In 1983, we began a series of clinical trials with the goal of reducing the relapse rate following allogeneic BMT for hematologic malignancies. Because of its anti-leukemic activity, the drug VP-16 was chosen and combined with total body irradiation (TBI). The first series (trial I) consisted of patients who had advanced leukemia. This trial showed a relapse rate of 32% and a disease-free survival rate of 43%. Thereafter, this regimen was tested in a randomized trial (trial II) under the auspices of the Southwest Oncology Group (SWOG study 8612). The FTBI/VP-16 regimen was compared with the combination of busulfan and cyclophosphamide (BU/CY). A recent analysis indicates a disease-free advantage for patients prepared with FTBI/VP-16; however this difference is not statistically significant. In another trial (trial III), patients in their first remission of leukemia were prepared with the FTBI/VP-16 regimen and long-term disease-free survival was found to be 60-70% with a relapse rate of approximately 10%. These results compare favorably with data obtained with alternative preparatory regimens. The FTBI/VP-16 regimen is currently being compared to the 'standard' regimen, FTBI/CY, in a prospective trial (trial IV). Since the regimen-related toxicity has been relatively low, we have added one dose of CY 60 mg/kg to the FTBI/VP-16 combination. This regimen (trial V) is currently being tested in patients with advanced leukemia. The preliminary results of this ongoing trial indicate further improvement in disease-free survival through a reduction of the post-transplant relapse rate.