engleski

Determination of P-glycoprotein profile in CML patients undergoing Imatinib mesylate therapy

Selective inhibition of the BCR-ABL tyrosine kinase by Imatinib mesylate (Glivec) has proven to be a promising frontline therapeutic strategy for patients with chronic myeloid leukemia (CML). Still, while Imatinib does induce a good cytogenetic and hematologic response, the molecular response remains poor with the development of clinical progression in some of the patients. Previously we have evaluated the occurrence of multidrug resistance (MDR) in cells of CML patients treated with Imatinib by monitoring the P-glycoprotein (Pgp) expression and function. Now we wanted to assess the link between the change in Pgp expression/activity and the clinical i.e. hematological, cytogenetic and molecular response to Imatinib. In a long term follow up (4 years in intervals of 3 months during first 2 years, every 6 months later on) of 34 adult CML patients (M/F=19/15 ; CP/AP=26/8), bone marrow (BM) and peripheral blood (PB) cells were examined using flow cytometry. Pgp phenotype was analyzed by specific antibody and Pgp activity was measured by Rhodamine (Rh123) efflux assay. Imatinib (400 mg/day for CP and 600 mg/day for AP) was started after an inefficient first line (HU, IFN-alpha and MDR-related) therapy. By now, 25 of 34 patients have been followed for ≥ 9 months. Molecular response at PCR analysis was demonstrated in 5 pts. The pts achieving hematological and cytogenetic response showed stable Pgp activity, well balanced after one year. We created individual Pgp profiles because of great variability in Pgp expression/activity of the BM and PB cells of our patients, especially in the early follow up period, Analyzing the association between the established Pgp profiles and the response to Imatinib, we were able to discern four types of Pgp profiles /response to therapy (Table): i) stable Pgp activity/molecular response ; ii) stable Pgp activity/clinical response ; iii) increasing Pgp activity/minor response– development of resistance to Imatinib ; iv) constant increase of Pgp activity/poor response – established resistance to Imatinib. We demonstrated that quantitive determination of Pgp status during Imatinib therapy does show differences in Pgp function, indicating that Pgp efflux could be one of the mechanisms of resistance to Imatinib. The increase of Pgp activity observed in pts refractory to Imatinib or relapsed pts and progression free survival in pts with stable Pgp activity indicate the importance of Pgp screening in pts with CML. From the prognostic point of view, long term follow up of the Pgp status with the determination of Imatinib-Pgp phenotypes may be helpful in the evaluation of the progression/relapse of CML.

Imatinib mesylate ; Pgp ; CML

Rad je kao poster pretentiran i na skupu Annual Meeting of the Croatian Immunological Society 2005. održanom od 29.09.-02.10.2005.g., Božava, Hrvatska ; objavljen u Knjizi sažetaka ; Rijeka, 2005.g. ; str. 33-33.