ESCALATING DOSE OF MITOXANTRONE WITH HIGH-DOSE CYCLOPHOSPHAMIDE, CARMUSTINE, AND ETOPOSIDE IN PATIENTS WITH REFRACTORY LYMPHOMA UNDERGOING AUTOLOGOUS BONE-MARROW TRANSPLANTATION

Purpose: We conducted a dose-finding study of mitoxantrone (MITO) in combination with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (CBV) in refractory lymphoma undergoing autologous bone marrow transplantation (ABMT). The objectives were to determine the following: (1) the maximum-tolerated dose of MITO, (2) the extramedullary toxicity of this regimen, (3) its antitumor activity, and (4) the pharmacokinetic characteristics of MITO at each dose level. Patients and Methods: Escalating doses of MITO (15 to 90 mg/m2, single bolus infusion on day -8) followed by CBV were administered to 20 patients (mean age, 38.5 years) with refractory lymphoma. MITO concentrations were determined by high-performance liquid chromatography (HPLC). Results: No toxic death occurred. The maximum- tolerated dose appears to be 75 mg/m2. Two of five patients treated with 90 mg/m2 developed severe organ toxicity, versus zero of 15 treated with doses up to 75 mg/m2. Duration of neutropenia was longer for patients treated with 90 mg/m2 (31.7 days) than for patients treated with doses up to 75 mg/m2 (22.1 days) (P < .05). A linear relationship was observed between administered dose of MITO and (1) plasma peak value, (2) area under the curve (AUC), and (3) plasma concentration on the day of marrow infusion (day 0). Hematologic toxicity was related to the terminal half-life (T( 1/2 )) of MITO, and day-0 plasma concentration. A high complete response (CR) rate was observed (60%), and eight of 11 (73%) patients treated with MITO ≥ 60 mg/m2 achieved a CR. Conclusion: MITO (up to 75 mg/m2) and CBV can be administered with acceptable toxicity and a promising CR rate in this poor-risk population, justifying further phase II studies.