title: Phase I-II trial of a monoclonal anti-tumor necrosis factor alpha antibody for the treatment of refractory severe acute graft-versus-host disease.
abstract: In a multicenter pilot study, 19 patients with severe acute graft-versus-host disease (aGVHD) refractory to conventional therapy and serotherapy with a monoclonal anti-interleukin-2 receptor antibody were treated by in vivo infusion of a monoclonal anti-tumor necrosis factor alpha (TNF alpha) antibody (B-C7). Ten patients were grafted from a genotypically identical sibling, five from an HLA-mismatched family member, and four from an HLA-matched unrelated donor. Before B-C7 treatment, 15 patients had grade IV and four had grade III GVHD. In all cases, patients received cyclosporine/methotrexate as aGVHD prophylaxis. Patients were administered increasing doses of antibody (from 0.1 to 0.4 mg/kg). The antibody was infused in bolus daily for 4 days and then every other day twice (6 doses). No side effects were observed during treatment regardless of the dose level used. Changes in peripheral blood cell counts occurred in 8 of the 19 patients and appeared to be unrelated to B-C7. No truly complete response was observed; eight patients achieved a very good partial response (42.6%) and six a partial response (31.5%). The treatment was ineffective in five patients (26.4%). When present, the response occurred early (less than 3 days). In the 14 responding patients, gut lesions responded best (100%), followed by skin (85%) and liver (35.7%) lesions. In 9 of 11 evaluable patients (81%), GVHD recurred when treatment was discontinued in a median delay of 3 days (range, 2 to 120 days). All except one died from aGVHD. Two patients did not experience GVHD recurrence and are still alive 13 and 18 months post-bone marrow transplantation. This pilot study shows that a monoclonal anti-TNF alpha antibody may be of benefit to some patients with severe refractory aGVHD, but is ineffective to prevent GVHD recurrence in the majority of cases.
authors.affiliation: Bone Marrow Transplant Unit, Besançon, France.
authors.forename: P
authors.initials: P
authors.lastname: Hervé
authors.forename: M
authors.initials: M
authors.lastname: Flesch
authors.forename: P
authors.initials: P
authors.lastname: Tiberghien
authors.forename: J
authors.initials: J
authors.lastname: Wijdenes
authors.forename: E
authors.initials: E
authors.lastname: Racadot
authors.forename: P
authors.initials: P
authors.lastname: Bordigoni
authors.forename: E
authors.initials: E
authors.lastname: Plouvier
authors.forename: J L
authors.initials: JL
authors.lastname: Stephan
authors.forename: H
authors.initials: H
authors.lastname: Bourdeau
authors.forename: E
authors.initials: E
authors.lastname: Holler
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D007223:Infant; D007700:Kinetics; D008297:Male; D012008:Recurrence; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha