PHASE-I STUDY OF HIGH-DOSE BUSULFAN, MELPHALAN AND THIOTEPA WITH AUTOLOGOUS STEM-CELL SUPPORT IN PATIENTS WITH REFRACTORY MALIGNANCIES

The purpose of this study was to determine the maximal tolerated dose of thiotepa administered with busulfan 12 mg/kg and melphalan 100 mg/m (2) followed by autologous stem cell transplantation in patients with refractory malignancies. Twenty-eight patients with refractory maligna ncies received high-dose busulfan 12 mg/kg, melphalan 100 mg/m(2) and escalating doses of thiotepa 450-550 mg/m(2) followed by infusion of c ryopreserved autologous peripheral blood stem cells (n = 26) or marrow (n = 2). The maximum tolerated dose was determined to be busulfan 12 mg/kg, melphalan 100 mg/m(2) and thiotepa 500 mg/m(2). Two of three pa tients receiving thiotepa 550mg/m(2) experienced grade 3 colitis. Twen ty patients were enrolled at the maximum tolerated dose and the incide nce of grade 3-4 regimen-related toxicity and mortality was 10% and 5% , respectively. Ninety-five per cent of patients experienced grade 1-2 mucositis, 50% grade 1-2 gastrointestinal toxicity, 35% grade I hepat ic toxicity and 20% experienced grade 1-2 skin toxicity. The median ti me to achieve a granulocyte count of 0.5 X 10(9)/I was 10 days (range 8-20 days) and platelet transfusion independence was 10 days (range 1- 26 days). Five of ten patients with stage 4 refractory breast cancer a chieved a complete and two a partial remission with a complete respons e rate of 50% and a overall response rate of 70%. In conclusion, busul fan, melphalan and thiotepa can be administered in high doses with tol erable mucositis as the major side-effect. This combination has signif icant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy sensitive malignan cies are warranted.