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

Imatinib mesylate (STI 571, Glivec), a small-molecule inhibitor of the BCR-ABL tyrosine kinase is now frontline therapy in chronic myeloid leukemia (CML). As rational therapeutic target, imatinib induces fast hematological and cytogenetic response with minimal toxicity. Unfortunately, the clinical relapse develops rapidly caused by different mechanisms. Clinical resistance is primarily mediated by mutation within BCR-ABL kinase domain and, to a lesser extent, by reduced intracellular imatinib accumulation. Since the cells in advanced CML overexpress multidrug resistance (MDR) gene and according the fact that MDR transporter inhibition rise intracellular imatinib in vitro, we presume that energy-dependent P-glycoprotein (Pgp) might have some impact on Imatinib distribution. As previous studies show Pgp as one of the reasons of increased efflux (1, 2), our objective was to estimate the occurrence of MDR and its relation to the treatment outcome. Therefore, in July 2001, we started the clinical trial that will tell us something about highest risk patients. During 3 years, in 3 months interval we monitored Pgp expression and activity in 30 adult (22-70) patients with advanced CML (5 in blast crisis BC, 10 in accelerated phase AP and 15 in chronic phase CP). Imatinib was administered orally: 600 mg/day for BC and AP and 400 mg/day for CP, respectively. Previous treatment included mostly HU and IFN alpha ; 9 patients received MDR-related therapy. Bone marrow (BM) and peripheral blood (PB) cells were examined using flow cytometry. Pgp phenotype was analyzed in anti HLA-DR/Pgp combination and Pgp activity was measured in Rhodamine (Rh123) functional efflux assay. Among 30 patients, 10 died, 8 relapsed and 2 were refractory. Pgp-associated MDR 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. 1. Blood 2000 ; 96:1070 2. Hematol J ; 2002 ; 3 (S1): 313,

Multidrug resistance; Imatinib mesylate; CML

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