This phase II clinical trial evaluates whether a modified modality of conditioning reduces treatment-related mortality (TRM) in patients who undergo a hematopoietic stem cell transplant (HSCT) for a hematological malignancy. HSCT is a curative therapy for many hematopoietic malignancies, however this regimen results in higher rates of TRM than other forms of treatment. In recent years, less intense conditioning regimens with radiation and chemotherapy prior to HSCT have been developed. Radiation therapy uses high energy sources to kill cancer cells and shrink tumors while chemotherapy drugs like fludarabine and cyclophosphamide work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This study evaluates whether a two-step approach with lower-intensity regimens of these treatments prior to HSCT reduces the rate of TRM.

PRIMARY OBJECTIVE:

I. To assess the 2 year cumulative incidence of TRM in patients undergoing reduced intensity conditioning (RIC) haploidentical (HI) HSCT in this protocol.

SECONDARY OBJECTIVES:

I. To assess the 2 year cumulative incidence of relapse in patients undergoing RIC HI HSCT in this protocol.

II. To assess the consistency and pace of engraftment. III. To assess the pace of T cell and B cell immune recovery. IV. To assess the incidence and severity of graft versus host disease (GVHD).

OUTLINE: Patients are assigned to 1 of 2 cohorts.

RADIATION-BASED COHORT: Patients receive fludarabine intravenously (IV) on days -11, -10, -9, and -8, undergo total-body irradiation (TBI) twice a day (BID) on days -10 and -9, undergo donor lymphocyte infusion (DLI) on day -6, and receive cyclophosphamide IV on days -3 and -2. Patients begin tacrolimus and mycophenolate mofetil IV on day -1. Patients then undergo HSCT on day 0. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy/aspiration, imaging and blood sample collection throughout the study.

CHEMOTHERAPY-BASED COHORT: Patients receive fludarabine IV on days -11, -10, -9, and -8 and melphalan IV on days -10 and -9. Patients undergo TBI and DLI once on day -6. Patients receive cyclophosphamide IV on days -3 and -2 and begin tacrolimus and mycophenolate mofetil on day -1. Patients undergo HSCT on day 0. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy/aspiration, imaging and blood sample collection throughout the study.

After completion of study treatment, patients are followed for 2 years.

Inclusion Criteria:

• Radiation-based cohort diagnoses:

  • Acute myeloid leukemia
  • Acute lymphoid leukemia in remission
  • Myelodysplasia (MDS)
  • Chronic lymphocytic leukemia (CLL) with no or minimal lymph node involvement
  • Multiple myeloma
  • Chronic myeloid leukemia
  • Myelofibrosis
  • Myeloid malignancy not otherwise specified
  • Chronic myelomonocytic leukemia
  • Essential thrombocytopenia or polycythemia vera
  • T cell leukemia
  • T cell lymphoma without significant lymph node disease burden
  • Any hematological malignancy or dyscrasia not cited above in which HSCT is potentially curable
  • Any patient who has a hematological disease that would normally be treated on a myeloablative study, but is prevented from doing so by factors in their past medical history. Examples are patients with previous treatment with radiation therapy precluding total-body irradiation (TBI), or a past history of myeloablative therapy, precluding a 2nd myeloablative regimen.
  • Patients must have a donor who is one-haplotype mismatched (number of mismatches in either direction not considered)

• Chemotherapy-based cohort diagnoses:

  • Hodgkin or non-Hodgkin lymphoma
  • Small lymphocytic lymphoma/CLL
  • Any other diagnosis in which chemotherapy is thought to be superior to radiotherapy for treatment of the disease
  • Hematological malignancy in patients who cannot receive > 2 Gy radiation
  • Aplastic anemia and other non-malignant hematologic dyscrasias
  • Patients must have a donor who is one-haplotype mismatched (number of mismatches in either direction not considered)

• Human leukocyte antigen (HLA) identical cohort diagnoses:

  * Patients in this group will be treated in parallel to the radiation-based cohort or the chemotherapy-based group based on what category their diagnosis falls into. However, these patients will have HLA identical related donors (one-antigen cross-over event included).

• Left ventricular ejection fraction of >= 50%

• Diffusion lung capacity of oxygen >= 50% and forced expiratory volume at 1 second >= 50% of predicted corrected for hemoglobin

• Serum bilirubin =< 1.8

• Aspartate aminotransferase or alanine aminotransferase =< 2.5 x upper limit of normal

• Creatinine clearance of >= 60 mL/min

• Patients must have adequate Karnofsky performance status (KPS) and Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) scores:

  • Patients < age 60 years must have a KPS of >= 60% and an HCT-CI score of 5 or less
  • Patients aged 60 to 65 years must have a KPS of >= 60% and an HCT-CI score of 4 or less
  • Patients aged 66 to 69 years must have a KPS of 90% and an HCT-CI score of 3 or less
  • Patients aged 70 years or more must have a KPS of 90% and an HCT-CI score of 2 or less
  • (Patients with greater than the allowable HCT-CI points for age can be enrolled for trial with approval of the principal investigator (PI) and at least 1 co-investigator (CI) not on the primary care team of the patient). This is an adjustment to account for healthy patients who meet the spirit of this protocol but have histories that result in higher than guideline HCT-CI points. An example is a patient with a solid tumor malignancy in their remote history (adds 3 points to HCT-CI total) where the treatment for the malignancy occurred years to decades before and there has been complete recovery of toxicities

• Patients must be willing to use contraception if they have childbearing potential

• Patient or patient's guardian is able to give informed consent

• Patients should have a life expectancy of >= 6 months for reasons other than their underlying hematologic/oncologic disorder

• Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol

• Patients should not be:

  • Human immunodeficiency virus positive
  • Have active involvement of the central nervous system with malignancy. This can be documented by a normal neurological exam, magnetic resonance imaging (MRI) of the head, and/or a negative cerebral spinal fluid analysis

• Pregnant or breastfeeding