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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- Susan Branford
- From the Institute of Medical and Veterinary Science, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne, Victoria; Mater Hospital, Brisbane, Queensland; Royal Perth Hospital, Perth, Western Australia; Peter MacCallum Cancer Institute, Melbourne, Victoria; Royal North Shore Hospital, Sydney, New South Wales; Sir Charles Gairdner Hospital, Perth, Western Australia; and Novartis Pharmaceuticals Australia, North Ryde, Sydney.
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- Zbigniew Rudzki
- From the Institute of Medical and Veterinary Science, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne, Victoria; Mater Hospital, Brisbane, Queensland; Royal Perth Hospital, Perth, Western Australia; Peter MacCallum Cancer Institute, Melbourne, Victoria; Royal North Shore Hospital, Sydney, New South Wales; Sir Charles Gairdner Hospital, Perth, Western Australia; and Novartis Pharmaceuticals Australia, North Ryde, Sydney.
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- Sonya Walsh
- From the Institute of Medical and Veterinary Science, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne, Victoria; Mater Hospital, Brisbane, Queensland; Royal Perth Hospital, Perth, Western Australia; Peter MacCallum Cancer Institute, Melbourne, Victoria; Royal North Shore Hospital, Sydney, New South Wales; Sir Charles Gairdner Hospital, Perth, Western Australia; and Novartis Pharmaceuticals Australia, North Ryde, Sydney.
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- Ian Parkinson
- From the Institute of Medical and Veterinary Science, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne, Victoria; Mater Hospital, Brisbane, Queensland; Royal Perth Hospital, Perth, Western Australia; Peter MacCallum Cancer Institute, Melbourne, Victoria; Royal North Shore Hospital, Sydney, New South Wales; Sir Charles Gairdner Hospital, Perth, Western Australia; and Novartis Pharmaceuticals Australia, North Ryde, Sydney.
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- Andrew Grigg
- From the Institute of Medical and Veterinary Science, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne, Victoria; Mater Hospital, Brisbane, Queensland; Royal Perth Hospital, Perth, Western Australia; Peter MacCallum Cancer Institute, Melbourne, Victoria; Royal North Shore Hospital, Sydney, New South Wales; Sir Charles Gairdner Hospital, Perth, Western Australia; and Novartis Pharmaceuticals Australia, North Ryde, Sydney.
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- Jeff Szer
- From the Institute of Medical and Veterinary Science, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne, Victoria; Mater Hospital, Brisbane, Queensland; Royal Perth Hospital, Perth, Western Australia; Peter MacCallum Cancer Institute, Melbourne, Victoria; Royal North Shore Hospital, Sydney, New South Wales; Sir Charles Gairdner Hospital, Perth, Western Australia; and Novartis Pharmaceuticals Australia, North Ryde, Sydney.
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- Kerry Taylor
- From the Institute of Medical and Veterinary Science, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne, Victoria; Mater Hospital, Brisbane, Queensland; Royal Perth Hospital, Perth, Western Australia; Peter MacCallum Cancer Institute, Melbourne, Victoria; Royal North Shore Hospital, Sydney, New South Wales; Sir Charles Gairdner Hospital, Perth, Western Australia; and Novartis Pharmaceuticals Australia, North Ryde, Sydney.
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- Richard Herrmann
- From the Institute of Medical and Veterinary Science, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne, Victoria; Mater Hospital, Brisbane, Queensland; Royal Perth Hospital, Perth, Western Australia; Peter MacCallum Cancer Institute, Melbourne, Victoria; Royal North Shore Hospital, Sydney, New South Wales; Sir Charles Gairdner Hospital, Perth, Western Australia; and Novartis Pharmaceuticals Australia, North Ryde, Sydney.
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- John F. Seymour
- From the Institute of Medical and Veterinary Science, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne, Victoria; Mater Hospital, Brisbane, Queensland; Royal Perth Hospital, Perth, Western Australia; Peter MacCallum Cancer Institute, Melbourne, Victoria; Royal North Shore Hospital, Sydney, New South Wales; Sir Charles Gairdner Hospital, Perth, Western Australia; and Novartis Pharmaceuticals Australia, North Ryde, Sydney.
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- Chris Arthur
- From the Institute of Medical and Veterinary Science, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne, Victoria; Mater Hospital, Brisbane, Queensland; Royal Perth Hospital, Perth, Western Australia; Peter MacCallum Cancer Institute, Melbourne, Victoria; Royal North Shore Hospital, Sydney, New South Wales; Sir Charles Gairdner Hospital, Perth, Western Australia; and Novartis Pharmaceuticals Australia, North Ryde, Sydney.
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- David Joske
- From the Institute of Medical and Veterinary Science, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne, Victoria; Mater Hospital, Brisbane, Queensland; Royal Perth Hospital, Perth, Western Australia; Peter MacCallum Cancer Institute, Melbourne, Victoria; Royal North Shore Hospital, Sydney, New South Wales; Sir Charles Gairdner Hospital, Perth, Western Australia; and Novartis Pharmaceuticals Australia, North Ryde, Sydney.
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- Kevin Lynch
- From the Institute of Medical and Veterinary Science, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne, Victoria; Mater Hospital, Brisbane, Queensland; Royal Perth Hospital, Perth, Western Australia; Peter MacCallum Cancer Institute, Melbourne, Victoria; Royal North Shore Hospital, Sydney, New South Wales; Sir Charles Gairdner Hospital, Perth, Western Australia; and Novartis Pharmaceuticals Australia, North Ryde, Sydney.
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- Tim Hughes
- From the Institute of Medical and Veterinary Science, Adelaide, South Australia; Royal Melbourne Hospital, Melbourne, Victoria; Mater Hospital, Brisbane, Queensland; Royal Perth Hospital, Perth, Western Australia; Peter MacCallum Cancer Institute, Melbourne, Victoria; Royal North Shore Hospital, Sydney, New South Wales; Sir Charles Gairdner Hospital, Perth, Western Australia; and Novartis Pharmaceuticals Australia, North Ryde, Sydney.
Abstract
<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 < .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 < .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>
Journal
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- Blood
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Blood 102 (1), 276-283, 2003-07-01
American Society of Hematology
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Details 詳細情報について
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- CRID
- 1361699995347007360
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- NII Article ID
- 30022495848
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- ISSN
- 15280020
- 00064971
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- Data Source
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- Crossref
- CiNii Articles