T-cell and B-cell Depletion in Allogeneic Peripheral Blood Stem Cell Transplantation
Study Details
Study Description
Brief 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.
Condition or Disease | Intervention/Treatment | Phase |
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|
Phase 3 |
Study Design
Outcome Measures
Primary Outcome Measures
- relapse []
- event-free survival []
- survival []
Secondary Outcome Measures
- clinical relevance of mHag-specific CTL responses for the GVL effect []
- Kinetics of NK-cel reconstitution []
- Differences in NK-cell repertoire []
- NK cell mediated anti tumor reactivity []
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patients with the diagnosis of:
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De novo acute myeloid leukaemia in first or second remission.
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Secondary acute myeloid leukaemia in first or second remission supervening after myelodysplastic syndrome or cytotoxic / immunosuppressive therapy.
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Acute lymphoblastic leukaemia in first or second remission.
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Myelodysplastic syndrome.
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Chronic myeloid leukaemia, patients who are candidate for SCT.
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Malignant lymphoma following relapse or first line therapy resistant.
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Aggressive mantle cell lymphoma in first complete remission.
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Age 18-65 years.
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WHO performance 0-1 (see appendix ).
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Availability of an HLA-identical sibling or HLA, A, B, DRB, DQB -identical VUD donor.
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Life expectancy > 3 months.
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Witnessed written informed consent.
Exclusion Criteria:
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Patients with severe cardiac dysfunction (NYHA-classification II-IV)
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Patients with severe pulmonary dysfunction (vital capacity or diffusion < 70% of predicted value).
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Patients with hepatic dysfunction, bilirubin or transaminases > 2.5 x upper normal limit
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Patients with renal dysfunction, serum creatinin > 150 umol/liter or clearance < 40 ml/minute.
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Patients with a history of moderate ore severe CNS disturbances and psychiatric problems.
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Prior treatment with chemotherapy, immunotherapy, radiation therapy or surgery within the last 3 weeks before entering the study.
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Patients with active uncontrolled infections.
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Patients who are poor medical risks because of non malignant systemic disease.
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Patients with severe coagulopathy.
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Patients to be known HIV positive.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | 476 Hematology, University Medical Centre St Radboud Nijmegen | Nijmegen | Netherlands | 6500 HB |
Sponsors and Collaborators
- Radboud University Medical Center
Investigators
- Principal Investigator: Nicolaas Schaap, MD, PhD, Radboud University Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
- Schaap N, Schattenberg A, Bär B, Preijers F, Geurts van Kessel A, van der Maazen R, de Boo T, de Witte T. Outcome of transplantation for standard-risk leukaemia with grafts depleted of lymphocytes after conditioning with an intensified regimen. Br J Haematol. 1997 Sep;98(3):750-9.
- Schaap N, Schattenberg A, Bär B, Preijers F, van de Wiel van Kemenade E, de Witte T. Induction of graft-versus-leukemia to prevent relapse after partially lymphocyte-depleted allogeneic bone marrow transplantation by pre-emptive donor leukocyte infusions. Leukemia. 2001 Sep;15(9):1339-46.
- Schattenberg A, Schaap N, Preijers F, van der Maazen R, de Witte T. Outcome of T cell-depleted transplantation after conditioning with an intensified regimen in patients aged 50 years or more is comparable with that in younger patients. Bone Marrow Transplant. 2000 Jul;26(1):17-22.
- PSCT10