Cyclosporin increases cellular idarubicin and idarubicinol concentrations in relapsed or refractory AML mainly due to reduced systemic clearance

The feasibility of adding both the multidrug resistance modulator cyclospor in (CsA) and granulocyte colony-stimulating factor (G-CSF) to a standard sa lvage regimen of idarubicin (IDA) and cytarabine was evaluated in patients with resistant or relapsed acute myeloid leukemia and myelodysplastic syndr ome. Three patients received IDA 12 mg/m(2)/day, the next four patients 9 m g/m(2)/day. The dose of CsA was 16 mg/kg/day, Six patients showed Pgp expre ssion and none MRP1 expression. Grade III or IV toxicity (CTC-NCIC criteria ) was registered in six patients for gastrointestinal, two patients for car diovascular and one patient for neurological complications. Three patients died in hypoplasia and three patients showed leukemic regrowth, Three contr ol patients were treated with IDA 12 mg/m(2)/day and cytarabine, but no CsA and G-CSF, The plasma IDA and idarubicinol (ida-ol) area under the curve's of patients treated with IDA 12 mg/m(2) plus CsA were higher (P < 0.05) th an in controls, Cellular IDA concentrations were almost similar, but cellul ar ida-ol concentrations were significantly higher (P < 0.05) in the presen ce of CsA than in controls. We conclude that the toxicity either with IDA 1 2 or 9 mg/m(2)/day was too high. The modulating effect of CsA was mainly ba sed on changes in plasma kinetics of IDA and ida-ol, although ida-ol cellul ar clearance was delayed in the presence of CsA.