title: Close simulation of acute graft-versus-host disease by interleukin-2 administered after autologous bone marrow transplantation for hematologic malignancy.
abstract: The high relapse rate of hematologic malignancy treated with autologous bone marrow transplantation (ABMT) may reflect the absence of a graft-versus-leukemia (GVL) effect usually associated with graft-versus-host disease (GVHD). The purpose of this study was to determine whether administration of interleukin-2 (IL-2) early after ABMT might induce or exacerbate acute skin GVHD. Fourteen patients at high risk for post-transplant relapse, eight with NHL and six with AML > or = first relapse, were conditioned with chemotherapy and total body irradiation (13) or chemotherapy alone (1), and received purged (10) or unpurged (4) marrow. A median of 35 days (range 25-58) after ABMT, they received a 5-day induction course of Roche IL-2 (9 x 10(6) U/m2/day) followed by apheresis, reinfusion of LAK cells, and a 10-day maintenance course of IL-2 (0.9 x 10(6) U/m2/day), all by continuous i.v. infusion. Serial skin biopsies were obtained before and after IL-2 therapy and were read blindly. Patients were studied prospectively for the development of acute cutaneous GVHD as reflected by rash ( > or = 25% body surface area), skin biopsy ( > or = grade II histologic changes) and T cell infiltration as assessed by staining of the biopsy with antibodies UCHL-1 and TIA-1. No patient had a rash before IL-2 therapy, but 12 of 14 (85%) developed a rash during the IL-2 induction course. Before IL-2 therapy, biopsies from three of 10 patients (30%) revealed histologic GVHD; after induction IL-2, biopsies from 11 of 14 patients (79%) revealed grade II acute GVHD. Biopsies from all patients with histologic GVHD after IL-2 therapy contained TIA-1 positive T cells. HLA-DR was negative in the keratinocytes of these paraffin-embedded sections. One patient died early of sepsis, one patient required and responded to topical corticosteroids and 12 had spontaneous resolution of the rash. Six patients relapsed at 3-13 months, while seven remain in complete remission 32+ to 41+ months after ABMT. The results demonstrate that IL-2 therapy after ABMT can induce effects which histologically and clinically mimic cutaneous acute GVHD in most patients. Prospective, randomized trials of IL-2 vs observation after transplantation of autologous marrow or stem cells for high-risk NHL and AML have been initiated which may allow us to determine whether this phenomenon is associated with a clinical GVL effect as reflected by a decreased relapse rate.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Massumoto
authors.forename: M C
authors.initials: MC
authors.lastname: Benyunes
authors.forename: G
authors.initials: G
authors.lastname: Sale
authors.forename: M
authors.initials: M
authors.lastname: Beauchamp
authors.forename: A
authors.initials: A
authors.lastname: York
authors.forename: J A
authors.initials: JA
authors.lastname: Thompson
authors.forename: C D
authors.initials: CD
authors.lastname: Buckner
authors.forename: A
authors.initials: A
authors.lastname: Fefer
mesh_terms: D000208:Acute Disease; D000328:Adult; D016026:Bone Marrow Transplantation; D005069:Evaluation Studies as Topic; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000139:chemically induced* / Q000453:epidemiology; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D007376:Interleukin-2 / Q000009:adverse effects*; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000473:pathology / Q000628:therapy*; D008223:Lymphoma / Q000150:complications / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012871:Skin Diseases / Q000209:etiology / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology; D014182:Transplantation, Autologous
chemical_list: D006684:HLA-DR Antigens; D007376:Interleukin-2