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

• One Year Relapse-Free Survival [ Time Frame: one year ] [ Designated as safety issue: No ]

  To assess one year relapse-free survival (RFS) in patients undergoing HSCT (hematopoietic stem cell transplantation) using the TJU 2 step-approach with two donors.

  Survival will be estimated by the Kaplan-Meier method. All estimates of rates will be presented with corresponding confidence intervals. For 1 year RFS rates, the method of Atkinson and Brown will be used to allow for the two-stage design; otherwise the method of Conover.

  
  

• Chimerism assessment [ Time Frame: one year ] [ Designated as safety issue: No ]
  To assess chimerism to ascertain whether one donor is emerging as dominant at regular intervals beginning at the time of engraftment.
  
  
• Assessment of dominance [ Time Frame: one year ] [ Designated as safety issue: No ]
  If dominance is observed, to compare the 2 donors with regard to degree of HLA mismatch, KIR types, 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, NK cell, or other cellular subsets prior to emerging in the graft as a whole.
  
  
• Relapse rates [ Time Frame: One Year ] [ Designated as safety issue: No ]
  To assess if establishment of a dominant donor versus persistent chimerism of both donors is associated with a lower relapse rate.
  
  
• Engraftment [ Time Frame: One Year ] [ Designated as safety issue: No ]
  To assess the consistency and pace of engraftment of both donors.
  
  
• Immune Reconstitution [ Time Frame: one year ] [ Designated as safety issue: No ]
  Assess T and B cell Reconstitution
  
  
• Non-relapse morbidity and mortality [ Time Frame: One year ] [ Designated as safety issue: Yes ]
  Assessment of regimen related toxicity, GVHD incidence and severity, and overall survival.
  
  
• Tolerance of DLI [ Time Frame: 2-6 days prior to transplant ] [ Designated as safety issue: Yes ]
  Assessment of 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
  
  
• Assessment for tumor escape mechanisms [ Time Frame: one year post transplant ] [ Designated as safety issue: No ]
  To test for loss of one or both HLA haplotypes in patients who relapse post-transplant and examine the relapse in the context of the characteristics of the 2 donors
  
  

At Jefferson, a 2 step process of performing bone marrow transplants (HSCT) was developed in 2005. In this process, subjects are given their donor cells at 2 different times. First, after receiving radiation and/or chemotherapy to help their immune system accept donor cells and further fight their disease, subjects receive a specific amount of donor T cells. (Step 1 of the HSCT). The donor T cells fight the cancer and help the subject fight infection and accept a new immune system. Donor T cells can also irritate the tissues of the subject's body, especially their skin, gut, and liver. This condition can be life threatening and is called graft versus host disease or GVHD. To decrease the incidence and severity of GVHD, after the subjects receive their donor's T cells, they are given a drug called cyclophosphamide (CY). This drug eliminates the most active donor T cells, but leaves behind some T cells to help fight infection. Step 2 of the HSCT occurs when the subject receives their donor's stem cells to help their blood counts recover.

There have been low rates of serious GVHD and toxicity using the 2 step approach. Over 100 transplants (using 1 donor) have been performed at TJUH using this method. Patients who go to transplant while their disease is under control have had good outcomes. However, subjects whose disease is active at the time of the HSCT (especially subjects with acute leukemia) have had a high incidence of relapsing after HSCT. Relapse after HSCT usually results in death. There have not been any significant advances in the field regarding improving outcomes for subjects with disease at HSCT.

The rationale for the current study is as follows. Transplants using donor cells work not just because the subject receives chemotherapy and radiation therapy, but because the donor cells themselves can recognize the cancer when it tries to come back and eradicate it. This is called a graft versus tumor effect or GVT. Therefore the recognition of the tumor by the donor cells is key to the prevention of relapse and long term survival. When a subject relapses after HSCT, it is because the cancer cells were able to avoid recognition by the new donor immune system. In this research study, the investigators will use two donors instead of one. Our hypothesis is that the cells from two donors will have a better chance at recognizing and eradicating the malignancy than cells from one donor.