title: TNF-receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome. A joint Pediatric Blood and Marrow Transplant Consortium and Children's Oncology Group Study (ASCT0521).
abstract: Idiopathic pneumonia syndrome (IPS) is an acute, noninfectious lung disorder associated with high morbidity and mortality after hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multicenter phase II trial investigating a soluble TNF-binding protein, etanercept (Enbrel, Amgen, Thousand Oaks, CA), for the treatment of pediatric patients with IPS. Eligible patients were < 18 years old, within 120 days after transplantation, and with radiographic evidence of a diffuse pneumonitis. All patients underwent a pretherapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (.4 mg/kg twice weekly × 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age, 11 years; range, 1 to 17) were enrolled, with 11 of 39 patients nonevaluable because of identification of pathogens from their pretherapy BAL. In the remaining 28 patients, the median fraction of inspired oxygen at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response of 10 days (range, 1 to 24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% versus 53%, P = .01). Overall survival at 28 days and 1 year after therapy were 89% (95% confidence interval [CI], 70% to 96%) and 63% (95% CI, 42% to 79%), respectively. Plasma levels of proinflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high-dose corticosteroids was associated with high response rates and survival in children with IPS.
authors.affiliation: Department of Pediatrics, Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan. Electronic address: gyanik@umich.edu.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Yanik
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.affiliation: Division of Hematology and Hematological Malignancies, Primary Children's Hospital, Salt Lake City, Utah.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pulsipher
authors.affiliation: Department of Pediatrics, Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: John E
authors.initials: JE
authors.lastname: Levine
authors.affiliation: Department of Pediatrics, Pediatric Hematology/Oncology/BMT, British Columbia Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Schultz
authors.affiliation: Department of Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Donna A
authors.initials: DA
authors.lastname: Wall
authors.affiliation: Children's Oncology Group Statistics and Data Center, University of Southern California, Arcadia, California.
authors.forename: Bryan
authors.initials: B
authors.lastname: Langholz
authors.affiliation: Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, California.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Dvorak
authors.affiliation: Department of Pediatrics, Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan.
authors.forename: Keith
authors.initials: K
authors.lastname: Alangaden
authors.affiliation: Division of Pediatric Hematology-Oncology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Goyal
authors.affiliation: Division of Critical Care and Pulmonary Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Eric S
authors.initials: ES
authors.lastname: White
authors.affiliation: School of Pharmacy, Indiana University-Riley Children's Hospital, Indianapolis, Indiana.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Collura
authors.affiliation: Department of Nursing, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Micah A
authors.initials: MA
authors.lastname: Skeens
authors.affiliation: Division of Hematology and Oncology, Department of Pediatrics, Case Western Reserve University, School of Medicine, Cleveland, Ohio.
authors.forename: Saada
authors.initials: S
authors.lastname: Eid
authors.affiliation: Division of Hematology and Oncology, Department of Pediatrics, Case Western Reserve University, School of Medicine, Cleveland, Ohio.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Pierce
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: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004359:Drug Therapy, Combination; D000068800:Etanercept; D005260:Female; D019337:Hematologic Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D054988:Idiopathic Interstitial Pneumonias / Q000209:etiology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007223:Infant; D008297:Male; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D012121:Respiration, Artificial; D035781:Siblings; D016019:Survival Analysis; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D061349:Unrelated Donors
chemical_list: D000305:Adrenal Cortex Hormones; D016207:Cytokines; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018124:Receptors, Tumor Necrosis Factor; D000068800:Etanercept
keywords: Bone marrow transplantation; Etanercept; Idiopathic pneumonia syndrome