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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-03-0777.
Submitted March 15, 2002
Accepted April 22, 2002
The Impact of Clonal Evolution on Response to Imatinib Mesylate (STI571) in Accelerated Phase CML
Michael E O'Dwyer*, Michael J Mauro, Gwen Kurlik, Motomi Mori, Suzanne Balleisen, Susan Olson, Ellen Magenis, Renaud Capdeville, and Brian J Drucker
Leukemia Center, Oregon Health & Science University, Portland, Oregon, USA
Oregon Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA
Molecular & medical Genetics, Oregon Health & Science University, Portland, Oregon, USA
Novartis Pharma, Basel, Switzerland
* Corresponding author; email: odwyerm{at}ohsu.edu.
In chronic myelogenous leukemia (CML), the development of chromosomal abnormalities in addition to the Philadelphia chromosome (clonal evolution) is considered by many to be a feature of accelerated phase (AP). Imatinib mesylate (STI571), a selective inhibitor of the Bcr-Abl tyrosine kinase, has significant activity in AP CML. As clonal evolution could allow Bcr-Abl independent proliferation, we analyzed its impact on the outcome of 71 AP patients treated with 600 mg of imatinib mesylate. 15 patients had clonal evolution alone (AP-CE), 32 had AP features but no evidence of clonal evolution (AP-HEM) and 24 had AP features plus clonal evolution (AP-HEM + CE). 73% of AP-CE patients had a major cytogenetic response compared to 31% HEM-AP (p=0.043) and 12.5% HEM-AP + CE (p = 0.007). Complete cytogenetic responses were seen in 60% of AP-CE patients compared to 31% of HEM-AP (p=0.19) and 8% HEM-AP + CE (p<0.001). With mean follow up of 11.2 months, 35% of all patients failed treatment. The lowest estimated rate of treatment failure at 1 year was seen in AP-CE patients, 0%, compared to 31% of HEM-AP and 69% of HEM-AP + CE (p=0.0004). After 1 year, 100% of AP-CE patients were still alive compared to 85% of HEM-AP and 67.5% of HEM-AP + CE, (p=0.01). In conclusion, in patients with clonal evolution as the sole criterion of disease acceleration, good responses to imatinib are still possible. Once patients have other signs of acceleration, this feature predicts lower response rates and a shorter time to treatment failure.
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