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 the following indications:

  * Acute leukemia with no circulating blasts and with less than 5% blasts in the bone marrow
  * Myelodysplasia/chronic myelomonocytic leukemia with no circulating blasts and with less than 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with \<5% versus 5-10% blasts in this disease).

    * Planned myeloablative (MAC) conditioning regimen (see eligible regimens in Section 9.2)
* Patients must have a related or unrelated peripheral blood stem cell 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 be willing to donate peripheral blood stem cells and meet institutional criteria for donation.
  * Unrelated donor must be an 8/8 match at HLA-A, -B, -C and -DRB1 at high resolution 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) corrected for hemoglobin at least 60% and FEV1 (forced expiratory volume at one second) predicted at least 60%
* Liver function: AST(Aspartate aminotransferase)/ALT(Alanine aminotransferase) \<3x Upper Limit of Normal (ULN); Total bilirubin \<2 mg/dL excluding Gilbert's syndrome or hemolysis
* Karnofsky Performance Score at least 70%.
* Female patients (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two (2) effective methods of contraception at the same time, or agree to completely abstain from heterosexual intercourse, from the time of signing the informed consent through 12 months post-transplant.
* Male patients (even if surgically sterilized), of partners of women of childbearing potential must agree to one of the following: practice effective barrier contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant.
* Plans for the use of targeted small molecule inhibitor post-transplant maintenance therapy must be disclosed upon enrollment. Planned use of investigational maintenance agents is not permitted. Planned hypomethylating agents as maintenance therapy 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 written consent obtained prior to the performance of any study-related procedure that is not a part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
  * There are no restrictions based on blood counts as this intervention is being used 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 myeloproliferative neoplasms or overlap syndromes, including CMML(chronic myelomonocytic leukemia) and MDS/MPN (myelodysplastic syndromes/myeloproliferative neoplasms) syndromes; patients with secondary acute myeloid leukemia arising from myelodysplastic neoplasm are eligible.
* Patients with uncontrolled bacterial, viral, or fungal infections (currently taking medication 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 viral load. HIV+ patients with an undetectable viral load on antiviral therapy are eligible.
* Evidence of uncontrolled hepatitis B virus (HBV) or hepatitis C virus (HCV). The study allows:

  * Positive HBV serology with undetectable viral load and ongoing antiviral prophylaxis to prevent potential HBV reactivation.
  * Positive HCV serology with quantitative PCR (polymerase chain reaction) for plasma HCV RNA below the lower limit of detection, with or without concurrent antiviral HCV treatment.
* Arterial or venous thrombosis including DVT (deep vein thrombois), PE (pulmonary embolism), stroke, and myocardial infarction within six (6) months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia. Catheter-associated DVT is not exclusionary.
* Female patients who are pregnant or lactating
* Patients with a serious medical or psychiatric illness likely to interfere with participation in this clinical study
* Patients with prior malignancies except resected non-melanoma skin cancer or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent \< 5 years previously must be reviewed 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 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
* 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) within six (6) months prior to conditioning
* History of congenital Long QT syndrome