PHASE-I STUDY OF ALPHA-INTERFERON AUGMENTATION OF CYCLOSPORINE-INDUCED GRAFT-VERSUS-HOST DISEASE IN RECIPIENTS OF AUTOLOGOUS BONE-MARROW TRANSPLANTATION

To explore the augmentation of cyclosporin-induced graft-versus-host d isease (GVHD) in autologous bone marrow transplantation (BMT), we cond ucted a phase I dose escalation trial of interferon (IFN)-alpha 2a. A dose of either 1 or 3 X 10(6) units of IFN-alpha 2a was given by daily sc injection starting on day 0 of BMT and continuing for 28 days. Cyc losporine (CYA) was also started on day 0 of BMT at a dose of 1 mg/kg/ day for 28 days. We enrolled 22 patients (median age 43 years, range 1 9-55 years, male/female ratio = 9/13) which included 11 patients with lymphoma, 5 patients with Hodgkin's disease, 4 patients with AML and 1 patient each with acute lymphoblastic leukemia (ALL) and myeloma. Pat ients were divided into four groups: two control groups received eithe r CYA or IFN-alpha 2a alone and the other two groups received IFN-alph a 2a at a dose of either 1 x 10(6) or 3 x 10(6) units/day sc concomita ntly with CYA for 28 days. IFN-alpha 2a treatment was terminated early in 5 patients: 2 patients receiving IFN-alpha 2a at a dose of 3 x 10( 6) units/day developed intractable fatigue, nausea and vomiting and 3 other patients had life-threatening transplant-related complications n ot related to IFN-alpha 2a (1 patient receiving 3 X 10(6) units/day, a nd 2 receiving 1x10(6) units/day). These patients were considered not evaluable. Of the 17 evaluable patients, all 13 who received IFN-alpha 2a developed GVHD regardless of whether they received CYA whereas onl y 2 of the 4 patients who received CYA alone developed detectable GVHD . Patients receiving 1 X 10(6) units/day of IFN-alpha 2a concomitantly with CYA showed a trend towards increasing severity of clinical GVHD when compared with patients receiving CYA alone (p=0.06). We conclude from this study that IFN-alpha 2a at a dose of 1x10(6) units/day after autologous BMT is the highest level tolerable. IFN-alpha 2a administr ation starting on day 0 of BMT can both induce autologous GVHD and enh ance autologous GVHD induced by CYA. The clinical and biologic signifi cance of autologous GVHD on minimal residual disease is unknown and wa rrants further studies.