t-cell and b-cell depletion in allogeneic peripheral blood stem cell transplantation

Conditions: Leukemia, Myeloid; Leukemia, Lymphocytic; Myelodysplastic Syndrome; Leukemia, Myeloid, Chronic; Lymphoma

Summary: t-cell and b-cell depletion in allogeneic peripheral blood stem cell transplantation by using immunomagnetic negative and positive selection procedures background: removal of t-cells from the donor graft (t-cell depletion) offers the possibility for prevention of gvhd and subsequently less transplant related morbidity and mortality after allogeneic stem cell transplantation (sct). there are several techniques to deplete t-cells from the stem cell grafts e.g. physical, immunological and combined physical / immunological separation methods. all these techniques result in a stem cell graft with sufficient cd34+ stem cells combined with an adequate depletion of t and b cells. cd34+ selected stem cell grafts are very pure and do not contain any additional cell populations. in contrast, cd3+/cd19+ depleted grafts still contain nk-cells, monocytes and dendritic cells that are part of the innate immune system. theoretically,the presence of these cells may positively influence immunological reconstitution and the graft-versus-leukaemia (gvl) effect, respectively, resulting in improved outcome after sct objectives: to evaluate the differences in immunological reconstitution, transplant related mortality, disease-free survival and overall survival after t-cell depleted allogeneic sct for haematological malignancies using either immunomagnetic cd34+ selection or immunomagnetic cd3+/cd19+ depletion using the clinimacs system in approximately 270 consecutive patients. additionally in this study in 20 consecutive patients the kinetics of nk-cel reconstitution and differences in nk-cell repertoire will be monitored. nk-cell mediated anti-tumor reactivity will be monitored in patients transplanted with and without nk-cells in the stem cell graft (cd3+/cd19+ depletion, versus cd34+ selection). secondary objectives are to evaluate the clinical relevance of minor histocompatibility-specific cytotoxic t-cell responses for the gvl effect, the kinetics of nk-cell reconstitution and differences in nk-cell repertoire using the different t-cell depletion protocols. design: single center prospective randomised phase iii study population: patients eligible for allogeneic sct according to the standard criteria of our institution who will receive an allogeneic t- and b-cell depleted sct with peripheral stem cells of an hla-identical sibling donor or an hla-identical unrelated voluntary (vud) donor. intervention: t-cell depletion will be conducted using two different techniques: either immunomagnetic cd34+ selection or immunomagnetic cd3+/cd19+ depletion. endpoints: primary endpoints are immunological reconstitution, relapse, disease free survival and overall survival. secondary endpoints: nk-cell reconstitution and nk-cell mediated anti-tumour reactivity. cytotoxic t-cell responses for the gvl effect. estimated efforts and risks for participating patients: we don't expect any extra patient efforts or risks because t-cell depletion is a standard procedure in our clinic for many years. there is extensive experience with immunological t-cell depletion techniques. we hypothesize cd3+/cd19+ depletion will favour stem cell transplant outcome. immunological and molecular biological studies will be performed on blood samples already obtained as part of the standard protocol.


Eligibility criteria:
inclusion criteria: * patients with the diagnosis of: * de novo acute myeloid leukaemia in first or second remission. * secondary acute myeloid leukaemia in first or second remission supervening after myelodysplastic syndrome or cytotoxic / immunosuppressive therapy. * acute lymphoblastic leukaemia in first or second remission. * myelodysplastic syndrome. * chronic myeloid leukaemia, patients who are candidate for sct. * malignant lymphoma following relapse or first line therapy resistant. * aggressive mantle cell lymphoma in first complete remission. * age 18-65 years. * who performance 0-1 (see appendix ). * availability of an hla-identical sibling or hla, a, b, drb, dqb -identical vud donor. * life expectancy \> 3 months. * witnessed written informed consent. exclusion criteria: * patients with severe cardiac dysfunction (nyha-classification ii-iv) * patients with severe pulmonary dysfunction (vital capacity or diffusion \< 70% of predicted value). * patients with hepatic dysfunction, bilirubin or transaminases \> 2.5 x upper normal limit * patients with renal dysfunction, serum creatinin \> 150 umol/liter or clearance \< 40 ml/minute. * patients with a history of moderate ore severe cns disturbances and psychiatric problems. * prior treatment with chemotherapy, immunotherapy, radiation therapy or surgery within the last 3 weeks before entering the study. * patients with active uncontrolled infections. * patients who are poor medical risks because of non malignant systemic disease. * patients with severe coagulopathy. * patients to be known hiv positive.

Keywords: allogeneic stem cell transplantation t-cell depletion b-cell depletion immunomagnetic selection