Mismatched Donor Lymphocyte Infusions for Relapsed Disease Following Allogeneic Stem Cell Transplantation
Condition: Leukemia, Myeloid, Acute; Leukemia, Lymphoblastic, Acute; Leukemia, Myelocytic, Chronic
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Study type: Interventional

Summary: 
      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.

      Human leukocyte antigen (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 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.
    

Detailed description: 
      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 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 is to evaluate the safety and efficacy
      of an 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 of 100% greater than the National Heart
      Lung and Blood (NHLBI) historical 25% at 6-months.

      Secondary endpoints will include: incidence and severity of induced GvHD, proportion of DLI
      engraftment, peak chimerism, leukemia response at 21 days post DLI, residual leukemia
      measured by patient chimerism, leukemia free survival from date relapse, and safety of the
      mismatched DLI procedure.
    

Intervention name(s): Miltenyi Magnetic cell sorter for CD3
Intervention type(s): Device
Intervention description(s): Receipts will receive 1 x 10 to eighth power CD3 cells/kg of familial haploidentical positively selected cluster of differentiation 34 (CD34)+ stem cells from the same DLI donor.
Other intervention name(s): CliniMACS Miltenyi
Intervention model: Single Group Assignment
Intervention model description: The CliniMACS CD34 Reagent System is a medical device used in vitro to select and enrich specific cell populations (CD34+ cells from heterogeneous hematological cell populations). In stage 1, subjects will receive 1 x 108 CD3 cells/kg on day 0. We will progress to stage 2 where the dose of CD3+ cells will be increased to 2 x 108 cells/kg.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute Myelogenous Leukemia (AML); Acute Lymphoblastic Leukemia (ALL); Chronic Lymphocytic Leukemia; Myelodysplastic Syndrome (MDS); Acute Myelogenous Leukemia; AML; Acute Lymphoblastic Leukemia; ALL; Myelodysplastic Syndrome; MDS