After allogeneic hematopoietic cell transplantation (HCT), approximately 8% of patients develop a syndrome of cutaneous sclerosis which can severely affect their mobility and quality of life, and is often refractory to standard immune suppressive therapies. Recent clinical and translational data suggest that alloimmune B cells and in particular, agonistic antibodies against platelet derived growth factor receptor (PDGFR), may be responsible for cutaneous collagen deposition. We hypothesize that targeting this pathogenic mechanism using either rituximab (a FDA-approved humanized anti-CD20 antibody) to eliminate alloimmune B cells or imatinib (a FDA-approved tyrosine kinase inhibitor) to block PDGFR activity will effectively treat cutaneous sclerosis. To test this hypothesis, we propose a 70 patient two-arm phase II crossover trial of imatinib and rituximab to determine efficacy against HCT-associated cutaneous sclerosis. Correlative studies of skin biopsies and blood samples will confirm target specificity. Blood measurements include: 1) B cell subsets, 2) B cell stimulatory factors and 3) allo- and auto-antibody changes. Skin assays include: 1) phosphorylation status of PDGFR, ABL, and other tyrosine kinase receptors, 2) B cell infiltration, antibody deposition, and complement activation, 3) collagen deposition, and 4) gene expression studies. Ancillary studies will evaluate clinical assessment tools and patient-reported measures. This project will provide insights into the pathogenesis of and best treatment for HCT-associated cutaneous sclerosis.

Public Health Relevance

Cutaneous sclerosis (skin thickening causing decreased flexibility) poses a vexing clinical problem with high morbidity due to ineffective therapies. By treating 70 people with HCT-associated cutaneous sclerosis with either rituximab or imatinib and testing skin and blood samples, we hope to learn how to prevent the disease or develop better treatments. Knowledge gained from these studies may help us to treat other patients with sclerosis

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA163438-04
Application #
8380388
Study Section
Special Emphasis Panel (ZRG1-HOP-Y)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$209,152
Indirect Cost
$54,231
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Martin, Paul J; Storer, Barry E; Inamoto, Yoshihiro et al. (2017) An endpoint associated with clinical benefit after initial treatment of chronic graft-versus-host disease. Blood 130:360-367
Lee, Stephanie J (2017) Classification systems for chronic graft-versus-host disease. Blood 129:30-37
Lee, Stephanie J; Nguyen, Tam D; Onstad, Lynn et al. (2017) Success of Immunosuppressive Treatments in Patients with Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant :
Cheng, Guang-Shing; Storer, Barry; Chien, Jason W et al. (2016) Lung Function Trajectory in Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplant. Ann Am Thorac Soc 13:1932-1939
Lazaryan, Aleksandr; Weisdorf, Daniel J; DeFor, Todd et al. (2016) Risk Factors for Acute and Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation with Umbilical Cord Blood and Matched Sibling Donors. Biol Blood Marrow Transplant 22:134-40
Arora, Mukta; Cutler, Corey S; Jagasia, Madan H et al. (2016) Late Acute and Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 22:449-55
Holtan, Shernan G; Khera, Nandita; Levine, John E et al. (2016) Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors. Blood 128:2350-2358
Müller, J A; Zirafi, O; Roan, N R et al. (2016) Evaluation of EPI-X4 as a urinary peptide biomarker for diagnosis and prognosis of late acute GvHD. Bone Marrow Transplant 51:1137-9
Palmer, Jeanne; Chai, Xiaoyu; Pidala, Joseph et al. (2016) Predictors of survival, nonrelapse mortality, and failure-free survival in patients treated for chronic graft-versus-host disease. Blood 127:160-6
Williams, Kirsten M; Cheng, Guang-Shing; Pusic, Iskra et al. (2016) Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 22:710-716

Showing the most recent 10 out of 44 publications