1. ¹Cell and Developmental Biology, Oregon Health & Science University, Portland, OR, USA
2. ²Division of Hematology and Medical Oncology, Oregon Health & Science University Cancer Institute, Portland, OR, USA
3. ³Portland VA Medical Center, Oregon Health & Science University, Portland, OR, USA
4. ⁴Department of Pathology, Oregon Health & Science University, Portland, OR, USA
5. ⁵Howard Hughes Medical Institute, Oregon Health & Science University, Portland, OR, USA

Correspondence: Dr M Deininger, Division of Hematology and Medical Oncology, L592, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA. E-mail: deininge@ohsu.edu

Received 10 May 2006; Revised 16 November 2006; Accepted 20 November 2006; Published online 25 January 2007.

Abstract

Residual leukemia is demonstrable by reverse transcriptase-polymerase chain reaction in most patients with chronic myeloid leukemia who obtain a complete cytogenetic response (CCR) to imatinib. In patients who relapse during imatinib therapy, a high rate of mutations in the kinase domain of BCR-ABL have been identified, but the mechanisms underlying disease persistence in patients with a CCR are poorly characterized. To test whether kinase domain mutations are a common mechanism of disease persistence, we studied patients in stable CCR. Mutations were demonstrated in eight of 42 (19%) patients with successful amplification and sequencing of BCR-ABL. Mutation types were those commonly associated with acquired drug resistance. Four patients with mutations had a concomitant rise of BCR-ABL transcript levels, two of whom subsequently relapsed; the remaining four did not have an increase in transcript levels and follow-up samples, when amplifiable, were wild type. BCR-ABL-kinase domain mutations in patients with a stable CCR are infrequent, and their detection does not consistently predict relapse. Alternative mechanisms must be responsible for disease persistence in the majority of patients.