Hematopoietic cell transplantation (HCT) has curative potential for individuals with sickle cell disease. While the results of conventional HCT have been good, this treatment carries risks of significant short- term and longterm toxicities. For this reason, HCT has been reserved for children who have experienced severe symptoms that predict a poor outcome. Of interest, some patients developed stable donor-host hematopoietic chimerism after conventional HCT. Due to a natural enrichment of donor erythrocytes in the blood, those who developed stable chimerism had a significant clinical benefit, even when there was a minority of donor cells. These observations have paralleled efforts to develop less-toxic, non-myeloablative preparative regiments for transplantation, proved first in a canine model of transplantation, and subsequently translated successfully in a clinical trial for older adults with hematological malignancies. Thus, this proposal, based on these supporting pre-clinical and clinical investigations, aims to investigate a modified transplant procedure for sickle cell disease that significantly reduces the toxicity of HCT, yet retains its therapeutic benefit. This is a novel approach, conducted in the outpatient setting, which will rely upon the ability to establish and maintain donorhost chimerism. It will be achieved by combining less toxic, non-myeloablative pre-transplant therapy with modulated post-grafting immuno-suppression aimed at controlling host-versus-graft and graft-versus-host reactions. This investigation will employ an existing network of collaborative sickle cell and transplant centers to identify and enroll eligible patients. The primary endpoint of stable donor cell engraftment will be determined and secondary endpoints to measure the impact on sickle cell-related symptoms and end-organ damage will be followed. If successful, this novel approach will expand the availability of HCT for patients with clinically significant hemoglobinopathies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL068091-03
Application #
6608590
Study Section
Special Emphasis Panel (ZRG1-CCVS (02))
Program Officer
Harvath, Liana
Project Start
2001-08-25
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
3
Fiscal Year
2003
Total Cost
$526,886
Indirect Cost
Name
Children's Hospital & Res Ctr at Oakland
Department
Type
DUNS #
076536184
City
Oakland
State
CA
Country
United States
Zip Code
94609
Walters, Mark C; Hardy, Karen; Edwards, Sandie et al. (2010) Pulmonary, gonadal, and central nervous system status after bone marrow transplantation for sickle cell disease. Biol Blood Marrow Transplant 16:263-72
Eggleston, B; Patience, M; Edwards, S et al. (2007) Effect of myeloablative bone marrow transplantation on growth in children with sickle cell anaemia: results of the multicenter study of haematopoietic cell transplantation for sickle cell anaemia. Br J Haematol 136:673-6
Horan, J T; Liesveld, J L; Fenton, P et al. (2005) Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin. Bone Marrow Transplant 35:171-7
Iannone, Robert; Casella, James F; Fuchs, Ephraim J et al. (2003) Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. Biol Blood Marrow Transplant 9:519-28
Atkins, Robert C; Walters, Mark C (2003) Haematopoietic cell transplantation in the treatment of sickle cell disease. Expert Opin Biol Ther 3:1215-24
Walters, M C; Patience, M; Leisenring, W et al. (2001) Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant 7:665-73