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 cyclosporin (CsA) and granulocyte colony-stimulating factor (G-CSF) to a standard salvage regimen of idarubicin (IDA) and cytarabine was evaluated in patients with resistant or relapsed acute myeloid leukemia and myelodysplastic syndrome. Three patients received IDA 12 mg/m2/day, the next four patients 9 mg/m2/day. The dose of CsA was 16 mg/kg/day. Six patients showed Pgp expression and none MRP1 expression. Grade III or IV toxicity (CTC-NCIC criteria) was registered in six patients for gastrointestinal, two patients for cardiovascular and one patient for neurological complications. Three patients died in hypoplasia and three patients showed leukemic regrowth. Three control patients were treated with IDA 12 mg/m2/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/m2 plus CsA were higher (P< 0.05) than in controls. Cellular IDA concentrations were almost similar, but cellular ida-ol concentrations were significantly higher (P < 0.05) in the presence of CsA than in controls. We conclude that the toxicity either with IDA 12 or 9 mg/m2/day was too high. The modulating effect of CsA was mainly based on changes in plasma kinetics of IDA and ida-ol, although ida-ol cellular clearance was delayed in the presence of CsA.
Department of Hematology, University Medical Center Nijmegen, The Netherlands.
M
M
Smeets
R
R
Raymakers
P
P
Muus
G
G
Vierwinden
P
P
Linssen
R
R
Masereeuw
T
T
de Witte
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D016572:Cyclosporine / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000378:metabolism / Q000493:pharmacokinetics*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D012008:Recurrence
D007166:Immunosuppressive Agents; D016572:Cyclosporine; C054440:idarubicinol; D015255:Idarubicin; D003630:Daunorubicin