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Branford, Susan; Rudzki, Zbigniew; Walsh, Sonya; Parkinson, Ian; Grigg, Andrew; Szer, Jeff; Taylor, Kerry; Herrmann, Richard; Seymour, John F.; Arthur, Chris; Joske, David; Lynch, Kevin; Hughes, Tim

Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis

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  • Medientyp: E-Artikel
  • Titel: Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis
  • Beteiligte: Branford, Susan; Rudzki, Zbigniew; Walsh, Sonya; Parkinson, Ian; Grigg, Andrew; Szer, Jeff; Taylor, Kerry; Herrmann, Richard; Seymour, John F.; Arthur, Chris; Joske, David; Lynch, Kevin; Hughes, Tim
  • Erschienen: American Society of Hematology, 2003
  • Erschienen in: Blood
  • Sprache: Englisch
  • DOI: 10.1182/blood-2002-09-2896
  • ISSN: 0006-4971; 1528-0020
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:p>Imatinib-treated chronic myeloid leukemia (CML) patients with acquired resistance commonly have detectable BCR-ABL kinase domain mutations. It is unclear whether patients who remain sensitive to imatinib also have a significant incidence of mutations. We evaluated 144 patients treated with imatinib for BCR-ABL kinase domain mutations by direct sequencing of 40 accelerated phase (AP), 64 late chronic phase (≥ 12 months from diagnosis, late-CP), and 40 early-CP patients. Mutations were detected in 27 patients at 17 different residues, 13 (33%) of 40 in AP, 14 (22%) of 64 in late-CP, and 0 of 40 in early-CP. Acquired resistance was evident in 24 (89%) of 27 patients with mutations. Twelve (92%) of 13 patients with mutations in the adenosine triphosphate (ATP) binding loop (P-loop) died (median survival of 4.5 months after the mutation was detected). In contrast, only 3 (21%) of 14 patients with mutations outside the P-loop died (median follow-up of 11 months). As the detection of mutations was strongly associated with imatinib resistance, we analyzed features that predicted for their detection. Patients who commenced imatinib more than 4 years from diagnosis had a significantly higher incidence of mutations (18 [41%] of 44) compared with those treated within 4 years (9 [9%] of 100), P &amp;lt; .0001. Lack of a major cytogenetic response (MCR) was also associated with a higher likelihood of detecting a mutation; 19 (38%) of 50 patients without a MCR had mutations compared with 8 (8.5%) of 94 with an MCR, P &amp;lt; .0001. In conclusion, the detection of kinase domain mutations using a direct sequencing technique was almost always associated with imatinib resistance, and patients with mutations in the P-loop had a particularly poor prognosis. (Blood. 2003; 102:276-283)</jats:p>
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