoing a T-cell depleted allogeneic transplantation (using ex vivo CD34 selection, or with serotherapy \[antithymocyte globulin or alemtuzumab\]).
3. Patients undergoing a second allogeneic transplant (after a previous allogeneic transplant).
4. Pre-planned treatment with JAK1/JAK2 inhibitor after transplant.
5. Previous exposure to axatilimab.
6. Receiving an investigational treatment ≤28 days prior to registration/randomization.
7. Major surgery ≤3 weeks prior to registration/randomization.
8. Chemotherapy ≤2 weeks prior to registration/randomization unless chemotherapy is part of the pre-transplant conditioning.
9. Radiation therapy ≤2 weeks prior to registration/randomization unless radiation is part of the pre-transplant conditioning.
10. Planned use of Donor Lymphocyte Infusion (DLI) therapy.
11. Exception: Use of maintenance regimens as routine clinical care will be permitted but must be declared prior to registration/randomization. The trial does not restrict subsequent treatment after meeting the GFS endpoint.
* Active central nervous system (CNS) involvement by malignant cells.
* Leukemia involvement in the CNS ≤4 weeks of registration for patients with a history of prior CNS leukemia involvement (i.e., leukemic blasts previously detected in the cerebral spinal fluid).
* History of acute or chronic pancreatitis.
* History of myositis.
* Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
* Patients with active hepatitis B or C.
a. Patients with a history of hepatitis B or C are allowed if HBV DNA or HCV RNA are undetectable.
* Any known infection with human immunodeficiency virus (HIV), HTLV-1.
* Uncontrolled bacterial, viral, or fungal infections (currently taking medication and with progression or no clinical improvement) at the time of registration/randomization.
* Psychiatric illness/social situations that would limit compliance with study requirements.
* Diagnosed with another malignancy (other than malignancy for which transplant was performed) ≤ 3 years of registration/randomization, unless previously treated with curative intent and approved by PI (e.g., but not limited to completely resected basal cell, squamous cell, or ductal carcinoma in situ, or low-risk prostate cancer after curative resection or on watchful waiting). In patients with transformed disease (e.g. aggressive lymphoma evolving from CLL, or acute leukemia from MDS), the original hematological disorder is not considered an exclusion. Cancer treated with curative intent \<3 years previously will not be allowed unless approved by any of the Study Chairs.
* History of myocardial infarction ≤6 months, or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia.
