A Study of Tacrolimus/Methotrexate/Ruxolitinib Versus Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in Non-Myeloablative/Reduced Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation (BMT CTN 2203)

Inclusion Criteria:

• Age 18.0 years or older at the time of enrollment.

• Participants undergoing allogeneic HCT for one of the following indications:

• Acute leukemia or chronic myelogenous leukemia with no circulating blasts andwith less than 5% blasts in the bone marrow. Therapy related myeloid neoplasmsare allowed.

• Myelodysplasia/chronic myelomonocytic leukemia with no circulating blasts andwith less than 10% blasts in the bone marrow (higher blast percentage allowedin MDS due to lack of differences in outcomes with < 5% versus 5-10% blasts inthis disease). Therapy related myeloid neoplasms are allowed.

• Lymphoma [follicular lymphoma, Hodgkin lymphoma, diffuse large B cell lymphoma,mantle cell lymphoma, peripheral T-cell lymphoma, angioimmunoblastic T-celllymphoma and anaplastic large cell lymphoma].

• Planned NMA/reduced intensity conditioning regimen.

• Participants must have a related or unrelated PBSC donor as follows:

• Sibling donor must be a 6/6 match for HLA-A and -B at intermediate (or higher)resolution, and -DRB1 at high resolution using DNA-based typing and must bewilling to donate peripheral blood stem cells and meet institutional criteriafor donation. HLA-matched parents and children may be used as donors.

• Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C and -DRB1 at highresolution using DNA-based typing. Unrelated donor must be willing to donateperipheral blood stem cells and meet NMDP criteria for donation.

• Donor selection must comply with 21 CFR 1271.

• Cardiac function: Left ventricular ejection fraction at least 45%.

• Estimated creatinine clearance greater than 60 ml/min using the 2021 CKD-EPI formulaor 24-hour urine creatinine clearance.

• Pulmonary function: DLCO corrected for hemoglobin at least 40% and FEV1 predicted atleast 50%.

• Liver function: AST/ALT < 3x ULN; Total bilirubin < 2 mg/dL excluding Gilbert'ssyndrome or hemolysis.

• Karnofsky Performance Score of at least 60%.

• Female participants (unless postmenopausal for at least one year before thescreening visit, or surgically sterilized), agree to practice two effective methodsof contraception at the same time, or agree to completely abstain from heterosexualintercourse, from the time of signing the informed consent through 15 monthspost-transplant. Fertility preservation methods will be left to institutionalstandards.

• Male participants (even if surgically sterilized), of partners of women ofchildbearing potential must agree to one of the following: practice effectivebarrier contraception or abstain from heterosexual intercourse from the time ofsigning the informed consent through 15 months post-transplant.

• Plans for the use of targeted small molecule inhibitor post-transplant maintenancetherapy must be disclosed upon enrollment and must be used irrespective of theoutcome of the randomization. Planned use of investigational maintenance agents isnot permitted. Planned hypomethylating agents as maintenance therapy is notpermitted.

• Voluntary written consent obtained prior to the performance of any study-relatedprocedure that is not a part of standard medical care, with the understanding thatconsent may be withdrawn by the participant at any time without prejudice to futuremedical care.

Exclusion Criteria:

• Prior allogeneic transplant.

• Active CNS involvement by malignant cells.

• Participants with secondary AML arising from myeloproliferative neoplasms or overlapsyndromes, including CMML and MDS/MPN syndromes; participants with secondary AMLarising from myelodysplastic neoplasm are eligible.

• Participants with primary myelofibrosis.

• Participants with uncontrolled bacterial, viral, or fungal infections (currentlytaking medication and with progression or no clinical improvement) at time ofenrollment.

• Active or inadequately treated latent infection with Mycobacterium tuberculosis (i.e., TB).

• Presence of clinically significant fluid collection (ascites, pleural or pericardialeffusion) that interferes with methotrexate clearance or makes methotrexate usecontraindicated.

• Participants seropositive for human immunodeficiency virus (HIV) with detectableviral load. HIV+ participants with an undetectable viral load on antiviral therapyare eligible.

• Evidence of uncontrolled hepatitis B virus (HBV) or hepatitis C virus (HCV). Thestudy allows:

• Positive HBV serology with undetectable viral load and ongoing antiviralprophylaxis to prevent potential HBV reactivation.

• Positive HCV serology with quantitative PCR for plasma HCV RNA below the lowerlimit of detection, with or without concurrent antiviral HCV treatment.

• Arterial or venous thrombosis including DVT, PE, stroke, and myocardial infarctionwithin six (6) months prior to enrollment or New York Heart Association (NYHA) ClassIII or IV heart failure, uncontrolled angina, severe uncontrolled ventriculararrhythmias, or electrocardiographic evidence of acute ischemia. Catheter-associatedDVT is not exclusionary.

• Female participants who are pregnant (as per institutional practice) or lactating.

• Participants with a serious medical or psychiatric illness likely to interfere withparticipation in this clinical study.

• Participants with prior malignancies except resected non-melanoma skin cancer ortreated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 yearspreviously will be allowed. Cancer treated with curative intent < 5 years previouslymust be reviewed and approved by the Protocol Officer or Chairs.

• Planned use of ATG or alemtuzumab in conditioning regimen.

• Planned use of prophylactic donor leukocyte infusions.

• Prior use of ruxolitinib.

• Prior use of immune checkpoint inhibitors (i.e., PD1, PDL1, CTLA4 modulators) withinsix (6) months prior to conditioning.

• For participants with 7/8 HLA-matched donors:

• Donor specific antibodies (DSAs) directed at the mismatched donor allele.

• Any use of desensitization protocols.

• Treatment with any other Investigational Medicinal Product (IMP) is not allowedwhile on study treatment. An IMP is defined as medications without any known FDA orEMA approved indications.