Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors

Abstract

Dasatinib and nilotinib are potent tyrosine kinase inhibitors (TKIs) with activity against many imatinib-resistant chronic myeloid leukemia (CML) clones with BCR-ABL kinase domain (KD) mutations, except T315I. We assessed for changes in the BCR-ABL KD mutation status in 112 patients with persistent CML who received a second-generation TKI after imatinib failure. Sixty-seven different KD mutations were detected before the start of therapy with a second TKI, with T315I seen in 15%. Equal numbers of patients received nilotinib or dasatinib following imatinib, and 18 received 3 TKIs. Response rates were similar for patients with and without mutations, regardless of mutation site except for T315I. Overall, 29 patients (26%) developed new KD mutations after therapy with a second (n ‫؍‬ 24) or third (n ‫؍‬ 5) TKI, but only 4 (4%) developed T315I. In 73% of cases, the KD mutations that persisted or developed following switch to new TKI were at sites also found in prior in vitro TKI mutagenesis assays. Although there is only a mild increase in mutation frequency with sequential TKI treatment, novel mutations do occur and mutation regression/acquisition/persistence generally reflects the in vitro differential sensitivity predicted for each TKI. In this study, there was no marked increase in development of T315I. (Blood. 2007;110: [4005][4006][4007][4008][4009][4010][4011]

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

“…All patients should have their CML cells tested for BCR-ABL kinase domain mutations, as this will help guide the decision on which TKI to select. Dasatinib and nilotinib retain activity against most of the known mutations that confer resistance to imatinib [65,66]. When selecting between dasatinib and nilotinib, in vitro and in vivo data have identified distinct mutations that exhibit decreased sensitivity to each of the agents [67,68].…”

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

“…For instance, the agent imatinib mesylate led to a large number of cytogenic and molecular responses in CML patients, resulting in greatly prolonged survival. However, a considerable proportion of these patients exhibited either primary or secondary resistance, or intolerance to imatinib (Cortes et al, 2007). In addition, in a multicenter, nonrandomized Stop Imatinib trial, B60% of the patients relapsed after an interruption to the imatinib therapy, although they had maintained a complete molecular response (Mahon et al, 2010).…”

HPLC–MS method for the simultaneous quantification of the antileukemia drugs imatinib, dasatinib and nilotinib in human peripheral blood mononuclear cell (PBMC)

“…In order to manage primary or acquired resistance to imatinib, clinical studies using dasatinib or nilotinib as second line therapy or combination of therapies with different TKIs, in sequential or simultaneous administration, are currently under evaluation [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. Sub-inhibitory intracellular drug concentrations, probably, and sequential treatment with multiple tyrosine kinase inhibitors promote the selection of BCR-ABL kinase domain mutations in CML patients [51][52]. Poor penetration of drugs into leukocytes or PBMC, inadequate treatment adherence, and variability in drug PK may also contribute to the occurrence of sub-therapeutic drug level.…”