This phase II trial studies how well total-body irradiation, donor lymphocyte infusion, and cyclophosphamide before donor stem cell transplant works in treating patients with high-risk hematologic malignancies. Giving total-body irradiation, donor lymphocyte infusion, and chemotherapy before a donor stem cell transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When certain stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Removing the T cells from the donor cells before transplant and giving tacrolimus and mycophenolate mofetil may stop this from happening.

PRIMARY OBJECTIVES:

1) To assess 1 year relapse free survival in high risk patients undergoing hematopoietic stem cell transplant (HSCT) using the Thomas Jefferson University (TJU) 2 step approach with 2 days inserted between the last fraction of total-body irradiation (TBI) and the infusion of donor T cells (donor lymphocyte infusion [DLI]).

SECONDARY OBJECTIVES:

1. To assess regimen related toxicity in this updated conditioning regimen, graft-versus-host disease (GVHD) incidence and severity, and overall survival in patients undergoing treatment on this protocol.
2. To assess the consistency and pace of engraftment.
3. To assess the pace of T cell and B cell immune recovery.

OUTLINE:

CONDITIONING REGIMEN: Patients undergo TBI twice daily (BID) on days -10 to -8, undergo DLI on day -6, and receive cyclophosphamide intravenously (IV) over 2 hours on days -3 and -2.

TRANSPLANT: Patients undergo cluster of differentiation (CD) 34+ selected allogeneic HSCT on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV or orally (PO) beginning on day -1 with taper beginning by day 42, and mycophenolate mofetil IV BID on days -1 to 28.

After completion of study treatment, patients are followed up for 1 year.

Inclusion Criteria:

1. This treatment is for patients with high risk hematologic malignancies. High risk is defined as:

   • Any patient with a hematologic malignancy with residual disease after treatment with 1 or more chemotherapy regimens in whom achievement of remission with additional chemoradiotherapy is felt to be unlikely
   • Patients without morphologic evidence of disease but with high risk features which would predict for relapse despite remission at HSCT such as adverse cytogenetics, 3rd or greater CR (complete response), or failure to recover peripheral blood counts to normal ranges. While these patients do not have detectable disease by current methods, like all patients they have non-detectable disease which in their case is highly aggressive.

2. Patients must have one related donor who is HLA (human leukocyte antigen) mismatched in the GVHD direction at two or more HLA loci

3. Patients must adequate organ function:

   • LVEF (left ventricular ejection fraction) of >50 %
   • Diffusing capacity of the lungs for carbon monoxide (DLCO) (adjusted for hemoglobin) >50 % of predicted and forced expiration to the full FEV-1 >50 %
   • Adequate liver function as defined by a serum bilirubin <1.8, AST (aspartate aminotransferase) or ALT (alanine aminotransferase) < 2.5X upper limit of normal
   • Creatinine clearance of > 60 ml/min

4. Karnofsky Performance Status (KPS) of > 80% on the modified (KPS) tool

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

6. Able to give informed consent

Exclusion Criteria:

1. Modified (KPS) Karnofsky Performance status of <80%
2. > 5 Comorbidity Points on the Hematopoietic cell transplantation - specific comorbidity (HCT-CI) Index (See Appendix B)
3. Class I or II antibodies against donor human leukocyte antigens (HLA)
4. HIV positive
5. Active involvement of the central nervous system with malignancy
6. Psychiatric disorder that would preclude patients from signing an informed consent
7. Pregnancy, or unwillingness to use contraception if they have child bearing potential
8. Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder
9. Alemtuzumab treatment within 8 weeks of HSCT admission
10. Anti-thymocyte globulin (ATG) level of > 2 ugm/ml
11. Patients with active inflammatory processes including T max >101 or active tissue inflammation are excluded
12. Inability to tolerate cyclophosphamide or undergo total body irradiation at the doses specified in the treatment plan