Split-Course High-Dose ARA-C Plus Idarubicin and Multidrug Blockade by short Cyclosporin-A Infusion for Refractory Acute Myeloid Leukemia

Abstract

Refractory acute myeloid leukemia (R-AML), defined as primary resistance to induction chemotherapy, early relapse (within 6-12 months from remission), and second or subsequent relapse, is typically a multidrugresistant illness, for which effective treatment is presently lacking. We have treated R-AML patients with a combination of intermediatedose ara-C, carboplatin and either mitoxantrone or idarubicin in a cross-over design, obtaining an encouraging response rate (46%) in a small group of 13 R-AML patients who were given an amended, low-toxicity regimen [1]. Five more patients were treated with a similar carboplatin-containing schedule delivered in a sequential manner, but only one remission was achieved, to an overall response rate of 33% (6/18). This result prompted a further change in retreatment strategy. In R-AML, clinical multidrug resistance is often associated with functional overexpression of the MDR1 drug efflux machinery and/or other mechanisms such as LRP (lung-related protein) and MRP (multidrug resistance-associated protein) [2-11]. Theoretically, in view of the high incidence of MDR1 activation in R-AML and its adverse clinical significance, functional MDR1 inhibition with cyclosporin A (CsA), verapamil, tamoxifen, PSC 833, quinine [12-19] or the use of drugs scarcely (Idarubicin=IDR) or not (high-dose ara-C=HiDAC, carboplatin) MDR1-sensitive could underlie therapeutic improvement. In preclinical in vitrostudies on a MDR1+ human leukemic cell line [20,21], we found that both cellular uptake and pro-apoptotic effects of IDR used at therapeutic concentration (50-100 ng/ml, corresponding to the ranges of peak plasma level obtainable after rapid intravenous administration of IDR 10-12 mg/m2) were significantly increased by co-incubation with CsA 1500 ng/ml. Interestingly, CsA enhanced IDR-related cytotoxicity only in the early phase of IDR-blast cell interaction while, contrary to daunorubicin, 12-hour IDR retention by blast cells was not modified by CsA. The study conclusion was that both cellular uptake of and related biologic effects from IDR can be upregulated by CsA in MDR1+ cells but, partly because IDR is highly lypophilic and partly because it is less vulnerable to MDR1, this effect does not require a prolonged CsA exposure. On this basis we initiated a new clinical study, using CsA and aiming to determine the upper IDR concentration tolerated by patients with R-AML. This new sequential regimen included HiDAC 3 g/m2 every 12 hours for two consecutive days followed by IDR 12.5 mg/m2 as starting dose level (both drugs were given for two times on days 1-3 and 8-10) together with CsA 6 mg/kg over 1 hour and then 7.5 mg/kg over 11 hours according to the List schedule [22]. IDR was delivered 4 hours after starting CsA. The three-day sequence was repeated on days 8-10. Recombinanat human granulocyte colony-stimulating factor (G-CSF) was administered from day 11 until response evaluation. We report the therapeutic results obtained in the first 10 patients, who received IDR from 12.5 to 17.5 mg/m²/dose.