CYCLOSPORINE-INDUCED GRAFT-VERSUS-HOST DISEASE AFTER AUTOLOGOUS BONE-MARROW TRANSPLANTATION FOR ACUTE MYELOID-LEUKEMIA

Rodents given cyclosporine (CSP) for several weeks after autologous or syngeneic bone marrow transplantation develop a syndrome that mimics allogeneic graft-versus-host disease (GVHD). Autologous GVHD has also been reported after administration of CSP in patients who have receive d autologous bone marrow transplantation (ABMT) with untreated marrow for lymphoma or acute myeloid leukemia (AML). Our study was designed t o determine whether CSP administration is associated with appearance o f autologous GVHD in patients with AML receiving ABMT with 4-hydropero xycyclophosphamide (4HC)-purged marrow and whether there was a dose-de pendent effect of CSP on development of the syndrome. Thirty-three pat ients with AML (18 in first remission [CR1], 10 in CR2, and 5 in CR3) received intravenous CSP, beginning on the day of ABMT, after a prepar ative regimen of busulfan and cyclophosphamide and ABMT with 4HC-treat ed marrow. Skin biopsies were obtained weekly after ABMT or on appeara nce of rash and were graded for GVH changes. In the first phase of thi s study, groups of patients received CSP dosages of either 1 mg/kg/day (7 patients), 2.5 mg/kg/day (8 patients), or 3.75 mg/kg/day (6 patien ts) for 28 days. Sixteen of the 21 patients (76%) developed cutaneous histopathologic grade 2 GVHD at a median of 34 days (range, 14-49) aft er ABMT, and cutaneous manifestations were present at time of positive biopsy in 11 of the 16 patients. There was no apparent difference in frequency, time to onset, or duration of GVHD among the three CSP dosa ge groups. In the subsequent trial, 12 patients received 1.0 mg/kg/day of CSP for 35 days; 6 developed biopsy-documented GVHD at a median of 42 days (range, 18-52) after ABMT. Overall, 22 of 33 patients (67%) h ad positive biopsies for GVHD, compared with a historical 7% incidence of spontaneous GVHD in ABMT recipients. No patients had hepatic or ga strointestinal dysfunction attributable to GVHD or required specific t herapy for GVHD. Six of the 33 patients died with ABMT-related complic ations; 3 had positive biopsies for cutaneous GVHD. Eleven patients (6 CR1, 4 CR2, 1 CR3) relapsed with AML at a median of 285 days (range, 115-633) after ABMT; 9 had positive biopsies. Sixteen patients (9 CRI, 3 CR2, 4 CR3) are alive without relapse at a median of 509+ days (ran ge, 96+-1176+) after ABMT; 10 had cutaneous GVHD. Randomized prospecti ve trials will be needed to determine whether autologous GVHD is assoc iated with alterations in relapse rate and disease-free survival after ABMT for acute leukemia and lymphoma.