This phase I trial studies the side effects and best dose of total bone marrow and lymphoid irradiation when given together with chemotherapy before donor stem cell transplant in treating patients with myelodysplastic syndrome or acute leukemia. Total marrow and lymphoid irradiation is a type of radiation therapy that targets bone marrow and blood, where the cancer is, instead of applying radiation to the whole body. Stem cell transplants use high doses of chemotherapy and radiation therapy, such as total marrow and lymphoid irradiation, to kill cancer cells, but these treatments kill normal cells as well. After chemotherapy, healthy cells from a donor are given to the patient to help the patient grow new blood cells.

PRIMARY OBJECTIVES:

I. To establish safety and determine the maximum tolerated dose of total marrow and lymphoid irradiation when given in combination with fludarabine (fludarabine phosphate) and pre-post-transplant cyclophosphamide, as conditioning for haploidentical hematopoietic cell transplantation (HCT) in patients with high-risk acute lymphocytic or myelogenous leukemia or intermediate/high-risk myelodysplastic syndrome.

II. To evaluate the safety of the regimen at each dose level by assessing adverse events: type, frequency, severity, attribution, time course, duration.

III. To evaluate the safety of the regimen at each dose level by assessing complications: including acute/chronic graft-versus-host disease (GvHD), infection and delayed engraftment.

SECONDARY OBJECTIVES:

I. To estimate overall survival (OS), progression-free survival (PFS), cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at +100 Days, 1 year and 2 years.

II. To characterize minimal residual disease from bone marrow aspirates on Days +30, +100, +180 post-transplant and describe in relation to total marrow and lymphoid irradiation (TMLI) dose level and patient disease status.

III. To describe the kinetics of immune cell recovery in the first year post-transplantation.

OUTLINE: This is a dose-escalation study of TMLI.

CONDITIONING: Patients undergo TMLI twice daily (BID) on days -7 to -4 or -3 (depending on the dose level). Patients also receive fludarabine phosphate intravenously (IV) on days -7 to -3 and cyclophosphamide IV on days -7, -6, 3, and 4.

TRANSPLANT: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.

GHVD PROPHYLAXIS: Patients receive tacrolimus* IV once daily (QD) or orally (PO) BID on days 5-180. Patients also receive mycophenolate mofetil PO thrice daily (TID) or IV on days 5-35. Treatment with tacrolimus and mycophenolate mofetil may continue in the presence of active GVHD.

*NOTE: Patients intolerant of tacrolimus may receive cyclosporine.

After completion of study treatment, patients are followed up twice weekly for 100 days, twice monthly until 6 months, monthly until the patient is off immunosuppressive therapy without evidence of GVHD, and then at least yearly for a total of 5 years.

Inclusion Criteria:

• Eligible patients will have a histopathologically confirmed diagnosis of hematologic malignancy in one of the following categories:

  • Acute myelogenous leukemia

    • In first complete remission (CR1) with poor risk cytogenetics according to National Comprehensive Cancer Network (NCCN) guidelines for acute myeloid leukemia (AML): monosomal karyotype, -5, 5q-,-7,7q-, inv (3), t(3;3), t(6;9), t(9;22) and complex karyotypes (>= 3 unrelated abnormalities [abn]) and normal cytogenetics with fms-related tyrosine kinase 3 (FLT3)-internal tandem duplications (ITD) mutation
    • In pediatrics, all of the above and 11q23-non t(9;11)
    • In second complete remission (CR2) or third complete remission (CR3)
    • With chemosensitive primary refractory disease

  • Acute lymphocytic leukemia

    • In CR1 with poor risk cytogenetics:

      • For adults according to NCCN guidelines for acute lymphoblastic leukemia (ALL): hypoploidy (< 44 chromosomes); t(v;11q23): mixed lineage leukemia (MLL) rearranged; t(9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomal abnormalities); high white blood cell (WBC) at diagnosis (>= 30,000 for B lineage or >= 50,000 for T lineage)
      • For pediatrics t(9;22), intrachromosomal amplification of chromosome 21 (iAMP21)loss of 13q, and abnormal 17p

    • In CR2 or CR3

    • With chemosensitive primary refractory disease

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

• Karnofsky or Lansky performance status >= 80

• A pretreatment measured creatinine clearance (absolute value) of >= 50 ml/minute

• Serum bilirubin =< 2.0 mg/dl

• Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) =< 2.5 times the institutional upper limits of normal

• Ejection fraction measured by echocardiogram or multigated acquisition scan (MUGA) >= 50%

• Diffusing capacity of the lung for carbon monoxide (DLCO) and forced expiratory volume in one second (FEV1) > 60% predicted

• 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 and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately

• The recipient must have a related donor genotypically human leukocyte antigen (HLA)-A, B,C and DRB1 loci haploidentical to the recipient

• No HLA matched sibling or matched unrelated donor is available

• Patients should be off all previous intensive therapy, chemotherapy or radiotherapy for 3 weeks prior to commencing therapy on this study

  * (NOTE: Low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted; these include: hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors [TKIs]; FLT-3 inhibitors such as sorafenib, crenolanib, quizartinib, midostaurin can also be given up to 3 days before conditioning regimen)

• Adequate organ function

• All subjects must have the ability to understand and the willingness to sign a written informed consent

• Prior radiation therapy that would exclude the use of TMLI

DONOR ELIGIBILITY CRITERIA:

• DONOR: Age =< 60 years of age
• DONOR: For younger donors, no more than 20 mL bone marrow may be harvested per kg of donor body weight
• DONOR: Medical history and physical examination confirm good health status as defined by institutional standards
• DONOR: Seronegative for human immunodeficiency virus (HIV) antigen (Ag), HIV 1+2 antibody (Ab), human T-lymphotropic virus (HTLV) I/II Ab, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) (immunoglobulin [Ig]M and IgG), hepatitis C virus (HCV) Ab, rapid plasma reagin (RPR) for syphilis within 30 days of apheresis collection
• DONOR: Genotypically haploidentical as determined by HLA typing, preferably a non-maternal HLA haploidentical relative; eligible donors include biological parents, siblings or half siblings, or children
• DONOR: Female donors of child-bearing potential must have a negative serum or urine beta-human chorionic gonadotropin (HCG) test within three weeks of mobilization
• DONOR: The donor must have been informed of the investigational nature of this study and have signed a consent form in accordance with federal guidelines and the guidelines of the participating institution
• DONOR: Selection of a haploidentical donor will require absence of pre-existing donor-directed anti-HLA antibodies in the recipient

Exclusion Criteria:

• Patients should not have any uncontrolled illness including ongoing or active bacterial, viral or fungal infection

• Patients may not be receiving any other investigational agents, or concurrent biological, intensive chemotherapy, or radiation therapy for the previous three weeks from conditioning

  * (NOTE: Low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted; these include: hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors [TKIs]; FLT-3 inhibitors such as sorafenib, crenolanib, quizartinib, midostaurin can also be given up to 3 days before conditioning regimen)

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to any in the pre- or post-transplant regimen

• Pregnant women are excluded from this study

• Patients with other active malignancies are ineligible for this study, other than non-melanoma skin cancers

• The recipient has a medical problem or neurologic/psychiatric dysfunction which would impair his/her ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery which in the opinion of the principal investigator would place the recipient at unacceptable risk

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

• HLA-matched or partially matched (7/8 or 8/8) related or unrelated donor is available to donate

• Patients may not have received more than 3 prior regimens, where the regimen intent was to induce remission

• Patients treatment history may not include anti-CD33 monoclonal antibody therapy (e.g., SGN-CD33 or Mylotarg)

• Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

DONOR EXCLUSION CRITERIA:

• DONOR: Evidence of active infection
• DONOR: Medical or physical reason which makes the donor unlikely to tolerate or cooperate with growth factor therapy and leukapheresis
• DONOR: Factors which place the donor at increased risk for complications from leukapheresis or granulocyte-colony stimulating factor (G-CSF) therapy
• DONOR: HIV positive