Total Marrow and Lymphoid Irradiation, Fludarabine, and Melphalan Before Donor Stem Cell Transplant in Treating Participants With High-Risk Acute Leukemia or Myelodysplastic Syndrome

Inclusion Criteria:

• Eligible patients with a histopathological confirmed diagnosis of hematologicmalignancy in one of the following categories:

• Acute myelogenous leukemia:

• Patients with de novo or secondary disease in unfavorable risk groupincluding poor risk cytogenetics according to National ComprehensiveCancer Network (NCCN) guidelines for AML i.e., monosomal karyotype, -5, 5q-, -7, 7q-, 11q23-non t (9;11), inv (3), t (3;3),t (6;9), t (9;22) andcomplex karyotypes (≥ 3 unrelated abnormalities), or all patient inintermediate risk groups accept patients with FLT3-NPM1+ disease

• Patients with active disease

• Patients with chemosensitive active disease

• Acute lymphocytic leukemia:

• Patients with de novo or secondary disease according to NCCN guidelinesfor ALL hypoploidy (< 44 chromosomes); t (v;11q23): MLL rearranged; t (9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomalabnormalities); high white blood cell (WBC) at diagnosis (≥ 30,000 for Blineage or ≥ 50,000 for T lineage); iAMP21loss of 13q, and abnormal 17p

• Patients with active disease

• Patients with chemosensitive active disease

• Myelodysplastic syndrome in high-intermediate (int-2) and high risk categories

• Patients ≥ 12 years and < 55 years are also included if they are not candidates formyeloablative conditioning regimens due to comorbidities

• Karnofsky or Lansky performance status of ≥ 70

• A pretreatment measured creatinine clearance (absolute value) of ≥ 60 ml/minute

• Patients must have a serum bilirubin ≤ 2.0 mg/dl

• Serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvictransaminase (SGPT) ≤ 2.5 times the institutional upper limits of normal

• Ejection fraction measured by echocardiogram or multigated acquisition (MUGA) ≥ 50%

• Carbon monoxide diffusing capacity (DLCO) and forced expiratory volume FEV1 > 50%predicted

• PATIENT-SPECIFIC INCLUSION CRITERIA

• Patients should have discontinued all previous intensive therapy, chemotherapy orradiotherapy for 2 weeks prior to commencing therapy on this study

• NOTE: low dose chemotherapy or maintenance chemotherapy given within 7 days ofplanned study enrollment is permitted; these include hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosinekinase inhibitors (TKIs); FLT-3 inhibitors can also be given up to 3 daysbefore conditioning regimen

• All patients with prior radiation treatment to the lung, liver, and kidney willbe excluded; for other scenarios of prior radiation treatment, up to 2000 cGYat 2 gray Gy per day will be allowed; inclusion of patients with previousradiation exposure will be determined based on the radiation oncologist MDevaluation and judgment

• DONOR: Arm A: All candidates for this study must have an human leukocyte antigen (HLA) (A, B, C, and DR) identical sibling who is willing to donate primed blood stemcells (preferred) or bone marrow, or have a 10/10 (A, B, C, DR and DQ) allelematched unrelated donor; DQ or DP mismatch is allowed per discretion of theprincipal investigator

• DONOR: Arm B: The recipient must have a related donor genotypically HLA-A, B, C andDRB1 loci haploidentical to the recipient; no HLA matched sibling or matchedunrelated donor is available; DSA is allowed with desensitization done ifrecommended by donor selection committee (DSC) per City of Hope (COH) standardoperating procedures (SOP)

• DONOR: Both arms: All donors in both arms should be evaluated and approved by DSC

Exclusion Criteria:

• Having any uncontrolled illness including ongoing or active bacterial, viral orfungal infection

• Receiving any investigational agents or concurrent biological, intensivechemotherapy or radiation therapy for the previous 2 weeks from conditioning

• NOTE: low dose chemotherapy or maintenance chemotherapy given within 7 days ofplanned study enrollment is permitted; these include: hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosinekinase inhibitors (TKIs), FLT-3 inhibitors can also be given up to 3 daysbefore conditioning regimen

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to any in the regimen

• Patients with other malignancies are ineligible for this study, other thannon-melanoma skin cancers

• The recipient has another medical problem or neurologic/psychiatric dysfunctionwhich would impair his/her ability to be compliant with the medical regimen and totolerate transplantation or would prolong hematologic recovery in which the opinionof the principal investigator would place the recipient at unacceptable risk

• Patients may not have had a prior autologous or allogeneic transplant

• Patients may not have received more than 3 prior lines of intensive chemotherapy,where the regimen intent was to induce remission

• In the opinion of the principal investigator (PI), the participant has a conditionthat will preclude them from complying with study treatment

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry andfor six months following duration of study participation; should a woman becomepregnant or suspect that she is pregnant while participating on the trial, sheshould inform her treating physician immediately

• All subjects must have the ability to understand and the willingness to sign awritten informed consent; they are to give voluntary written informed consent beforeperformance if any study-related procedure not part of normal medical care, with theunderstanding that consent may be withdrawn by the subject at any time withoutprejudice to future medical care; cognitively impaired subjects will be includedonly if their guardian or legal representative agrees to sign the written informedconsent

• DONOR: Donor selection for both arms must be approved by the donor selectioncommittee

• DONOR: Evidence of active infection

• DONOR: Medical or physical reason which makes the donor unlikely to tolerate orcooperate with growth factor therapy or leukapheresis

• DONOR: Factors which place the donor at increased risk for complications fromleukapheresis or granulocyte-colony stimulating factor (G-CSF) therapy could beharvested for bone marrow (BM) if safer for the donor and if approved by theprincipal investigator (PI)

• DONOR: Human immunodeficiency virus (HIV) positive