HIGH-DOSE MITOXANTRONE WITH PERIPHERAL-BLOOD PROGENITOR-CELL RESCUE -TOXICITY, PHARMACOKINETICS AND IMPLICATIONS FOR DOSAGE AND SCHEDULE

The optimal use of mitoxantrone (NOV) in the high-dose range requires elucidation of its maximum tolerated dose with peripheral blood progen itor cell (PBPC) support and the time interval needed between drug adm inistration and PBPC reinfusion in order to avoid graft toxicity. The aims of this study were: (1) to verify the feasibility and haematologi cal toxicity of escalating NOV up to 90 mg m(-2) with PBPC support; an d (2) to verify the safeness of a short (96 h) interval between NOV ad ministration and PBPC reinfusion. Three cohorts of ten patients with b reast cancer (BC) or non-Hodgkin's lymphoma (NHL) received escalating doses of NOV, 60, 75 and 90 mg m(-2) plus melphalan (L-PAM), 140-180 m g m(-2), with PBPC rescue 96 h after NOV. Haematological toxicity was evaluated daily (WHO criteria). NOV plasma pharmacokinetics was also e valuated, as well as NOV cytotoxicity against PBPCs. Haematological re covery was rapid and complete at each NOV dose level without statistic ally significant differences, and there were no major toxicities. NOV plasma concentrations at the time of PBPC reinfusion were below the to xicity threshold against haemopoietic progenitors. It is concluded tha t, when adequately supported with PBPCs, NOV can be escalated up to 90 mg m(-2) with acceptable haematological toxicity. PBPCs can be safely reinfused as early as 96 h after NOV administration.