MANNHEIM, GermanyDespite encouraging initial responses, patients with chronic myelogenous leukemia (CML) frequently become resistant in the advanced, or blast crisis, phase of the disease after initially responding to selective inhibition of the Bcr-Abl tyrosine kinase by imatinib(Drug information on imatinib) (Gleevec, also known as STI571).
Andreas Hochhaus, MD, and colleagues at the University of Heidelberg in Mannheim, Germany, analyzed the molecular mechanism behind this resistance and found it to be the result of any of several well-established mechanisms for cancer drug resistance. Dr. Hochhaus reported in a plenary presentation at the 43rd Annual Meeting of the American Society of Hematology that the variety of mechanisms identified suggests that "Bcr-Abl is still a good target. A useful strategy might be to continue imatinib and add chemotherapeutic agents in these patients." Dr. Hochhaus is on the clinical medicine faculty at the University of Heidelberg.
The researchers investigated mechanisms of resistance in 50 CML patients who were refractory or resistant to imatinib (400 to 800 mg/d orally). Patients were from six multicenter phase II studies. The median duration of therapy was 123 days (range: 13-741 days). Twenty-six patients relapsed after initial responses to imatinib, and 24 had primary resistance to the drug.
Molecular and cytogenetic characteristics were determined prior to imatinib treatment and at the time of resistance. The assays included the expression level of Bcr-Abl transcripts in peripheral blood leukocytes measured by quantitative reverse transcription PCR assay, the number of genomic Bcr-Abl copies measured by interphase fluorescence in situ hybridization, and karyotypic evolution measured by metaphase cytogenetics. The Bcr-Abl tyrosine kinase domain was sequenced from cDNAs derived from resistant blasts.
Dr. Hochhaus reported that although the median level of Bcr-Abl mRNA transcripts expressed as the ratio Bcr-Abl /G6PD was not significantly changed at the time of resistance, 5 of 46 patients had a greater than 10-fold increase in Bcr-Abl levels. Fifteen patients had novel cytogenetic aberrations, of whom eight had multiple changes. Eight patients had reactivation of Bcr-Abl. Eleven patients had mutations of the adenosine(Drug information on adenosine) triphosphate (ATP) binding site of Bcr-Abl, leading to impaired binding of imatinib. These mutations occurred only in patients who had previously responded to imatinib.
Causes of Resistance Identified