Abstract for presentation at 11th International Congress of Human Genetics

Limited clinical value of regular bone marrow cytogenetic analysis in imatinib-treated patients with chronic myeloid leukaemia (CML) in chronic phase who maintain a major molecular response

  • Ms Rebecca Lawrence, Institute of Medical and Veterinary Science, Australia
  • Dr David Ross, Institute of Medical and Veterinary Science, Australia
  • Dr Zbigniew Rudzki, Institute of Medical and Veterinary Science, Australia
  • Ms Sarah Moore, Institute of Medical and Veterinary Science, Australia
  • Prof Timothy Hughes, Institute of Medical and Veterinary Science, Australia
  • Dr Susan Branford, Institute of Medical and Veterinary Science, Australia

    • CML is causally related to the formation of the BCR-ABL oncogene. The gene is the product of the Philadelphia translocation, which is visible by cytogenetic analysis. The Bcr-Abl inhibitor imatinib has significantly improved response rates. Real-time quantitative PCR (RQ-PCR) for BCR-ABL mRNA in peripheral blood provides an accurate and reliable measure of imatinib response and an indication of drug resistance. Patients who achieve a major molecular response (MMR) have a significant survival advantage. Resistance is indicated by rising levels of BCR-ABL, which is significantly associated with the detection of somatic mutations in the BCR-ABL kinase domain. These mutations are the major mechanism of resistance. Our aim was to determine whether routine bone marrow cytogenetic analysis provided additional, clinically relevant information compared to a strategy of RQ-PCR monitoring and selective bone marrow examination following a significant rise in BCR-ABL levels. 828 simultaneous RQ-PCR and bone marrow cytogenetic analyses were performed on 183 imatinib-treated patients. Cytogenetic progression, defined as Philadelphia (Ph)-positive clonal evolution, loss of complete cytogenetic response or an increase of ≥20% Ph-positive cells, occurred in 24 of 183 (13%) patients. Of these 24 patients, cytogenetic progression occurred with a simultaneous or preceding rise in BCR-ABL in 20 (83%). No cytogenetic progression was detected in the corresponding cytogenetic analyses of 320 RQ-PCR results from 95 patients with a MMR. The data suggest that routine cytogenetic analysis is not necessary for patients with a MMR, which represents greater than 50% of patients. In 3 patients with a MMR, rising levels of BCR-ABL triggered the detection of imatinib resistant mutations prior to cytogenetic progression. Early detection of imatinib resistance by regular RQ-PCR monitoring and mutation analysis where indicated may allow therapeutic intervention before the loss of cytogenetic response.

    Conference Organiser - ICMS Pty Ltd