Cytokine Induced Killer (CIK) Cells In Leukemia Patients (CIK2)

Sequential Infusion of Unmanipulated Donor Lymphocytes and Cytokine Induced Killer (CIK)Cells After Allogeneic Stem Cell Transplantation

The purpose of the Phase IIA study are to: define the safety profile evaluate the efficacy of a sequential infusion of unmanipulated Donor Lymphocyte Infusions (DLI) and Cytokine Induced Killer (CIK) cells for the treatment of molecular, cytogenetic or hematologic relapse after hematopoietic stem cell transplantation and The progression free survival and the overall survival after the sequential infusion of Donor Lymphocyte Infusions (DLI) and Cytokine Induced Killer(CIK) cells.

This study is an open-label, multicenter, exploratory phase IIA study to evaluate the safety (dose-finding) and efficacy of a sequential administration of donor derived unmanipulated DLI and in vitro expanded Cytokine Induced Killer(CIK) cells. Two infusions of unmanipulated donor lymphocytes (1x106/Kg each) will be given with a minimum interval of 3 weeks. Three infusions of donor Cytokine Induced Killer (CIK) cells will be administered according to a dose escalating program, starting 3 weeks after second Donor Lymphocyte Infusions (DLI). In presence of grade 2 or more acute graft versus host disease(GVHD), the patient will not receive the next scheduled infusion. Only grade 4 acute graft versus host disease (aGVHD) is considered for the dose limiting toxicity (DLT). Once identified the maximally tolerated dose (MTD), this same combination of doses will be administered up to 24 patients in a two-stage minimax design. Primary Endpoints The primary endpoints of the Phase IIA study are: the Maximally Tolerated Dose (MTD) - (safety end-point) the cumulative incidence of molecular, karyotypic or haematologic responses at day +100 after the end of the cell therapy program - (efficacy end-point) Secondary Endpoints Progression Free Survival (PFS) Progression Free Survival (PFS) will be defined as any evidence of molecular, cytogenetic or haematologic disease progression. Cytogenetic and/or molecular relapse will be defined where available as any evidence of a pre-transplant defined abnormality using conventional cytogenetics or FISH techniques or molecular probes. Assessments will be performed at 1 year after the end of the cell therapy program Overall Survival (OS) The Overall Survival(OS) will be assessed by 1 year after the end of the cell therapy program. For assessment of the Overall Survival (OS), events will be deaths for any causes, patients being censored if alive.

patients will be offered Cytokine Induced Killer(CIK) cells., Four combinations of escalating Cytokine Induced Killer (CIK) cells infusions will be provided, until the MTD will be defined., Combination 1st CIK cells infusion 2nd CIK cells infusion 3rd CIK cells infusion, 1 1x106/Kg 1x106/Kg 5x106/kg, 2 1x106/Kg 5x106/kg 5x106/kg, 3 1x106/Kg 5x106/kg 10x106/kg, 4 5x106/kg 5x106/kg 10x106/kg

Three infusions of donor Cytokine Induced Killer (CIK) cells will be administered according to a dose escalating program, starting 3 weeks after second Donor Lymphocyte Infusions (DLI). Cytokine Induced Killer administrations will be separated by 3 weeks intervals

The occurrence of a grade 4 acute graft versus host disease (GVHD), judged to be related to the study medication. Grading and staging will be performed using the Glucksberg scale

The proportion of patients achieving a complete, a partial or a hematologic improvement in responses to the experimental infusion of cytokine induced killer (CIK)cells

The clinical response will be registered at day +100 after the last Cytokine Induced Killer (CIK) cell infusion

Inclusion Criteria: Patients with haematologic malignancies (excluding chronic myeloid Leukemia- CML) with a molecular, cytogenetic or haematologic relapse after allogeneic transplantation. Patients with an available donor willing to donate peripheral blood lymphocytes Immunosuppression must be withdrawn at the beginning of the cell therapy program Written informed consent prior to any study procedures being performed Exclusion Criteria: Donors positive for HIV, HBV or HCV, or unfit to undergo leukapheresis Patients with active acute or chronic Graft versus host disease (GvHD) Patients with rapidly progressive disease or not controlled by palliative supportive treatments including chemotherapy and with a life expectancy less than 8 weeks Patients with severe psychiatric illness or any disorder that compromises ability to give truly informed consent for participation in this study

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