Abstract
To date, more than 50 BCR-ABL kinase domain mutations have been described in patients with imatinib-resistant (IM-R) chronic myeloid leukemia (CML) and 66% of these reported cases have mutations occurring at seven amino acid substitutions (G250, Y253, E255, T315, M351, F359 and H396) (Apperley JF. Lancet Oncol.2007;8:1018–29). These data have been derived from a predominantly Caucasian population and the pattern of mutations among Asian patients has not been well characterized. In this study, direct sequencing of the BCR-ABL kinase domain was performed in 94 IM-R CML patients of different Asian ethnicities (52% Chinese, 19% Malay, 18% Indian and 11% of other Asian ethnic origins). The median age at diagnosis of CML was 43 years with 90% diagnosed in the chronic phase (CP), 3% in the accelerated phase (AP) and 7% in blast crisis (BC). At diagnosis, 16% had a low Sokal score, 29% an intermediate score and 54% a high score. At the time of mutation analysis, the median duration of disease was 35 months (1–192) and 56% were in CP, 16% in AP and 28% in BC. The median dose of imatinib (IM) was 600 mg OD and the median duration of treatment was 24 months (1–80). Primary IM resistance occurred in 64% and 36% had acquired resistance. The incidence of mutations detected is listed in the table below. A total of 46 BCR-ABL kinase domain mutations were detected in 42 patients. Three patients had more than 1 mutation. Compared to the reported incidence of mutations in the Caucasian population, the distribution of mutations in our study cohort was fairly similar with 55% of the mutations occurring at six amino acid substitutions (G250, Y253, E255, T315, F359 and H396). A significant difference is the absence of M351T mutation which accounts for approximately 10% of mutations detected in the Western population (p=0.017, Fisher’s exact test). This mutation has a low level IM-insensitivity (cellular proliferation IC50 = 880 nM) and is thought to be associated with a loss of function and may be selected on drug exposure (Griswold IJ. Mol Cell Biol.2006;26:6082–93). A possible hypothesis for the absence of the M351T mutation in our population is that, at the same doses of IM, plasma IM levels in Asian patients are higher than that of Caucasian patients, thus resulting in the suppression of this low level IM-insensitive mutation but not of the high level IM-insensitive mutations. Pharmacokinetic analysis in a separate cohort of 27 patients treated with IM 400 mg OD in our institution revealed a mean steady-state plasma trough level of 2782 ng/ml. This level is higher than the level of 979 ng/ml reported in patients from the IRIS trial which enrolled a predominantly Caucasian population (Larson RA. Blood2008;111:4022–28). Our study suggests that the incidence of certain BCR-ABL kinase domain mutations may vary in different ethnic origins and that this variation may be related to different pharmacokinetic profiles. This observation may have important implications for planning and monitoring the ideal therapeutic IM dose for CML patients from different ethnicities.
Mutation n % Approx reported incidence (%) (Apperley, 2007) T240A 1 2 Not reported M244V 2 4 4 L248V 1 2 2 G250E 3 7 10 (incl G250A) Q252H 2 4 2 (incl Q252R) Y253F/H 7 15 11 E255K/V 6 13 11 (incl E255D/R) T277A 1 2 Not reported E279K 2 4 <1 L298V 1 2 <1 T315I 4 9 14 F317L 2 4 3 (incl F317C/V) M351T 0 0 10 E355A/G 2 4 3 (incl E355K) F359C/V 3 7 6 (incl F359L) H396R 2 4 5 (incl H396P) S438C 2 4 <1 E453K 2 4 1 (incl E453V) E459K 3 7 1 (incl E459L)
Choosing the Best Second‐Line Tyrosine Kinase Inhibitor in Imatinib‐Resistant Chronic Myeloid Leukemia Patients Harboring Bcr‐Abl Kinase Domain Mutations: How Reliable Is the IC
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