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Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase.
- Source :
-
Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2009 Sep 01; Vol. 27 (25), pp. 4204-10. Date of Electronic Publication: 2009 Aug 03. - Publication Year :
- 2009
-
Abstract
- Purpose: Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed.<br />Patients and Methods: Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial.<br />Results: Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC(50)] <or= 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC(50) > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13%, 43%, and 9% of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR.<br />Conclusion: For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib.
- Subjects :
- Australia
Benzamides
Drug Resistance, Neoplasm genetics
Europe
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Leukemic
Humans
Imatinib Mesylate
Korea
Leukemia, Myelogenous, Chronic, BCR-ABL Positive enzymology
Piperazines therapeutic use
Time Factors
Treatment Outcome
United States
Antineoplastic Agents therapeutic use
Fusion Proteins, bcr-abl antagonists & inhibitors
Fusion Proteins, bcr-abl genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
Mutation
Protein Kinase Inhibitors therapeutic use
Pyrimidines therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1527-7755
- Volume :
- 27
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 19652056
- Full Text :
- https://doi.org/10.1200/JCO.2009.21.8230