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Molecular Studies Suggest Combining Imatinib With Other Agents in Resistant CML

Molecular Studies Suggest Combining Imatinib With Other Agents in Resistant CML

MANNHEIM, Germany—Despite 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 (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.

Study Design

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
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

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