A population study of imatinib in chronic myeloid leukaemia demonstrates lower efficacy than in clinical trials

Lucas, Claire; Wang, L; Austin, Gemma; Knight, Katy; Watmough, Simon; Shwe, K. H.; Dasgupta, Ranjit; Butt, Nauman M.; Galvani, D. W.; Hoyle, Charles H.V.; Seale, Jim; Clark, Richard E.

doi:10.1038/leu.2008.225

Cited by 98 publications

(71 citation statements)

References 7 publications

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“…2 Imatinib is a tyrosine kinase inhibitor which has become the treatment of choice for newly diagnosed patients in chronic phase CML, and a recent report suggests that modern drug treatment may produce superior results to allogeneic stem cell transplantation. 3 We have recently shown in a population-based study 4 that by 24 months 49% of patients will fail imatinib treatment; similar findings were recently reported in a single center study. 5 This suggests that the identification of prognostic markers predictive of treatment response may be useful in order to avoid delay in offering second-line treatment such as stem cell transplantation or second-generation tyrosine kinase inhibitors.…”

Section: Introductionsupporting

confidence: 66%

Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript

Lucas¹,

Harris²,

Giannoudis³

et al. 2009

Haematologica

105

116

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BackgroundChronic myeloid leukemia is characterized by a reciprocal translocation between chromosomes 9 and 22, creating the fusion gene BCR-ABL. The clinical significance of the type of BCR-ABL transcript in newly diagnosed patients in chronic phase treated with imatinib 400 mg from initial diagnosis remains unknown. Design and MethodsWe analyzed the clinical outcome of 78 newly diagnosed chronic phase patients, aged 16 or over, treated with imatinib 400 mg. Of these, 71 expressed either e13a2 or e14a2 transcripts. BCR-ABL transcripts were assayed by quantitative real-time polymerase chain reaction. ResultsAfter 12 months of treatment, 54% of the e14a2 patients had achieved a complete cytogenetic response, compared to 25% of the e13a2 patients (p=0.01). Kaplan-Meier analysis of the time to achieve complete cytogenetic response revealed that e14a2 patients had more rapid response rates, compared to e13a2 patients (p=0.006). e14a2 patients had a higher event-free survival rate in the first 12 months of treatment, although overall survival did not differ significantly between the patients with the two types of transcript. Human organic cation transporter protein 1 mRNA levels did not differ between the patients with the two types of transcript. The pre-treatment pCrKL/CrKL ratio (a surrogate marker of BCR-ABL tyrosine kinase activity) was higher in patients with e13a2 transcripts than in those with e14a2 (p=0.017). ConclusionsPatients expressing the e14a2 transcript type have a higher rate and more rapid complete cytogenetic responses than e13a2-expressing patients, which may be due to higher BCR-ABL tyrosine kinase activity. Knowledge of the transcript type may yield additional prognostic information, although this requires testing on larger datasets.Key words: chronic myeloid leukemia, BCR-ABL fusion transcript, imatinib. Haematologica 2009;94:1362-1367. doi:10.3324/haematol.2009 This is an open-access paper.

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Section: Introductionsupporting

confidence: 66%

Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript

Lucas¹,

Harris²,

Giannoudis³

et al. 2009

Haematologica

105

116

View full text Add to dashboard Cite

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“…2 However, it is estimated that ;20% to 40% of newly diagnosed CML-CP patients eventually require alternative therapies because of intolerance or resistance. 3,4,[27][28][29][30] Missense mutations in the BCR-ABL1 kinase domain [5][6][7] explain only 30% to 40% of clinical imatinib-resistance cases.…”

Section: Discussionmentioning

confidence: 99%

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

Khorashad

Eiring

Mason

et al. 2015

Blood

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The mechanisms underlying tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) patients lacking explanatory BCR-ABL1 kinase domain mutations are incompletely understood. To identify mechanisms of TKI resistance that are independent of BCR-ABL1 kinase activity, we introduced a lentiviral short hairpin RNA (shRNA) library targeting ∼5000 cell signaling genes into K562 R , a CML cell line with BCR-ABL1 kinaseindependent TKI resistance expressing exclusively native BCR-ABL1. A customized algorithm identified genes whose shRNA-mediated knockdown markedly impaired growth of K562 R cells compared with TKI-sensitive controls. Among the top candidates were 2 components of the nucleocytoplasmic transport complex, RAN and XPO1 (CRM1). shRNA-mediated RAN inhibition or treatment of cells with the XPO1 inhibitor, KPT-330 (Selinexor), increased the imatinib sensitivity of CML cell lines with kinase-independent TKI resistance. Inhibition of either RAN or XPO1 impaired colony formation of CD34 1 cells from newly diagnosed and TKI-resistant CML patients in the presence of imatinib, without effects on CD34 1 cells from normal cord blood or from a patient harboring the BCR-ABL1 T315I mutant. These data implicate RAN in BCR-ABL1 kinase-independent imatinib resistance and show that shRNA library screens are useful to identify alternative pathways critical to drug resistance in CML. (Blood. 2015;125(11):1772-1781

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“…Indeed, several studies have suggested that the outcomes with imatinib outside of the context of a clinical trial are substantially worse than those reported in the IRIS study, which may reflect in part a lower threshold of acceptable toxicity. 2,15 In some instances, the ability of CP-CML patients to tolerate higher doses of imatinib may be linked to BM reserve-the capacity of the BM to rapidly reestablish karyotypically normal hematopoiesis and thereby avoid cytopenias. In addition, the German CML IV study found a benefit for 800-mg imatinib in Sokal low-and intermediate-risk CP-CML patients, but not in Sokal high-risk patients.…”

Section: Imatinibmentioning

confidence: 99%

Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia: Approach to Patients with Treatment-Naive or Refractory Chronic-Phase Disease

Smith

Shah

2011

Hematology

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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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A population study of imatinib in chronic myeloid leukaemia demonstrates lower efficacy than in clinical trials

Cited by 98 publications

References 7 publications

Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript

Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia: Approach to Patients with Treatment-Naive or Refractory Chronic-Phase Disease

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