1. ¹Department of Haematology, Hammersmith Hospitals Trust, Imperial College London, London, UK
2. ²Biotage Ltd, Hertford, UK

Correspondence: Dr JM Goldman, Hematology Branch, NHLBI, Building 10, Room 3-5140, 10 Center Drive, Bethesda, MD 20892-1202, USA. E-mail: goldmanj2@nhlbi.nih.gov

Received 27 July 2005; Revised 18 November 2005; Accepted 22 November 2005; Published online 9 February 2006.

Abstract

The expansion of a leukemia clone bearing a Bcr-Abl kinase domain mutation is associated with acquired resistance to imatinib and may also predict disease progression in patients with Philadelphia-positive chronic myeloid leukemia (CML). Here we report results of pyrosequencing to quantitate the non-mutated and mutant alleles in 12 CML patients monitored over periods ranging from 11 to 58 months, and describe three contrasting kinetic patterns: Group 1 – in four patients total BCR-ABL transcript numbers remained high with the mutant allele predominating; Group 2 – in four patients the total number of BCR-ABL transcripts fell to low levels but the mutant allele predominated; and Group 3 – in four other patients the total level of transcripts remained high (n=2) or fell (n=2) but the mutant clone persisted at relatively low level. In Group 2 the mutant leukemia clone was presumably still relatively sensitive to imatinib but in Group 1 the leukemia could be classified as resistant. In Group 3 patients the imatinib sensitivity of the leukemia was variable. We conclude that a mutant clone does not necessarily have a proliferative advantage and its presence does not always account for resistance to imatinib. Other mechanisms underlie resistance in at least some patients.