Soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome following allogeneic stem cell transplantation

Abstract

Non-infectious lung injury is as a frequent and severe complication of allogeneic bone marrow transplantation (BMT). In the acute setting, a diffuse non-infectious process termed Idiopathic Pneumonia Syndrome (IPS) may occur. Despite advances in supportive care and the use of high dose steroids, mortality from IPS remains unacceptably high (> 70%). Etanercept is a soluble tumor necrosis factor (TNF) receptor, consisting of two soluble p75 TNF receptors fused to the Fc portion of a human IgG1. A trial examining etanercept in the treatment of IPS following allogeneic transplant has now been undertaken. Fourteen patients (median 18 yrs, range 1–60 yrs), each meeting the diagnostic criteria for IPS were treated. Broncho-alveolar lavage (BAL) specimen were obtained pre and post therapy, undergoing analysis for both infectious pathogens (viral, bacterial, fungal, PCP, AFB) and for inflammatory cytokine markers (TNF, TNFR1, sCD-14, LBP, and MCP-1). Patients in whom the pre-therapy BAL was positive for a potential pathogen (by specific stain or culture) were ineligible for therapy. Etanercept was administered subcutaneously at a dose of 0.4 mg/kg (maximum dose 25 mg) twice weekly, for a maximum of 8 doses. All patients required supplemental oxygen at therapy onset, with seven patients requiring mechanical ventilation. Etanercept therapy was initiated a median of 17 days (range 11–87 days) post transplant. Results: Therapy was well tolerated, with no infusion related reactions. Eight of 14 patients had a complete response, defined as the ability to withdraw completely from supplemental oxygen support. In those responding, the median time to complete response was 7 days (range 3–18 days), and the median time to normalization of radiographic findings was 6 days (range 2–10 days). Two other patients had a significant reduction in their FiO2 requirement during therapy. Three patients died while on therapy, from progressive organ dysfunction. Post therapy BAL fluid analysis noted a significant reductions in all inflammatory cytokines tested, including TNFa, TNFR1, sCD14, LBP and MCP-1 (Table below). Conclusion: Etanercept therapy was well tolerated, with minimal toxicity and favorable response in patients with IPS post allogeneic transplant. The clinical and biochemical responses seen with therapy support a mechanistic role for TNFa in the pathogenesis of this disorder. Further trials, investigating the responsiveness of IPS to etanercept therapy are warranted.