High-dose idarubicin in combination with Ara-C in patients with relapsed or refractory acute lymphoblastic leukemia: a pharmacokinetic and clinical study

Cancer Chemother Pharmacol (2007) 59:771779

DOI 10.1007/s00280-006-0332-4

ORIGINAL ARTICLE

High-dose idarubicin in combination with Ara-C in patients with relapsed or refractory acute lymphoblastic leukemia:a pharmacokinetic and clinical study

Alessandra Tedeschi Marco Montillo Elena Strocchi Anna Maria Cafro Elisabetta Tresoldi Liliana Intropido Michele Nichelatti Laura Marbello Claudia Barat Carlo Maurizio Camaggi Enrica Morra

Received: 16 May 2006 / Accepted: 14 August 2006 / Published online: 26 January 2007 Springer-Verlag 2007

Abstract

Objective High dose (HD) Ara-C combined with a single HD idarubicin dose (IDA) is an eYcient and safe salvage regimen for patients with refractory or relapsed acute lymphoblastic leukemia as indicated by phase II studies. No data are available on the pharmacokinetics of IDA after a rapid HD intravenous infusion. An open phase II pharmacokinetic and clinical study was performed to evaluate antileukemic eYcacy, IDA pharmacokinetics and to investigate the presence of IDA and its reduced metabolite idarubicinol (IDAol) in cerebrospinal Xuid (CSF) of patients treated with HD-IDA.

Patients and methods Twenty-Wve patients with refractory or relapsed acute lymphoblastic leukemia received Ara-C 3 g/m2 from days 15, idarubicin (HDIDA) 40 mg/m2 as rapid intravenous (i.v.) infusion on day 3 and subcutaneous G-CSF 5 [afii9839]g/kg from day 7 until PMN recovery. Pharmacokinetics of IDA was evaluated after HD idarubicin administration in nine of these patients. CSF samples were collected in 15

patients at diVerent times. IDA and IDAol concentrations were quantiWed by a validated HPLC assay described in detail elsewhere.

Results Eleven patients (44%, 95% CI: 2365%) achieved complete remission with median disease free survival for 6 months. After administration of HDIDA i.v. bolus of 40 mg/m2, plasma level proWles of unchanged drug and IDAol were similar to those previously described after standard dose and measured with the same analytical method. The mean terminal half-life measured for IDA in this group of patients(14.9 h) was not signiWcantly diVerent from the mean value observed after standard dose (13.9 h, P =0.72). IDAol t1/2 was also similar after HD-IDA (46.2 h) and standard dose (39.4 h, P = 0.79). Pharmacokinetic data reveal that in our series of patients IDA and IDAol clearances are signiWcantly higher than those observed in patients treated with 12 mg/m2 of IDA but, although the administered dose (mg/m2) of the drug is 3.3 times...