The effect of post-transplant immunosuppressive agents used in anti-GVHD prophylaxis on leukemic relapse was tested using a murine model of originally spontaneous, subsequently transplantable and non-immunogenic B cell leukemia (BCL1). (BALB/c x C57BL/6)F1 mice inoculated with 10(7) BCL1 cells were conditioned by total lymphoid irradiation (TLI) (1600 cGy), cyclophosphamide (200 mg/kg) or total body irradiation (TBI) 750 cGy and reconstituted with C57BL/6 (C57) bone marrow cells (30 x 10(6] or 10 x 10(6) bone marrow cells with additional 2 x 10(6) donor-type spleen cells, respectively. Mice were treated by cyclosporine A (CSA) 20 mg/kg i.p., or methylprednisolone (MP) 10 mg/kg i.p. for 10 days each and one group of controls received no post-transplant therapy. Stable chimerism was documented in all recipients with greater than or equal to 90% donor-type C57 cells in the peripheral blood. Eighty-nine percent of the mice treated by CSA following conditioning with TLI developed leukemia within 70 days, whereas none of the MP-treated mice and none of untreated chimeras showed any evidence of leukemia for more than 150 days. Adoptive transfer experiments using 10(5) spleen cells obtained from recipients conditioned with TBI were done to monitor residual leukemic cells following different post-transplant treatments. Eight-five percent of recipients of spleen cells obtained from mice treated with CSA developed leukemia in contrast with 33% and 25% when spleen cells were obtained from mice treated with MP or untreated controls, respectively (p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)