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Increased P-Glycoprotein In Chronic Myeloid Leukaemia Predicts Poor Response to Imatinib: Presented at EHA

By Paula Moyer

LYON, FRANCE -- June 19, 2003 -- Patients with chronic myeloid leukaemia who have an increase in P-glycoprotein (P-gp) activity when given imatinib mesylate (Gleevec) may have a poor response to therapy, according to researchers.

"Our long-term follow-up of patients showed that an increase in P-gp activity may predict a poor treatment outcome," said Ivna Svoboda-Beusan, MD, a researcher at the Institute of Immunology in Zagreb, Croatia. "This development may indicate the onset of chemoresistance to further therapy in those patients." She presented her and her colleagues' findings here June 13^th at the 8^th World Congress of the European Haematology Association.

The study was undertaken because, despite imatinib's success in chronic myeloid leukaemia (CML), some patients are either inherently resistant or become resistant during treatment. In a previous pilot study, the investigators had monitored CML patients, and their findings showed that the changes in P-gp phenotype and function might influence the response to imatinib.

In the current research they sought to evaluate P-gp expression and function in long-term follow-up in CML patients treated with imatinib. They also wanted to assess the occurrence of multi-drug resistance and its relationship to treatment outcome.

Twenty four patients who were more than 22 years old and had advanced CML were recruited: 4 in blast crisis; 12 in accelerated phase disease; and 8 in chronic phase disease. The patients were monitored in 3-month intervals that started in July 2001.

The patients' previous treatments included hydroxyurea (HU) and interferon-alpha. Two of the patients had received cytosine arabinoside (Ara-C) therapy to address multiple drug resistance (MDR). The patients received imatinib as oral monotherapy in doses related to their disease status. Those in blast crisis and accelerated phase received 600 mg daily; patients with chronic phase disease received 400 mg daily.

The protocol required that bone marrow and peripheral blood cells be stained simultaneously with anti-human leukocyte antigen-derived (HLA-DR)-P-gp monoclonal antibodies. The P-gp phenotype was expressed as the ratio of mean fluorescences (RMF) of specific antibodies and isotype control. The investigators assessed P-gp activity by comparing uptake-efflux rates of P-gp-related Rhodamine dye (Rh123) with P-gp reversing agent, which was also expressed as RMF.

Eight patients died during treatment; among them, the Rh123 tests showed increased activity of P-gp activity in BM and PB. Although the investigators found lower P-gp activity in the 16 responding patients, at the end of the 1-year follow-up period, they observed a tendency to in these patients to an increase P-gp activity. That finding indicates that those patients may be developing chemoresistance as well, the investigators reported. They stressed that these findings show the importance of longitudinal follow-up of patients' MDR status.


[Study title: Could Increased PGP-Related Activity Predict Outcome In Patients Undergoing Gleevec Therapy? Abstract 0101]

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