Serial Analysis of Chimerism in Patients With Refractory Cytopenia (RC) Transplanted With Reduced Intensity Conditioning (RIC)
This is a prospective, non-randomized multi-center multi-national study to evaluate the chimerism measured by STR and SNP in patients with hypoplastic RC and normal karyotype transplanted with a preparative regimen of reduced intensity.
- To study hematopoietic chimerism in whole blood and different cell population (CD14, CD15, CD 56, CD3, CD19) as well as in dendritic cells and regulatory T-cells after SCT with RIC in patients with RC
- To compare the results of chimerism obtained with standard STR PCR (sensitivity 1%) with those obtained with SNP PCR (sensitivity 0.1- 0.01%)
- To evaluate the relationship between mixed chimerism and hematological engraftment, OS and EFS
- To study the impact of mixed chimerism in plasmacytoid dendritic and regulatory T-cells on the incidence of acute and chronic GVHD
Refractory Cytopenia of Childhood
Reduced Intensity Conditioning (RIC)
Myelodysplastic Syndrome (MDS)
Hematopoietic Stem Cell Transplantation (SCT)
|Study Design:||Time Perspective: Prospective|
|Official Title:||Serial Analysis of Chimerism in Patients With Refractory Cytopenia (RC) Transplanted With Reduced Intensity Conditioning (RIC) EWOG MDS SCT RC RIC-06|
- To study hematopoietic chimerism in whole blood and different cell population (CD14, CD15, CD 56, CD3, CD19) as well as in dendritic cells and regulatory T-cells after SCT with RIC in patients with RC [ Time Frame: 5 years ] [ Designated as safety issue: No ]
- To compare the results of chimerism obtained with standard STR PCR (sensitivity 1%) with those obtained with SNP PCR (sensitivity 0.1- 0.01%) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
- To evaluate the relationship between mixed chimerism and hematological engraftment, OS and EFS [ Time Frame: 5 years ] [ Designated as safety issue: No ]
- To study the impact of mixed chimerism in plasmacytoid dendritic and regulatory T-cells on the incidence of acute and chronic GVHD [ Time Frame: 5 years ] [ Designated as safety issue: No ]
Biospecimen Retention: Samples With DNA
Hematopoietic chimerism will be investigated from PB samples. Prior to transplant 5 ml EDTA PB from patient and donor are required and will be sent to the laboratory of the Coordinating Investigator (P.B.). Post transplant PB samples (5 -10 ml EDTA blood) from day +30 (4 days), +60(4 days), +100 (7 days) and +180 (7 days) will also being sent to the laboratory of the Coordinating Investigator (P.B.) From EDTA PB cell subpopulations will be isolated and DNA will be extracted and stored for further investigations.
|Study Start Date:||April 2007|
|Study Completion Date:||March 2013|
|Primary Completion Date:||March 2013 (Final data collection date for primary outcome measure)|
Research Question 3.1.1 Chimerism and post transplant outcome During the past 3 decades, SCT has become a well established treatment procedure for many malignant and hematopoietic disorders in children and adults.1-8 After transplantation, it has been of central interest whether the newly developed hematopoietic system is of recipient or donor origin. The investigations of the genotypic origin of post transplant hematopoiesis are called chimerism analysis. Originally, it was believed that complete donor hematopoiesis is essential to maintain engraftment after allogeneic SCT in humans.9 In the last decades, however, it became evident that donor and recipient hematopoiesis could coexist after allo-SCT in the recipient. This state of coexistence of hematopoietic cells is called mixed chimerism which might end in an "autologous recovery". In patients with refractory cytopenia SCT after myeloablative conditioning regimen allowed prompt and sustained engraftment in virtually all patients. In this disease relapse has become a very rare event. Consequently, transplant related mortality and long term squeals have become major obstacles yet to be overcome to improve the children's well being and the prognosis of the disease. In SCT with RIC, the reduction of early and late toxicity may be counterbalanced by delayed engraftment, graft rejection, mixed chimerism and GVHD.
Graft rejection It is well known that less myeloablative conditioning regimens predispose for a higher rate of mixed chimerism. Consequently, graft rejection or non engraftment is a major cause of treatment failure.
Sensitization to minor histocompatibility antigens by prior transfusions of blood products can increase this risk. The rapid development of complete chimerism in NK-cells and T-cells seems to play an important role to achieve sustained engraftment specifically in patients transplanted with a dose reduced preparative regimen. Therefore, it is important to elucidate the development of post transplant chimerism in different cell subpopulations. This will allow following and documenting proper engraftment, and will detect early hints of ongoing graft rejection.
Graft versus host disease The occurrence of GVHD is influenced by many well known factors. Although the use of nonmyeloablative SCT can reduce the severity of GVHD, GVHD remains a major complication. In our pilot study using the reduced intensity preparative regimen in RC, the probability for developing GVHD grade IIIV was 0.48. It is accepted that in comparison to myeloablative SCT, in reduced intensity preparative regimens higher proportions of host immune hematopoietic cells may persist. While donor-derived alloreactive lymphocytes are being infused, these autologous cells might possibly serve as host antigen presentation for continuous stimulation of donor T-cells. Consequently, it was speculated by the group Shapira and Slavin10 that GVHD may be similarly amplified by reduced conditioning followed by intentional administration of host cells. This hypothesis was tested in a preclinical animal model. Increased incidence of GVHD, higher mortality and increased levels of chimerism were observed in recipients reconstituted with additional host cells, particularly with non-irradiated spleen cells. Graft-versus-Leukaemia (GVL) effect was not impaired by post transplant cell administration. These results suggested that GVHD may be amplified by recipient cell infusion using either irradiated or viable stimulatory host cells. This could possibly explain the higher than anticipated incidence of GVHD and consequently the rapid displacement of host cells with conversion to 100% donor type cells in reduced intensity SCT. The present study will therefore investigate whether autologous antigen presenting cells (Auto-APC) do survive the conditioning regimen and favour to occurrence of GVHD.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00682799
|University Children´s Hospital|
|Frankfurt am Main, Hessen, Germany, 60590|
|Principal Investigator:||Peter Bader, M.D.||University Children´s Hospital Frankfurt am Main|