title: Treatment of steroid-resistant acute graft-versus-host disease with rabbit antithymocyte globulin.
abstract: Acute graft-versus-host disease (A-GVHD) is a life-threatening complication of allogeneic stem cell transplantation (SCT), and primary therapy consists of high-dose corticosteroids. Patients who fail to respond adequately to corticosteroids require salvage treatment, with anti-T cell antibodies being the most commonly utilized group of agents. We report our institution's experience treating steroid-resistant GVHD in 36 adult patients (median age 39 years, range 24-55) with a rabbit antithymocyte globulin product (thymoglobulin). Eleven patients had undergone sibling SCT (10 histocompatible, 1 one-antigen mismatched) and 25 patients had received unrelated donor bone marrow (17 matched, 8 one-antigen mismatched); 32 patients (89%) had grade III or IV A-GVHD. Thymoglobulin was administered in two different regimens; group 1 patients (n = 13) received 2.5 mg/kg/day x 4-6 consecutive days with maintenance of all other immunosuppressives. Group 2 patients (n = 21) were given the same dose of thymoglobulin on days 1, 3, 5, and 7 with discontinuation of cyclosporine for 14 days, during which the corticosteroid dose was held at 2-3 mg/kg/day. Two patients had severe adverse reactions to thymoglobulin (hypoxemia and hypotension) and could not complete treatment, however, in the other patients, aside from transient leukopenia (25%) and and hepatic dysfunction (25%), the antibody preparation was well tolerated. Of the 34 evaluable patients, 13 patients had a complete response (38%) and 7 patients (21%) had a partial response, for an overall response rate of 59%. Response rate was higher in group 1 patients (77%) compared to group 2 patients (48%), (p = 0.15); skin GVHD was more responsive (96% of patients) than gut GVHD (46% of patients) or hepatic GHVD (36% of patients). Opportunistic infections were a significant complication, with 11 patients developing systemic fungal infections and 9 patients serious viral infections; there were seven episodes of bacteremia following thymoglobulin treatment and one fatal protozoal infection. There were 9 patients (25%) who developed post-SCT lymphoproliferative disorder (PTLD) and 4 patients who had a relapse of underlying primary malignancy; none of these patients survived. Of the 36 patients entered on the study, only 2 patients (6%) survive, at 15+ and 34+ months post-unrelated donor SCT. Although thymoglobulin is associated with an impressive response rate when administered for advanced steroid-resistant GVHD, long-term survival is uncommon, even in responders, primarily due to the high risk of developing either an opportunistic infection or a PTLD.
authors.affiliation: Division of Hematology, Vancouver General Hospital and the University of British Columbia, Canada.
authors.forename: K G
authors.initials: KG
authors.lastname: McCaul
authors.forename: T J
authors.initials: TJ
authors.lastname: Nevill
authors.forename: M J
authors.initials: MJ
authors.lastname: Barnett
authors.forename: C L
authors.initials: CL
authors.lastname: Toze
authors.forename: C J
authors.initials: CJ
authors.lastname: Currie
authors.forename: H J
authors.initials: HJ
authors.lastname: Sutherland
authors.forename: E A
authors.initials: EA
authors.lastname: Conneally
authors.forename: J D
authors.initials: JD
authors.lastname: Shepherd
authors.forename: S H
authors.initials: SH
authors.lastname: Nantel
authors.forename: D E
authors.initials: DE
authors.lastname: Hogge
authors.forename: H G
authors.initials: HG
authors.lastname: Klingemann
mesh_terms: D000208:Acute Disease; D000305:Adrenal Cortex Hormones; D000328:Adult; D000818:Animals; D000961:Antilymphocyte Serum / Q000627:therapeutic use* / Q000633:toxicity; D004351:Drug Resistance; D005260:Female; D005334:Fever / Q000209:etiology; D006086:Graft vs Host Disease / Q000150:complications / Q000188:drug therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007239:Infections / Q000209:etiology; D008232:Lymphoproliferative Disorders / Q000209:etiology; D008297:Male; D008875:Middle Aged; D011817:Rabbits; D012074:Remission Induction; D016879:Salvage Therapy; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D000961:Antilymphocyte Serum