The goal of this project is to improve means to prevent and treat chronic graft-versus-host disease (GVHD) which is the major determinant of late nonrelapse mortality following allogeneic stem cell transplantation. Currently 1,029 individuals survive 5 to 25 years after allogeneic transplantation at this Center. Among a cohort of 443 patients with chronic myelogenous leukemia in chronic phase transplanted since 1987 from HLA-identical sibling (n=251) or mismatched/unrelated (n=192) donors, late complications included: chronic GVHD (n=257), bacteremia (n=142 episodes), cataracts (n=119), lung disease (n=59), bone disease (n=50), and secondary neoplasms (n=10). Multivariate analysis confirmed a highly significant association of all infections developing after day 120 with chronic GVHD. Use of alternative donor marrow and use of corticosteroids before onset of chronic GVHD were also significant independent covariates. Accordingly, we propose four interrelated specific aims to improve morbidity-free survival: 1) Provide comprehensive follow-up to identify evolving late effects of transplant regimens; 2) Evaluate means to prevent chronic GVHD and steroid toxicity by prolonging the duration of cyclosporine (CSP) prophylaxis or by use of a novel regimen of CSP/rapamycin immunosuppression; 3) Improve treatment of chronic GVHD by selecting thalidomide, FK506, rapamycin, or mycophenolate mofetil from pilot studies for study in Phase III trials; 4) Evaluate new diagnostic and interventive methods to reduce other causes of posttransplant morbidity (e.g. cataract formation and bone disease) and determine in a placebo- controlled study of immunoglobulin prophylaxis whether infections and mortality can be reduced after unrelated donor transplantation. This project is the clinical hub providing continuous monitoring of a large number of transplant recipients for real time investigation of abnormalities of hematopoietic function, graft rejection and GVHD. Although long-term survival has improved in recent years, clinical study of chronic GVHD and late events is vital for further improvement in patient outcome.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA018221-25
Application #
6300145
Study Section
Project Start
2000-04-01
Project End
2001-03-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
25
Fiscal Year
2000
Total Cost
$326,368
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
Mielcarek, Marco; Storer, Barry E; Boeckh, Michael et al. (2009) Initial therapy of acute graft-versus-host disease with low-dose prednisone does not compromise patient outcomes. Blood 113:2888-94
Tseng, Li-Hui; Storer, Barry; Petersdorf, Effie et al. (2009) IL10 and IL10 receptor gene variation and outcomes after unrelated and related hematopoietic cell transplantation. Transplantation 87:704-10
Bensinger, W I (2009) Role of autologous and allogeneic stem cell transplantation in myeloma. Leukemia 23:442-8
Bensinger, William (2008) Stem-cell transplantation for multiple myeloma in the era of novel drugs. J Clin Oncol 26:480-92
Storek, Jan (2008) Immunological reconstitution after hematopoietic cell transplantation - its relation to the contents of the graft. Expert Opin Biol Ther 8:583-97
Bensinger, William I (2007) Is there still a role for allogeneic stem-cell transplantation in multiple myeloma? Best Pract Res Clin Haematol 20:783-95
Carpenter, Paul A; Hoffmeister, Paul; Chesnut 3rd, Charles H et al. (2007) Bisphosphonate therapy for reduced bone mineral density in children with chronic graft-versus-host disease. Biol Blood Marrow Transplant 13:683-90
Bensinger, William I (2007) Reduced intensity allogeneic stem cell transplantation in multiple myeloma. Front Biosci 12:4384-92
Zaucha, Renata E; Buckner, Dean C; Barnett, Todd et al. (2006) Modified total body irradiation as a planned second high-dose therapy with stem cell infusion for patients with bone-based malignancies. Int J Radiat Oncol Biol Phys 64:227-34
Alkindi, S; Deeg, J H; Flowers, M E D (2006) Recovery of normal autologous myelopoiesis after graft rejection following allogeneic bone marrow transplant for agnogenic myeloid metaplasia. Clin Lab Haematol 28:134-7

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