title: TNF-inhibition with etanercept for graft-versus-host disease prevention in high-risk HCT: lower TNFR1 levels correlate with better outcomes.
abstract: 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.
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI 48109-5942, USA.
authors.forename: Sung W
authors.initials: SW
authors.lastname: Choi
authors.forename: Patrick
authors.initials: P
authors.lastname: Stiff
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cooke
authors.forename: James L M
authors.initials: JL
authors.lastname: Ferrara
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: Carrie
authors.initials: C
authors.lastname: Kitko
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
authors.forename: Gregory
authors.initials: G
authors.lastname: Yanik
authors.forename: Shin
authors.initials: S
authors.lastname: Mineishi
authors.forename: Sophie
authors.initials: S
authors.lastname: Paczesny
authors.forename: David
authors.initials: D
authors.lastname: Hanauer
authors.forename: Attaphol
authors.initials: A
authors.lastname: Pawarode
authors.forename: Edward
authors.initials: E
authors.lastname: Peres
authors.forename: Tulio
authors.initials: T
authors.lastname: Rodriguez
authors.forename: Scott
authors.initials: S
authors.lastname: Smith
authors.forename: John E
authors.initials: JE
authors.lastname: Levine
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D000068800:Etanercept; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D016019:Survival Analysis; D014019:Tissue Donors; D019172:Transplantation Conditioning; D014916:Whole-Body Irradiation
chemical_list: D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D000068800:Etanercept