• Overall survival at 6 month post relapse time point.
  

• Incidence and severity induced GvHD, proportion of DLI engrafement, peak chimerism, leukemia response at days post DLI, residual leukemia measured by patient chimerism, leukemia free survival from date relapse, safety of mismatched DLI procedure.
  

Other: Allogeneic Lymphocytes
N/A
Drug: Fludarabine
N/A
Drug: Cyclophosphamide
N/A
Drug: Methylprednisolone
N/A
Drug: Cyclosporine
N/A

Patients receiving allogeneic stem cell transplantation for hematological malignancies who suffer a relapse of their disease post-transplant have limited treatment options and a poor prognosis. With the exception of patients with chronic leukemias who may achieve prolonged remissions after donor lymphocyte infusions (DLIs), treatments using either chemotherapy or a DLI achieve less than a 10% median survival beyond 6 months. Most of these patients die of progressive leukemia, underlying the need for new therapeutic approaches.

HLA-mismatched DLIs appear to possess a more potent graft-versus-leukemia (GvL) effect. However, when given after an HLA-mismatched transplant DLIs have a high risk of causing graft-versus-host disease (GvHD) which can be severe. To reduce the risk of GvHD, infusions of mismatched lymphocytes from an alternative donor may be used to avoid permanent engraftment and associated risk of GvHD.

In this study, we propose to use a novel strategy to treat leukemias relapsing after HLA matched allogeneic stem cell transplantation by using haplo-identical DLIs to promote the associated antileukemic effect while minimizing the possibility of permanent engraftment and associated GvHD. To achieve only temporary engraftment and to promote disease control we will give cyclophosphamide and fludarabine immunosuppression prior to the DLI. We anticipate the infusion of HLA-mismatched donor lymphocytes in this setting will produce no detectible engraftment or only temporary engraftment, but may result in a strong GvL effect regardless of engraftment outcome. We will select patients for this protocol who fall into the worst category for post-transplant relapse. Specifically, we will enroll patients with acute leukemia or MDS relapsing within 6 months of transplant, of which less than 5% survive beyond a year from relapse.

The primary objective of this phase II clinical trial will be to evaluate the safety and efficacy of using a non-engraftment model and a lymphocytes infusion from a haplo-identical donor to treat relapsed disease following matched sibling stem cell transplantation in subjects who are not candidates for alternative treatment options.

We therefore propose this is a phase II clinical trial the primary objective of which is to evaluate the safety and efficacy of a novel non-myeloablative but highly immunosuppressive disease specific conditioning regimen and infusion of unmanipulated lymphocytes from a haplo-identical donor in subjects with relapsed disease following matched sibling stem cell transplantation who are not candidates for alternative treatment options.

The primary endpoint of this phase 2 study is survival at 6 month post-relapse of disease. Successful outcome of the study will be a survival 100% greater than the NHLBI historical 25% at 6 months.

Secondary endpoints will include: incidence and severity induced GvHD, proportion of DLI engraftment, peak chimerism, leukemia response at days post DLI, residual leukemia measured by patient chimerism, leukemia free survival from date relapse, safety of the mismatched DLI procedure.