engleski

Longitudinal follow up of Pgp related multidrug resistance in patients undergoing Imatinib mesylate therapy

The efficacy of imatinib mesylate (STI571, Glivec) in the treatment of chronic myeloid leukemia (CML) is well documented. Although imatinib potently suppresses tyrosine kinase activity of BCR-ABL and induces apoptosis of Ph+ cells, after significant hematological and cytogenetic response some patients become resistant or are even inherently resistant. The fact that multidrug resistance (MDR) could be reversed in vitro with rising of intracellular imatinib by P-glycoprotein (Pgp) efflux pump inhibitor suggests energy-dependent ABC-transporter Pgp as one of the reasons of MDR. Since the cells in advanced CML have MDR1 gene overexpression and Pgp could enhance imatinib efflux, to prevent therapy failure, our objective was to estimate the occurrence of MDR and its relation to the treatment outcome. Starting with July 2001, in 3 months intervals we monitored Pgp expression and activity in thirty adult patients with advanced CML (5 in BC, 10 in AP and 15 in CP). Previous treatment included mostly HU and IFN alpha ; 6 patients received MDR-related therapy. Imatinib was administered orally: 600 mg/day for BC and AP and 400 mg/day for CP, respectively. Bone marrow (BM) and peripheral blood (PB) cells were examined using flow cytometry. Pgp phenotype was analysed in anti HLA-DR/Pgp combination and Pgp activity was measured in Rhodamine (Rh123) functional efflux assay. Among 30 patients, 9 died, 8 relapsed and 2 were refractory. Pgp-associated resistant cells were found both in BM and PB. As central and peripheral myelogenous cells confirmed similar status in the absence of BM aspirate Pgp-related MDR status could be assessed on PB samples. Our results indicate the importance of longitudinal MDR screening. Most of the patients achieving hematological response showed stable Pgp activity, well balanced only after one year. In those who underwent clinical relapse and died, the Rh123 dynamic was higher and tendency of Pgp activity increase was observed. Moreover, from the prognostic point of view, long-term follow up of MDR status may be helpful in determination of imatinib– resistant patients which might be crucial for their further treatment.

Imatinib mesylate; Multidrug resistance

nije evidentirano