High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy

Willis, Stephanie G.; Lange, Thoralf; Demehri, Shadmehr; Otto, Sandra; Crossman, Lucy C.; Niederwieser, Dietger; Stoffregen, Eric P.; McWeeney, Shannon K.; Kovács, I.; Park, Byung; Druker, Brian J.; Deininger, Michael W.

doi:10.1182/blood-2005-03-1036

Cited by 285 publications

(258 citation statements)

References 32 publications

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“…Because previous retrospective studies had identified de novo kinase domain (KD) mutations, Willis and colleagues 29,30,34 prospectively assessed the frequency of mutations in imatinibnaive patients with CML, as well as the longer-term clinical significance of these mutations. Utilizing a combination of an allele-specific PCR assay, together with conventional sequencing, mutations were identified in 15 of 66 patients (23%) before therapy, and they were detected in individuals with accelerated and blast phase disease, but not in CP patients.…”

Section: Spotlightmentioning

confidence: 99%

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

2010

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Although only 5000 new cases of chronic myeloid leukemia (CML) were seen in the United States in 2009, this neoplasm continues to make scientific headlines year-after-year. Advances in understanding the molecular pathogenesis coupled with exciting developments in both drug design and development, targeting the initiating tyrosine kinase, have kept CML in the scientific limelight for more than a decade. Indeed, imatinib, a small-molecule inhibitor of the leukemia-initiating Bcr-Abl tyrosine kinase, has quickly become the therapeutic standard for newly diagnosed chronic phase-CML (CP-CML) patients. Yet, nearly one-third of patients will still have an inferior response to imatinib, either failing to respond to primary therapy or demonstrating progression after an initial response. Significant efforts geared toward understanding the molecular mechanisms of imatinib resistance have yielded valuable insights into the cellular biology of drug trafficking, enzyme structure and function, and the rational design of novel small molecule enzyme inhibitors. Indeed, new classes of kinase inhibitors have recently been investigated in imatinibresistant CML. Understanding the pathogenesis of tyrosine kinase inhibitor resistance and the molecular rationale for the development of second and now third generation therapies for patients with CML will be keys to further disease control over the next 10 years.

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Section: Spotlightmentioning

confidence: 99%

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

2010

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“…For a relatively few CML patients, resistance to imatinib is present before, or develops during treatment. [8][9][10][11] Several strategies are available to treat imatinib-resistant patients, including imatinib dose escalation, dose adjustment based on pharmacokinetic assessments and the use of novel TKIs ( Figure 1, Table 1). …”

Section: Introductionmentioning

confidence: 99%

Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

2009

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Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia (CML), offering patients several targeted therapeutic options that provide the possibility of sustained remissions and prolonged survival. With the availability of imatinib, nilotinib and dasatinib, physicians must weigh the efficacy and safety profile of each agent when choosing the best therapeutic option for individual patients. Each agent targets tyrosine kinases within the cell uniquely to cause the desired antiproliferative effect. In addition to inhibiting the BCR-ABL kinase, imatinib and nilotinib target the same array of other tyrosine kinases, including c-KIT and plateletderived growth factor receptor (PDGFR), albeit with differing potencies. While targeting BCR-ABL with the highest potency among approved agents in CML, dasatinib also targets a broad array of off-target kinases, including SRC family members, PDGFR and EPHB4. The differences in kinase inhibition profiles among these agents in vitro probably account for the differing clinical safety profiles of these agents. This paper reviews the various kinases inhibited by imatinib, nilotinib and dasatinib, and describes the potential impact of kinase inhibition on the efficacy and safety of each agent.

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“…Nested PCRs were performed to isolate and sequence a BCR-ABL fragment spanning the kinase domain using (iProof GC 2 Â Master Mix (no. 172-5320, Bio-Rad, Hercules, CA, USA) and published primers (Willis et al, 2005; Supplementary material).…”

Section: Samples From Patientsmentioning

confidence: 99%

Quantitative monitoring by polymerase colony assay of known mutations resistant to ABL kinase inhibitors

et al. 2007

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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.

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High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy

Cited by 285 publications

References 32 publications

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

Quantitative monitoring by polymerase colony assay of known mutations resistant to ABL kinase inhibitors

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