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

INTRODUCTION AND OBJECTIVES A small-molecule inhibitor of the BCR-ABL tyrosine kinase Imatinib mesylate (STI 571, Glivec) is frontline therapy in chronic myeloid leukemia (CML). As rational therapeutic target it induces fast hematological and cytogenetic response with minimal toxicity. However, caused by different mechanisms, clinical progression develops in some patients. Clinical resistance to Imatinib is 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, regarding the fact that in vitro inhibition of efflux MDR1 protein P-glycoprotein (Pgp) rise intracellular Imatinib, we presume that Pgp might ruin chances of resistant patients in the long term inefficient use. PATIENTS AND METHODS To estimate the link between Pgp expression and activity on one side and the rate of hematological, cytogenetic and molecular responses and treatment outcome on the other side, in July 2001 we conducted a clinical trial on thirty four adult CML patients (M/F=19/15 ; CP/AP=26/8). First line treatment included mostly HU and IFN alpha, 12 patients received MDR-related therapy. Imatinib was administered orally: 400 mg/day for CP and 600 mg/day for AP. Bone marrow (BM) and peripheral blood (PB) cells were examined using flow cytometry. Pgp phenotype was analyzed by appropriate MRK-16 monoclonal antibody and Pgp activity was measured in Rhodamine (Rh123) efflux assay. RESULTS By now, 22 of 34 patients have been followed up ≥ 9 months, 6 died, 8 relapsed and 2 were refractory. Molecular response was demonstrated in 4 patients. Most of those achieving hematological and cytogenetic responses showed stable Pgp activity, well balanced only after one year. Pgp-associated resistance developed with a median time of 6 months, resistant cells were found both in BM and PB. In patients who underwent clinical relapse and died, the Rh123 dynamic was higher and tendency of Pgp activity increase was observed, indicating that Imatinib efflux is mediated by Pgp. CONCLUSION Our experimental results provide a rationale for long-term follow up of MDR status: Moreover, from the prognostic point of view, longitudinal MDR screening may be helpful in determination of Imatinib-resistant patients and MDR1/Pgp modulation would be beneficial for their further treatment.