Dose-Expansion Study of Low Dose Post-Transplant Cyclophosphamide/Tacrolimus/Ruxolitinib for Graft-versus-Host Disease (GVHD) Prophylaxis in Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation

Inclusion Criteria:

• Age 18.0 years or older at the time of enrollment

• Patients undergoing allogeneic hematopoietic cell transplantation for one of thefollowing indications:

• Acute leukemia with no circulating blasts and with less than 5% blasts in thebone marrow

• 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).

• Planned myeloablative (MAC) conditioning regimen (see eligible regimens inSection 9.2)

• Patients must have a related or unrelated peripheral blood stem cell donor asfollows:

• 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.

• Unrelated donor must be an 8/8 match at HLA-A, -B, -C and -DRB1 at highresolution using DNA-based typing.

Unrelated donor must be willing to donate peripheral blood stem cells and meet National Marrow Donor Program (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 (C-G formula)

• Pulmonary function: DLCO (diffusing capacity of lung for carbon monoxide) correctedfor hemoglobin at least 60% and FEV1 (forced expiratory volume at one second)predicted at least 60%

• Liver function: AST(Aspartate aminotransferase)/ALT(Alanine aminotransferase) <3xUpper Limit of Normal (ULN); Total bilirubin <2 mg/dL excluding Gilbert's syndromeor hemolysis

• Karnofsky Performance Score at least 70%.

• Female patients (unless postmenopausal for at least 1 year before the screeningvisit, or surgically sterilized), agree to practice two (2) effective methods ofcontraception at the same time, or agree to completely abstain from heterosexualintercourse, from the time of signing the informed consent through 12 monthspost-transplant.

• Male patients (even if surgically sterilized), of partners of women of childbearingpotential must agree to one of the following: practice effective barriercontraception or abstain from heterosexual intercourse from the time of signing theinformed consent through 12 months post-transplant.

• Plans for the use of targeted small molecule inhibitor post-transplant maintenancetherapy must be disclosed upon enrollment. Planned use of investigationalmaintenance agents is not permitted. Planned hypomethylating agents as maintenancetherapy is not permitted.

Allowed maintenance includes:

• FLT3 inhibitors: gilteritinib, sorafenib, midostaurin

• IDH inhibitors: enasidenib, ivosidenib

• BCR/ABL inhibitors: imatinib, ponatinib, dasatinib, nilotinib

• Other targeted therapies may be discussed with protocol chairsVoluntary writtenconsent obtained prior to the performance of any study-related procedure thatis not a part of standard medical care, with the understanding that consent maybe withdrawn by the patient at any time without prejudice to future medicalcare.

• There are no restrictions based on blood counts as this intervention is beingused in combination with intensive chemotherapy with intent to myeloablate.

Exclusion Criteria:

• Prior allogeneic transplant

• Active CNS (central nervous system) involvement by malignant cells

• Patients with secondary acute myeloid leukemia arising from myeloproliferativeneoplasms or overlap syndromes, including CMML(chronic myelomonocytic leukemia) andMDS/MPN (myelodysplastic syndromes/myeloproliferative neoplasms) syndromes; patientswith secondary acute myeloid leukemia arising from myelodysplastic neoplasm areeligible.

• Patients with uncontrolled bacterial, viral, or fungal infections (currently takingmedication and with progression or no clinical improvement) at time of enrollment.

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

• Patients seropositive for human immunodeficiency virus (HIV) with detectable viralload. HIV+ patients with an undetectable viral load on antiviral therapy areeligible.

• 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 (polymerase chain reaction) forplasma HCV RNA below the lower limit of detection, with or without concurrentantiviral HCV treatment.

• Arterial or venous thrombosis including DVT (deep vein thrombois), PE (pulmonaryembolism), stroke, and myocardial infarction within six (6) months prior toenrollment or New York Heart Association (NYHA) Class III or IV heart failure,uncontrolled angina, severe uncontrolled ventricular arrhythmias, orelectrocardiographic evidence of acute ischemia. Catheter-associated DVT is notexclusionary.

• Female patients who are pregnant or lactating

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

• Patients with prior malignancies except resected non-melanoma skin cancer or treatedcervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previouslywill be allowed. Cancer treated with curative intent < 5 years previously must bereviewed and approved by the Protocol Officer or Chairs, qualifying as below.

• the participant has been disease-free for at least 2 years and is deemed by theinvestigator 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 duringthe course of study and follow-up

• the only prior malignancy was cervical cancer in situ and/or basal cell orsquamous cell carcinoma of the skin

• 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

• History of congenital Long QT syndrome