Kinetics of BCR-ABL Mutant Clones Determines Resistance in CML on Second Generation TKI Treatment
| Autor: | Ingvild Mikkola, Martin C. Müller, Dietger Niederwieser, Jaqueline Maier, Thomas Ernst, Thoralf Lange, Franz X Gruber, Andreas Hochhaus, Kimmo Porkka |
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| Rok vydání: | 2008 |
| Předmět: | |
| Zdroj: | Blood. 112:2127-2127 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.v112.11.2127.2127 |
| Popis: | BCR-ABL kinase domain (KD) mutations are the major mechanism of acquired imatinib resistance in patients (pts) with chronic myeloid leukemia (CML). Second generation tyrosine kinase inhibitors (TKI) are effective against most imatinib resistance mutations but treatment can be hampered by the emergence of secondary drug-resistant clones over time. Furthermore, individual KD mutations differ according to their in vitro transforming potency and tyrosine kinase activity which in vivo upon presence of multiple mutations may result in competition between different clones. Using a novel sensitive and quantitative monitoring approach we systematically investigated the kinetics of drug-resistant mutants on second generation TKI in order to identify patterns of dynamics and to understand mechanisms of polyclonal drug resistance. Fourty CML pts (24 m; median age 64 years, range 39–74) with resistance to imatinib in chronic phase (n=31), accelerated phase (n=7), or blast crisis (n=2) were treated with dasatinib (D, n=20) or nilotinib (N, n=20). Peripheral blood samples taken at baseline and after 3, 6, 9, and 12 months on second generation TKI therapy were subjected to standard genotyping performed by D-HPLC/sequencing and two high-sensitive allele-specific approaches (ligation PCR [L-PCR] and amplification refractory mutation system PCR [ARMS-PCR]) for a panel of 13 key mutations: G250E, Q252H, Y253F/H, E255K/V, V299L, T315I, F311I, F317L, M351T, E355G, F359V. All mutational findings obtained by at least two methods were subjected to quantitative monitoring of BCR-ABLmutant/GUS by ARMS-PCR allowing (i) a dynamical detection range of mutant BCR-ABL over 3 to 4 orders of magnitude and (ii) quantification of the mutant cell subset towards BCR-ABL/GUS ratio. We identified a total of 53 mutated clones in 28 imatinib resistant subjects, of which 46 were assessed quantitatively over time. The following patterns of kinetics were observed: I. A parallel decrease (>2 orders of magnitude) of BCR-ABLmutant/GUS and BCR-ABL/GUS ratio without further mutations emerging (monoclonal resistance, good molecular response, n=11). II. Persistence of a single mutated clone (change |
| Databáze: | OpenAIRE |
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