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

Gregory A. Yanik, Mary M. Horowitz, Daniel J. Weisdorf, Brent R. Logan, Vincent T. Ho, Robert J. Soiffer, Shelly L. Carter, Juan Wu, John R. Wingard, Nancy L. Difronzo, James L. Ferrara, Sergio Giralt, David K. Madtes, Rebecca Drexler, Eric S. White, Kenneth R. Cooke

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45 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)858-864
Number of pages7
JournalBiology of Blood and Marrow Transplantation
Volume20
Issue number6
DOIs
StatePublished - Jun 2014

Bibliographical note

Funding Information:
Has IPS changed over the past 2 decades? The statistical plan for BMT CTN0403 was based on historical data from the University of Michigan Medical Center (1996 to 2002) in which IPS occurred in 9.0% of transplants, a median 15 days post-transplant, with a day 28 survival of 33% when treated with corticosteroids plus supportive care. This incidence of IPS was supported by data from the Center for International Blood and Marrow Transplant Research during a similar time period. However, significant differences in supportive care practices, conditioning regimen intensity, the frequency of performing BAL, and the ability to isolate pathogens on a BAL have occurred over the past decade. With molecular-based assays for a wide variety of pathogens now in common use, the potential exists that IPS identified in the 1990s may not be identified as such now. Additionally, the use of reduced-intensity conditioning has increased significantly over this same time period, with 41.1% of patients on BMT CTN0403 treated after receiving reduced-intensity regimen. By comparison, none of the historical control subjects in the University of Michigan IPS database received reduced-intensity conditioning. The intensity of the conditioning regimen has been postulated to impact the incidence of IPS, with significantly lower rates of IPS seen with reduced intensity [9] . Could the intensity of the conditioning regimen also impact response to therapy once IPS develops? As such, are there subjects for whom corticosteroids alone are sufficient to treat IPS without the addition of a TNF inhibitor (etanercept)? Conversely, are their subjects with IPS who are more likely to benefit from the addition of TNF-α inhibition?

Keywords

  • Bone marrow transplantation
  • IPS
  • Pneumonia
  • Pulmonary
  • TNF

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