engleski

Long term assessment of Pgp-related multidrug resistance in chronic myeloid leukemia patients undergoing imatinib mesylate therapy

BACKGROUND: Imatinib mesylate (Glivec, Novartis, Switzerland) becomes the first line treatment of chronic myeloid leukemia (CML). Although imatinib mesylate represents successful treatment strategy in CML, some patients develop resistance during the treatment, some are even inherently resistant to imatinib and its long-term unsuccessful use may ruin chances of resistant patients to benefit from other therapies. Therefore it is important to predict the responsiveness among patients what would allow them to get the most adequate treatment. AIM: To assess in CML patients undergoing imatinib therapy in long-term follow up study the Pgp expression and activity , to estimate the occurrence of P-glycoprotein (Pgp)– related multidrug resistance (MDR), and to determine the correlation of Pgp expression and activity to the treatment outcome. METHODS: Thirty adult patients with advanced CML (5 in blast crisis (BC), 10 in accelerated phase (AP) and 15 in chronic phase (CP)) were monitored in 3 months intervals starting with July 2001. Previous treatment included mostly HU and IFN alpha ; 6 patients received MDR-related therapy. Imatinib was administered as oral therapy: 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: the cells were stained simultaneously with anti HLA-DR/Pgp moAbs and the Pgp phenotype was expressed as the ratio of mean fluorescences (RMF) of specific antibodies and isotype control. Pgp activity was measured with specific Pgp-modulator Cyclosporine (CsA) by comparing uptake/efflux rates of Pgp-related Rhodamine dye (Rh123) with reversing agent and the function was expressed as RMF comparing the mean fluorescence of Rh123 in CsA and CsA-free sample. RESULTS: Among 30 patients, 9 died, 8 relapsed and 2 were refractory. Central and peripheral myelogenous cells confirmed similar MDR status ; Pgp-associated resistant cells were found both in BM and PB. Most of the patients achieving hematological remission showed stable Pgp activity, whereas in those who underwent clinical relapse and died the tendency of Pgp activity increase was observed. CONCLUSION: Our results showed that longitudinal follow up of Pgp-related MDR status could detect resistant patients what might be crucial for their further treatment. Moreover, in the absence of BM aspirate it is possible to assess Pgp phenotype and transport activity only on PB samples. As increased Pgp-related MDR activity could be associated with chemoresistance to imatinib therapy, Pgp-related Rhodamine assay could become a sensitive prognostic tool for clinical practice in the management of CML.

Multidrug resistance; Imatinib mesylate; CML

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