Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)–based mutagenesis screen: high efficacy of drug combinations
“…88 We tested several known PDGFR inhibitors for their activity against the imatinib-resistant T674I mutant form of FIP1L1-PDGFRa using a cellular screen in Ba/F3 cells (Table 7). PKC412, a potent FLT3 inhibitor that is in clinical development for the treatment of AML, was the first inhibitor to be identified with activity against the FIP1L1-PDGFRa T674I mutant.…”
“…88 We tested several known PDGFR inhibitors for their activity against the imatinib-resistant T674I mutant form of FIP1L1-PDGFRa using a cellular screen in Ba/F3 cells (Table 7). PKC412, a potent FLT3 inhibitor that is in clinical development for the treatment of AML, was the first inhibitor to be identified with activity against the FIP1L1-PDGFRa T674I mutant.…”
“…In June 2006, the patient showed a white blood count of >60 000 cells/mm 3 with numerous blasts. Resistance to nilotinib in patients with the E255K mutation was predicted by in vitro studies (Bradeen et al, 2006) and recently observed in patients (Quintas-Cardama et al, 2007). It resulted in rapid dramatic increase of mutated leukemic cells.…”
Section: Resultsmentioning
confidence: 88%
“…Consequently, new kinase inhibitors are being developed that are active against imatinib-resistant mutants. Although these new inhibitors have a broad spectrum of activity against imatinib-resistant BCR-ABL variants, they remain ineffective against a handful of mutants and will elicit their own unique set of resistant mutations (Bradeen et al, 2006;Talpaz et al, 2006).…”
Resistance to molecularly targeted chemotherapy, and the development of novel agents that are active against resistant forms of target proteins create the need for a sensitive and quantitative assay to monitor drug-resistant mutations in patients to guide treatment and assess response. Here, we describe an application of the polymerase colony (polony) method to identify and quantify known point mutations in the BCR-ABL oncogene in patients with chronic myelogenous leukemia who evolve resistance to ABL kinase inhibitors. The assay can detect mutations with a sensitivity of 10 À4 , quantify the burden of drug-resistant cells, and simultaneously monitor the dynamics of several coexisting mutations. As a proof of concept, we analysed blood samples from three patients undergoing therapy with ABL kinase inhibitors and found that the patients' response to therapy correlated with our molecular monitoring. We were also able to detect mutations emerging in patients long before clinical relapse. Therefore, the polony assay could be applied to a larger patient sample to assess the utility of early mutation detection in patient-specific treatment decisions. Finally, this methodology could be a valuable research tool to shed light on the natural behavior of mutations pre-existing kinase inhibitors therapy and either disappearing over time or slowly taking over.
“…In the 5-year analysis of the IRIS data, a CCyR at 12 months was associated with freedom from progression to accelerated phase (AP) or blast crisis (BC) in 97% of patients at 60 months follow-up compared with 81% of patients without a major cytogenetic response (0%-35% Ph ϩ metaphases) (P Ͻ .001). 1 In a large single-institution analysis of 204 consecutive newly diagnosed CP-CML patients treated with imatinib, CCyR at 12 months was associated with better OS 98.0% versus 74.1% (P ϭ .03) and progression-free survival (PFS) 96.0% versus 74.0% (P ϭ .007), respectively, compared with those not achieving CCyR. 2 Moreover, patients with a partial cytogenic response at 12 months (1%-35% Ph ϩ metaphases) also had poorer PFS (82%, P ϭ .01).…”
Section: Clinical Response Depth Of Response and The Impact On Disementioning
The 21st century ushered in the dawn of a new era of targeted therapeutics and a dramatic shift in the management of chronic-phase chronic myeloid leukemia (CP-CML) patients. Groundbreaking scientific and translational studies have led to the rapid development and approval of several effective BCR-ABL tyrosine kinase inhibitors (TKIs). In the United States, there are currently 3 approved BCR-ABL TKIs for newly diagnosed CP-CML patients. It is anticipated that clinical outcomes will continue to improve as more TKIs that address unmet medical needs are approved. However, to achieve this goal, it is critical to carefully monitor and optimally manage patients. To this end, the latest seminal clinical trial results of approved and investigational BCR-ABL TKIs and some of the salient unique features of each of these agents are summarized herein.
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