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Idiopathic pneumonia syndrome (IPS) is a noninfectious pulmonary disorder occurring acutely post-SCT, associated with mortality rates >50% within 28 days of diagnosis. We previously established that TNFα is involved the pathogenesis of the disorder, with elevated levels of TNFα in both plasma and broncho-alveolar lavage (BAL) fluid of affected patients. We now report results from a multi-center, phase II, single arm, open label trial investigating a soluble TNF binding protein, etanercept (Enbrel®, Amgen) for the treatment of children with IPS. Eligible patients were <18 years, within 120 days post-SCT, with radiographic evidence of diffuse pulmonary infiltrates, and no evidence of active infection, sepsis syndrome, congestive heart failure, or iatrogenic fluid overload. Absence of infection was established by a negative BAL at study entry. In addition to standard therapy with corticosteroids (2.0 mg/kg/day), patients received etanercept (0.4 mg/kg/dose) twice weekly x 8 doses. Steroid taper was allowed after 7 days, per investigator discretion. Response was defined as survival to day 28 plus complete discontinuation of all supplemental oxygen support for >72 hours within the 28 day period. We enrolled 39 patients (median age 11y, range 1-17y) between 2006 - 2011. Eleven patients were ineligible for study treatment due to evidence of infection by BAL, with the remaining 28 patients receiving study therapy. At study entry, the median baseline FiO2 was 45%, and 17 patients were mechanically ventilated. Complete responses were seen in 20 (71%) of 28 patients, with a median time to response 10 days (range 1-24). There were no significant differences in response based upon age, gender, stem cell source, donor type, conditioning (TBI vs non-TBI), or HLA match. Response rates were significantly higher for patients not requiring mechanical ventilation at study entry (100% vs 53%, p=0.01). A non-significant trend towards improved response was seen in patients treated within the initial 3 days of requiring supplemental oxygen (83% vs 50%, p=0.09). When compared to historical reports, the combination of etanercept plus corticosteroids was associated with strikingly high overall survival at day 28 [89% (95% CI: 70-96)] and at 1-year [63% (95% CI: 42-79)]. Serious infectious complications during study therapy included HSV (2), CMV (2), fungal (1), and enterocolitis (1). Grade 3-5 organ toxicities included renal (2), GI bleed (1), hepatic (1), and CNS (2). In conclusion, the addition of etanercept to high dose corticosteroids was associated with high response rates and survival in children with IPS. Response rates were highest in patients who did not require mechanical ventilation at initiation of therapy. Therapy was well tolerated in this high risk patient population. Given these promising results, further study in children comparing this approach to standard therapy is warranted.
