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TNF-inhibition with etanercept for graft-versus-host disease prevention in high-risk HCT: lower TNFR1 levels correlate with better outcomes.

TitleTNF-inhibition with etanercept for graft-versus-host disease prevention in high-risk HCT: lower TNFR1 levels correlate with better outcomes.
Publication TypeJournal Article
Year of Publication2012
AuthorsChoi, SW, Stiff, P, Cooke, K, Ferrara, JLM, Braun, T, Kitko, C, Reddy, P, Yanik, G, Mineishi, S, Paczesny, S, Hanauer, DA, Pawarode, A, Peres, E, Rodriguez, T, Smith, S, Levine, JE
JournalBiol Blood Marrow Transplant
Date Published2012 Oct
KeywordsAdolescent, Adult, Child, Child, Preschool, Drug Administration Schedule, Female, Gene Expression, Graft vs Host Disease, Hematologic Neoplasms, Hematopoietic Stem Cell Transplantation, Histocompatibility Testing, Humans, Immunoglobulin G, Immunosuppressive Agents, Male, Middle Aged, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Severity of Illness Index, Survival Analysis, Tissue Donors, Transplantation Conditioning, Whole-Body Irradiation

Graft-versus-host disease (GVHD) causes most non-relapse mortality (NRM) after alternative donor (unrelated and mismatched related) hematopoietic cell transplant (HCT). We previously showed that increases in day +7 TNF-receptor-1 (TNFR1) ratios (posttransplantation day +7/pretransplantation baseline) after myeloablative HCT correlate with outcomes including GVHD, NRM, and survival. Therefore, we conducted a phase II trial at 2 centers, testing whether the addition of the TNF-inhibitor etanercept (25 mg twice weekly from start of conditioning to day +56) to standard GVHD prophylaxis would lower TNFR1 levels, reduce GVHD rates, and improve NRM and survival. Patients underwent myeloablative HCT from a matched unrelated donor (URD; N = 71), 1-antigen mismatched URD (N = 26), or 1-antigen mismatched related donor (N = 3) using either total body irradiation (TBI)-based conditioning (N = 29) or non-TBI-based conditioning (N = 71). Compared to historical controls, the increase in posttransplantation day +7 TNFR1 ratios was not altered in patients who received TBI-based conditioning, but was 40% lower in patients receiving non-TBI-based conditioning. The latter group experienced relatively low rates of severe grade 3 to 4 GVHD (14%), 1-year NRM (16%), and high 1-year survival (69%). These findings suggest that (1) the effectiveness of TNF-inhibition with etanercept may depend on the conditioning regimen, and (2) attenuating the expected rise in TNFR1 levels early posttransplantation correlates with good outcomes.

Alternate JournalBiol. Blood Marrow Transplant.
PubMed ID22469883
PubMed Central IDPMC3443302
Grant List2P01CA039542 / CA / NCI NIH HHS / United States
5P30CA046592 / CA / NCI NIH HHS / United States
AI091623-01 / AI / NIAID NIH HHS / United States
K23 AI091623 / AI / NIAID NIH HHS / United States
P01 CA039542 / CA / NCI NIH HHS / United States
David Hanauer
University of Michigan Comprehensive Cancer Center at North Campus Reserach Complex
1600 Huron Parkway, Bldg 100, Rm 100 
Mailing Address: 2800 Plymouth Rd, NCRC 100-1004
Ann Arbor, MI 48109-2800 
Ph. (734) 764-8848 Fax. (734) 615-0517
Please acknowledge the Cancer Center Support Grant (P30 CA046592) when publishing manuscripts or abstracts that utilized the services of the University of Michigan's Comprehensive Cancer Center's Shared Resource: Cancer Informatics.
Suggested language: "Research reported in this [publication/press release] was supported by the National Cancer Institute of the National Institutes of Health under award number P30CA046592."

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