Interim analysis has shown that the objectives of this study can not be reached

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.

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.