Tailoring Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia

Mauro, Michael J.

doi:10.1177/107327480901600203

Cited by 8 publications

(2 citation statements)

References 101 publications

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“…In CML confirmed by the presence of the appropriate genetic variant (cytogenetically as the Philadelphia chromosome or molecularly as the BRC-ABL1 gene, or the encoded constitutively activated oncoprotein), imatinib is now the first-line treatment in settings where the drug is affordable. This pharmacogenetictargeting benefits from conventional TDM, which ensures that the target level is reached without uncritical doseescalation, thereby reducing the risk of a severe unwanted adverse effect [20].…”

Section: Value Of Tdmmentioning

confidence: 99%

Integrating pharmacogenetics and therapeutic drug monitoring: optimal dosing of imatinib as a case-example

Li-Wan-Po

Farndon

Craddock

et al. 2010

Eur J Clin Pharmacol

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Purpose To illustrate the interface of pharmacogenetics and therapeutic drug monitoring and to estimate target blood level for imatinib in the treatment of chronic myelogenous leukemia Methods A literature review to provide the evidence and necessary data to support the case for the interface, and quantitative analysis of the data to estimate the target blood level for imatinib using receiver operating curve (ROC; signal detection theory) analysis. Results and discussion One study estimated the optimum target level of imatinib in chronic myelogenous leukaemia as 1002 ng/mL (1.70 µM) through ROC analysis. Using individual-patient level data reported in another study and the same methodology, we estimated the target level as 0.95 µM. This is consistent with the results of other observational studies where dose-response was not the primary research objective. The available evidence suggests considerable inter-individual variability in dose-blood level response. In addition to the pharmacogenetics of metabolic enzymes and transporters, genetic mutations in genes participating in the signalling pathways may also account for the wide inter-individual variability in dose-blood level and dose-clinical response relationships. Conclusion A single-dose regimen for all pharmacogenetically eligible patients is not the optimum strategy for prescribing imatinib to patients with chronic myelogenous leukaemia. We suggest that therapeutic drug monitoring aimed at ensuring a trough target level of 1 µM would reduce the incidence of pseudo-resistance and hence personalize treatment and optimise response to imatinib. Persistent resistance can then be probed further for other causes.

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Section: Value Of Tdmmentioning

confidence: 99%

Integrating pharmacogenetics and therapeutic drug monitoring: optimal dosing of imatinib as a case-example

Li-Wan-Po

Farndon

Craddock

et al. 2010

Eur J Clin Pharmacol

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“…33,35 Moreover, although cardiac events were present, albeit uncommon, in both dasatinib and nilotinib clinical trials, sudden death on nilotinib or dasatinib because of cardiac events has rarely been reported and can be further safeguarded against by performing baseline electrocardiogram. 36 Still, at this time, there is insufficient evidence to exclude a relationship between the rare occurrence of sudden death in patients treated with either nilotinib or dasatinib and cardiac AEs.…”

Section: Tablementioning

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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Imatinib for treating patients with chronic myelogeneous leukemia

Navas¹,

Simancas‐Racines²,

González³

et al. 2010

Cochrane Database of Systematic Reviews

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Tailoring Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia

Abstract: Treatment for CML should be individualized and, when resistance to imatinib can be predicted, therapy should be modified so that patients do not progress beyond chronic phase and respond as promptly and deeply as required to maximally reduce risk.

Cited by 8 publications

References 101 publications

Integrating pharmacogenetics and therapeutic drug monitoring: optimal dosing of imatinib as a case-example

Integrating pharmacogenetics and therapeutic drug monitoring: optimal dosing of imatinib as a case-example

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

Imatinib for treating patients with chronic myelogeneous leukemia

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