Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for many hematologic diseases, but development of serious immune mediated disorders after transplantation limits greater success. Although some immune mediated disorders are very rare (<1%), others such as acute and chronic grafl-versus-host disease (GVHD) are more common (30-50%) and cause high morbidity and mortality. Project 1 is a longitudinal study with the aim of better characterizing the incidence, characteristics, and outcomes of these disorders. We particularly focus on three syndromes with high morbidity and mortality: cutaneous sclerosis, bronchiolitis obliterans syndrome (BOS) and persistent, recurrent or late-onset acute GVHD (late acute GVHD). These syndromes have distinct clinical characteristics and respond poorly to currently available therapies. Based on our current knowledge about potential pathophysiology and response to treatments, we propose biomarker studies and clinical trials of targeted agents elsewhere in the grant proposal. Project 1 will enroll approximately 1000 patients before allogenic HCT who will be followed for two years to collect detailed data about any immune mediated disorders of interest that arise. In addition, research samples will be obtained to provide longitudinal biologic material on affected cases and samples from controls. We will use a subset of these research samples to validate and extend three biomarker models: the Ferrara model of 4 proteins associated with early acute GVHD, the Schultz model of 4 biomarkers associated with chronic GVHD, and the Weissinger urine proteomic patterns associated with acute and chronic GVHD. Since the criteria for positive and negative samples have been determined, we will be able to select purely informative the models. Project 1 is synergistic but not overlapping with a U01 funded observational trial limited to patients with chronic GVHD (2007-2012)

Public Health Relevance

Project 1 will collect observational clinical data and serial research specimens to achieve the following aims: 1. Characterize and more completely define the onset and course of key immune mediated disorders that are associated with high morbidity and/or mortality after allogeneic HCT. 2. Validate several biomarker models. This study will improve our understanding of these disorders and lead to better treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA163438-04
Application #
8380387
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
$382,256
Indirect Cost
$99,116
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Holtan, Shernan G; DeFor, Todd E; Panoskaltsis-Mortari, Angela et al. (2018) Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802. Blood Adv 2:1882-1888
Du, Jing; Flynn, Ryan; Paz, Katelyn et al. (2018) Murine chronic graft-versus-host disease proteome profiling discovers CCL15 as a novel biomarker in patients. Blood 131:1743-1754
Hamilton, Betty K; Rybicki, Lisa; Arai, Sally et al. (2018) Association of Socioeconomic Status with Chronic Graft-versus-Host Disease Outcomes. Biol Blood Marrow Transplant 24:393-399
Lee, Stephanie J; Nguyen, Tam D; Onstad, Lynn et al. (2018) Success of Immunosuppressive Treatments in Patients with Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 24:555-562
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
Arai, Sally; Pidala, Joseph; Pusic, Iskra et al. (2016) A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation. Clin Cancer Res 22:319-27
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
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
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

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