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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-03-0777.
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Blood, 1 September 2002, Vol. 100, No. 5, pp. 1628-1633
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
The impact of clonal evolution on response to imatinib mesylate
(STI571) in accelerated phase CML
Michael E. O'Dwyer,
Michael J. Mauro,
Gwen Kurilik,
Motomi Mori,
Suzanne Balleisen,
Susan Olson,
Ellen Magenis,
Renaud Capdeville, and
Brian J. Druker
From the Leukemia Center, Oregon Health and Science
University Cancer Institute, and Department of Molecular and Medical
Genetics, Oregon Health and Science University, Portland; Department of
Haematology, University College Hospital, Galway, Ireland; and Novartis
Pharma, Basel, Switzerland.
In chronic myelogenous leukemia (CML), the development of
chromosomal abnormalities in addition to the Philadelphia chromosome (clonal evolution) is considered by many to be a feature of accelerated phase (AP). Imatinib mesylate (STI571), a selective inhibitor of the
Bcr-Abl tyrosine kinase, has significant activity in AP CML. As clonal
evolution could allow Bcr-Abl independent proliferation, we analyzed
its impact on the outcome of 71 AP patients treated with 600 mg of
imatinib mesylate. Fifteen patients had clonal evolution alone (AP-CE),
32 had AP features but no evidence of clonal evolution (HEM-AP), and 24 had AP features plus clonal evolution (HEM-AP + CE). Of the AP-CE
patients, 73% had a major cytogenetic response, compared with 31% of
the HEM-AP patients (P = .043) and 12.5% of the
HEM-AP + CE patients (P = .007). Complete cytogenetic responses were seen in 60% of AP-CE patients, compared with 31% of HEM-AP patients (P = .19) and 8% of
HEM-AP + CE patients (P < .001). With mean follow-up
of 11.2 months, 35% of all patients failed treatment. The lowest
estimated rate of treatment failure at 1 year, 0%, was seen in AP-CE
patients, compared with rates of 31% for HEM-AP patients and 69% for
HEM-AP + CE patients (P = .0004). After 1 year,
100% of AP-CE patients were still alive, compared with 85% of HEM-AP
patients and 67.5% of HEM-AP + CE patients (P = .01). In conclusion, in patients with clonal evolution as the sole
criterion of disease acceleration, good responses to imatinib are still
possible. Once patients have other signs of acceleration, clonal
evolution predicts lower response rates and a shorter time to
treatment failure.
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