title: Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow transplant clinical trials network protocol.
abstract: Idiopathic pneumonia syndrome (IPS) is a diffuse, noninfectious lung injury that occurs acutely after allogeneic hematopoietic cell transplantation (HCT). IPS-related mortality has been historically high (>50%) despite treatment with systemic corticosteroids and supportive care measures. We have now examined the role of tumor necrosis factor inhibition in a randomized, double-blind, placebo-controlled trial of corticosteroids with etanercept or placebo. Thirty-four subjects (≥18 years) with IPS after HCT were randomized to receive methylprednisolone (2 mg/kg/day) plus etanercept (0.4 mg/kg twice weekly × 4 weeks; n = 16) or placebo (n = 18). No active infections and a pathogen-negative bronchoscopy were required at study entry. Response (alive, with complete discontinuation of supplemental oxygen support) and overall survival were examined. This study, originally planned to accrue 120 patients, was terminated prematurely due to slow accrual. In the limited number of patients examined, there were no differences in response rates at day 28 of study. Ten of 16 patients (62.5% [95% confidence interval {CI}, 35.4% to 84.8%]) receiving etanercept and 12 of 18 patients (66.7% [95% CI, 41.0% to 86.7%]) receiving placebo met the day 28 response definition (P = 1.00). The median survival was 170 days (95% CI, 11 to 362) with etanercept versus 64 days (95% CI, 26 to 209) with placebo (P = .51). Among responders, the median time to discontinuation of supplemental oxygen was 9 days (etanercept) versus 7 days (placebo). Therapy was well tolerated, with 1 toxicity-related death from infectious pneumonia in the placebo arm. The treatment of IPS with corticosteroids in adult HCT recipients was associated with high early response rates (>60%) compared with historical reports, with poor overall survival. The addition of etanercept did not lead to further increases in response, although the sample size of this truncated trial preclude a definitive conclusion.
authors.affiliation: Department of Pediatrics and Internal Medicine, Blood and Marrow Transplant Program, University of Michigan Medical Center, Ann Arbor, Michigan. Electronic address: gyanik@umich.edu.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Yanik
authors.affiliation: Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Horowitz
authors.affiliation: Department of Internal Medicine, University of Minnesota Blood and Marrow Transplantation Program, Minneapolis, Minnesota.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisdorf
authors.affiliation: Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Brent R
authors.initials: BR
authors.lastname: Logan
authors.affiliation: Department of Hematologic Malignancies, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.affiliation: Department of Hematologic Malignancies, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.affiliation: The EMMES Corporation, Rockville, Maryland.
authors.forename: Shelly L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: The EMMES Corporation, Rockville, Maryland.
authors.forename: Juan
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of Florida, Gainesville, Florida.
authors.forename: John R
authors.initials: JR
authors.lastname: Wingard
authors.affiliation: Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Difronzo
authors.affiliation: Department of Pediatrics and Internal Medicine, Blood and Marrow Transplant Program, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: James L
authors.initials: JL
authors.lastname: Ferrara
authors.affiliation: Department of Stem Cell Transplantation, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sergio
authors.initials: S
authors.lastname: Giralt
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center and Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington.
authors.forename: David K
authors.initials: DK
authors.lastname: Madtes
authors.affiliation: National Marrow Donor Program, Minneapolis, Minnesota; Center for International Blood and Marrow Transplant Research, Minneapolis, Minnesota.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Drexler
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Eric S
authors.initials: ES
authors.lastname: White
authors.affiliation: Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, Maryland.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Cooke
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D000068800:Etanercept; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D054988:Idiopathic Interstitial Pneumonias / Q000188:drug therapy* / Q000209:etiology; D007074:Immunoglobulin G / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000068800:Etanercept
keywords: Bone marrow transplantation; IPS; Pneumonia; Pulmonary; TNF