Graft Versus Host Disease-Reduction Strategies for Donor Blood Stem Cell Transplant Patients With Acute Leukemia or Myelodysplastic Syndrome (MDS)

Inclusion Criteria:

• Patients who are considered appropriate candidates for myeloablative, TBI-containingallogeneic hematopoietic stem cell transplantation and have one of the followingdiagnoses:

• Acute lymphocytic leukemia (ALL) in first or subsequent morphological remission (< 5% marrow blasts by morphology).

• Acute myeloid leukemia (AML) in first or subsequent morphological remission (< 5% marrow blasts by morphology).

• Other acute leukemia or related neoplasm (including but not limited to 'mixedphenotype' 'biphenotypic', 'acute undifferentiated' or 'ambiguous lineage'acute leukemia, blastic plasmacytoid dendritic cell neoplasm, lymphoblasticlymphoma, Burkitt leukemia/lymphoma, mast cell leukemia, chronic myeloidleukemia [CML] with blast crisis or other chronic myeloproliferative neoplasm)in first or subsequent morphological remission (<5% marrow blasts bymorphology).

• Myelodysplastic syndrome (MDS) with a history of excess blasts (≥ approximately 5% in marrow blasts by morphology) and a history of receiving cytoreductivetherapy (including but not limited to BCL-2 inhibitors or cytotoxicchemotherapy) within the past 3 months.

• Patient age 1-60 years old (inclusive) at the time of informed consent

• Patients aged 1-50 years old (inclusive) are eligible for TBI-basedconditioning regimens.

• Patients aged 1-60 years old (inclusive) are eligible for busulfan-basedconditioning regimens (with or without TBI 4 Gy).

• Patient with an HLA-matched (HLA-A, B, C, DRB1, and DQB1 matched) related orunrelated donor capable of donating PBSC.

• Recipient informed consent/assent and/or legal guardian permission must be obtained.

• DONOR: HLA-matched related and unrelated donors (HLA-A, B, C, DRB1 and DQB1 matchedbased on high-resolution typing).

• DONOR: >= 18 years old.

• DONOR: Willing to donate PBSC.

• DONOR: Matched related donors:

• Must give informed consent using the related donor informed consent form.

• Must meet institutional donor eligibility criteria or be ineligible withstatement that the donor is a first or second degree relative (exception 21Code of Federal Regulations [CFR] 1271.65(b)(i)).

• DONOR: Matched unrelated donors:

• Must consent according to the applicable National Marrow Donor Program (NMDP)donor regulatory requirements.

• Must meet eligibility criteria as defined by the NMDP or be ineligible withstatement of urgent medical need (exception 21 CFR 1271.65(b)(iii)).

Exclusion Criteria:

• Patients with central nervous system (CNS) involvement refractory to intrathecalchemotherapy and/or standard cranial-spinal radiation. A patient may have a historyof CNS disease. However, any CNS disease must be cleared by the end of thepre-conditioning evaluation time frame. If CNS disease is identified oncerebrospinal fluid (CSF) evaluation within 30 days of the start of the preparativeregimen a repeat CSF evaluation must be performed and show no evidence of disease inorder for the patient to be eligible for the protocol.

• Patients on other experimental protocols for prevention of GVHD.

• Patient weight:

• Patients with HLA-matched related donors will be excluded if they weigh >= 110kg.

• Patients with HLA-matched unrelated donors will be excluded if they weigh >= 110 kg and must be discussed with the Fred Hutch protocol principalinvestigator (PI) if they weigh >= 90 kg.

• Patients who are positive for human immunodeficiency virus (HIV)-1, HIV-2, humanT-cell lymphotropic virus (HTLV)1 or HTLV2.

• Patients with uncontrolled infections for whom myeloablative HCT is consideredcontraindicated by the consulting infectious disease physician; i.e. patients withactive infections require infectious disease consultation and documentation by theinfectious disease team that myeloablative HCT is not considered to becontraindicated. Upper respiratory tract infection is not considered to represent anuncontrolled infection in this context.

• Patients with organ dysfunction, including:

• Renal insufficiency (creatinine > 1.5 mg/dl) at the time of evaluation for theprotocol. Patients with a known history of creatinine > 1.5 mg/dl or a currentserum creatinine above the normal range for age must have a current creatinineclearance of > 60 ml/min/1.73 m^2 (measured by 24-hr urine specimen or nuclearglomerular filtration rate [GFR]).

• Left ventricular ejection fraction < 45%.

• Carbon monoxide diffusing capability (DLCO) corrected < 60%. Patients who areunable to perform pulmonary function tests (for example, due to young ageand/or developmental status) will be excluded if the oxygen (O2) saturation is < 92% on room air.

• Liver function abnormality. Patients who have liver function test (LFT)s (specifically, total bilirubin, aspartate aminotransferase [AST] or alanineaminotransferase [ALT]) >= twice the upper limit of normal should be evaluatedby a gastrointestinal (GI) physician unless there is a clear precipitatingfactor (such as an azole, MTX, trimethoprim-sulfamethoxazole, or another drug).If the GI physician considers that HCT on the protocol is contraindicated, thatpatient will be excluded from the protocol. Patients with Gilbert's syndromerequire GI physician consultation but may be included on the protocol. Patientswith no other known liver function abnormality or with reversible drug-relatedtransaminitis do not necessarily require GI consultation and may be included onthe protocol.

• Patients who have received previous myeloablative allogeneic or autologoustransplantation.

• Patients with a life expectancy < 12 months from co-existing disease other than theleukemia or MDS.

• Patients who are pregnant or breast-feeding.

• Patients of childbearing age who are presumed to be fertile and are unwilling to usean effective birth control method or refrain from sexual intercourse during and for 12 months post-HCT.

• Patients with any other significant medical conditions that would make themunsuitable for transplantation, as determined by the PI.

• Patients with a known hypersensitivity to tacrolimus or MTX

• Patients who have received checkpoint inhibitors within three months oftransplantation unless an exception is made by the PI

• DONOR: Donors who are HIV-1, HIV-2, HTLV-1, HTLV-2 seropositive or with activehepatitis B or hepatitis C virus infection. Test must be performed using Food andDrug Administration (FDA) licensed, cleared, and approved test kits (serologicaland/or nucleic acid amplification test [NAT] and/or other approved testing) in aClinical Laboratory Improvement Act (CLIA)-certified laboratory.

• Unrelated donors donating outside of the USA.