A Two-Step Approach to Bone Marrow Transplant Using Cells From Two Partially-Matched Relatives

This phase II clinical trial studies how well two donors stem cell transplant work in treating patients with high-risk hematologic malignancies. After receiving radiation to help further treat the disease, patients receive a dose of donors' T cells. T cells can fight infection and react against cancer cells. Two days after donors' T cells are given, patients receive cyclophosphamide (CY) to help destroy the most active T cells that may cause tissue damage (called graft versus host disease or GVHD). Some of the less reactive T cells are not destroyed by CY and they remain in the patient to help fight infection. A few days after the CY is given, patients receive donors' stem cells to help their blood counts recover. Using two donors' stem cell transplant instead of one donor may be more effective in treating patients with high-risk disease and may prevent the disease from coming back.

PRIMARY OBJECTIVES:

I. To assess 1 year relapse free survival in patients undergoing hematopoietic stem cell transplant (HSCT) using the Thomas Jefferson University (TJU) 2 step approach using 2 donors.

SECONDARY OBJECTIVES:

I. To assess the consistency and pace of engraftment. II. To assess the pace of T cell and B cell immune recovery in patients in each arm.

III. To assess regimen related toxicity, graft-versus-host disease (GVHD) incidence and severity, and overall survival.

IV. To assess the tolerance of the period of fever, diarrhea, and rash after the introduction of second donor and qualitatively compare it to prior patient groups or concurrent patient groups.

V. To assess chimerism to ascertain whether one donor is emerging as dominant at regular intervals beginning at the time of engraftment.

VI. If dominance is observed, to compare the donors with regard to degree of human leukocyte antigen (HLA) mismatch, killer Ig-like receptor (KIR) types, cluster of differentiation (CD)34+ cell doses, infusion order, donor age, and donor alloreactivity points in an effort to identify potential biologic factors that predict for dominance. To determine if trends toward dominance occur in T cell, natural killer (NK) cell, or other cellular subsets prior to emerging in the graft as a whole.

VII. To assess if establishment of a dominant donor versus persistent chimerism of both donors is associated with a lower relapse rate.

VIII. To collect leukemia samples prior to transplant and after relapse whenever possible. To assess the overall degree of HLA-class I and class II expression on these paired samples. To test for loss of one or both HLA haplotypes in the relapsed tumor specimens. When observed, to correlate loss of one HLA haplotype with: a) receipt of a transplant capable of targeting only that haplotype; b) establishment of dominance in a 2 haplotype transplant such that the lost haplotype would be the primary target of the dominant donor; c) being the target of the donor predicted to be more alloreactive in a 2 haplotype transplant.

OUTLINE:

CONDITIONING: Patients undergo total-body irradiation (TBI) twice daily (BID) on days -9 to -6, undergo donor lymphocyte infusion (DLI) on day -6, and receive cyclophosphamide intravenously (IV) over 2 hours on days -3 and -2.

TRANSPLANTATION: Patients undergo CD34+ selected allogeneic HSCT on day 0.

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

After completion of study treatment, patients are followed up for 1 year, and then periodically thereafter.

Eligibility Criteria:
Inclusion Criteria:

1. Any patient with a hematologic malignancy with residual disease (morphological, cytogenetic, molecular, or radiographic) after treatment with 1 or more chemotherapy regimens in whom achievement of remission with additional chemoradiotherapy is felt to be unlikely or who is in 3rd or greater CR. Patients with marrow based diseases in which the marrow biopsy does not meet criteria for active disease (i.e. \<5% blasts in acute leukemia) but who does not have full count recovery will be eligible for treatment on this high risk trial.
2. Patients must have two related donors that meet an acceptable scenario as described above.
3. Patients must adequate organ function:

   * LVEF of \>= 50%
   * DLCO (adjusted for hemoglobin) \>= 50% of predicted
   * Adequate liver function as defined by a serum bilirubin =\< 1.8, AST or ALT \< 2.5X upper limit of normal
   * Creatinine clearance of \>= 60 ml/min
4. Karnofsky Performance Status of \> 80 % on the modified KPS tool (see Appendix A).
5. Patients must be willing to use contraception if they have childbearing potential.
6. Able to give informed consent

Exclusion Criteria:

1. Modified KPS of \< 80%
2. \>= 5 Comorbidity Points on the HCT-CI Index (See Appendix B)
3. Class I or II antibodies against donor HLA antigens
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. ATG level of \>= 2 ugm/ml
11. Patients with active inflammatory processes (such as flair of an autoimmune disease) 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.