Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia

Picard, Stéphane; Titier, Karine; Étienne, Gabriel; Teilhet, Emmanuelle; Ducint, Dominique; Bernard, Marie-Agnès; Lassalle, R.; Marit, Gérald; Reiffers, Josy; Bégaud, Bernard; Moore, Nicholas; Molimard, Mathiéu; Mahon, François‐Xavier

doi:10.1182/blood-2006-07-036012

Cited by 547 publications

(554 citation statements)

References 18 publications

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“…Moreover, in patients with an MMR, the median trough concentration (1020 ng ml -1 ) was greater than the 1002 ng ml -1 threshold reportedly required for efficacy, 5 further supporting the observed statistical association between plasma IM levels and clinical response. In addition, our study identified a significant correlation between ABCG2 421C4A (p.Q141K) and IM trough concentration, suggesting an important role for the BCRP efflux transporter in IM metabolism.…”

Section: Discussionsupporting

confidence: 69%

“…3 Recently, two studies suggested that plasma IM trough concentration variability influences clinical response among CML patients. 4,5 In addition, Picard et al reported that the threshold for IM trough concentration should be set above 1002 ng ml -1 , as this level was significantly associated with a major molecular response (MMR). 5 Although several important clinical trials indicated that 400 mg of IM should be the standard daily dose for chronic phase CML patients, 1,2 in clinical practice, lower doses of IM are administered to B40% of Japanese patients.…”

Section: Introductionmentioning

confidence: 99%

“…4,5 In addition, Picard et al reported that the threshold for IM trough concentration should be set above 1002 ng ml -1 , as this level was significantly associated with a major molecular response (MMR). 5 Although several important clinical trials indicated that 400 mg of IM should be the standard daily dose for chronic phase CML patients, 1,2 in clinical practice, lower doses of IM are administered to B40% of Japanese patients. 6,7 This is largely because of the fact that for some Japanese patients, lower IM doses have sufficient trough concentration for therapeutic CML treatment.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

et al. 2010

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Imatinib mesylate (IM) trough concentration varies among IM-treated chronic myeloid leukemia (CML) patients. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. In this study, associations between IM trough concentration, clinical response and 11 single-nucleotide polymorphisms in genes involved in IM pharmacokinetics (ABCB1, ABCC2, ABCG2 CYP3A5, SLC22A1 and SLCO1B3) were investigated among 67 Japanese chronic phase CML patients. IM trough concentration was significantly higher in patients with a major molecular response than in those without one (P¼0.010). No significant correlations between IM trough concentration and age, weight, body mass index or biochemical data were observed. However, the dose-adjusted IM trough concentration was significantly higher in patients with ABCG2 421A than in those with 421C/C (P=0.015). By multivariate regression analysis, only ABCG2 421A was independently predictive of a higher dose-adjusted IM trough concentration (P¼0.015). Moreover, previous studies have shown that the ABCG2 421C4A (p.Q141K) variant is prevalent among Japanese and Han Chinese individuals and less common among Africans and Caucasians. Together, these data indicate that plasma IM concentration monitoring and prospective ABCG2 421C4A genotyping may improve the efficacy of IM therapy, particularly among Asian CML patients.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

et al. 2010

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“…c o m / l o c a t e / c l i n b i o c h e m to treatment, which, in turn, correlates with clinical outcome [3]. Picard et al determined that the ideal trough IM plasma concentration should be at least 1000 ng/mL [4].…”

Section: Contents Lists Available At Sciencedirectmentioning

confidence: 99%

The clinical relevance of imatinib plasma trough concentrations in chronic myeloid leukemia. A Belgian study

Obbergh

Knoops

Devos

et al. 2017

Clinical Biochemistry

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This retrospective multicenter study in patients with chronic myeloid leukemia in chronic phase was undertaken to confirm the clinical relevance of imatinib plasma concentrations monitoring in daily practice. Forty-one patients, with 47 imatinib plasma measurements, were analyzed during treatment with imatinib given at a fixed 400 mg daily dose. A significant inverse relationship of imatinib concentration with the patients' weight was observed (Pearson's test: p = 0.02, R 2 = 0.1). More interestingly, patients with poor response (switched to another tyrosine kinase inhibitor because of imatinib failure, or because of disease progression after an initial response) displayed a significantly lower mean imatinib concentration as compared to patients maintained on imatinib (822 ng/mL vs 1099 ng/mL; Student's t-test, p = 0.04). Failure or disease progression occurred more often in patients in the lowest quartile of imatinib concentrations compared to patients in the highest quartile (p = 0.02, logrank test). No correlation could be established with other biological or clinical parameter, including complete cytogenic response and major molecular response. In conclusion: in patients treated with imatinib at a fixed daily dose of 400 mg, imatinib plasma concentrations decreased with increasing body weight and were lower in patients switched to another tyrosine kinase inhibitor due to imatinib failure. Systematic determination of imatinib plasma trough levels should be encouraged in such patients.

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“…Preliminary experiments showed that these concentrations are sufficient to completely inhibit irradiation-induced c-Abl activity in all cell lines used (not shown). The concentrations are in the range of those found in plasma from patients treated with 400 or 600 mg imatinib (Picard et al, 2007). The HPRT mutation frequency was evaluated as described (van der Kuip et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells

et al. 2008

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Imatinib inhibits the kinase activity of Bcr-Abl and is currently the most effective drug for treatment of chronic myeloid leukemia (CML). Imatinib also blocks c-Abl, a physiological tyrosine kinase activated by a variety of stress signals including damaged DNA. We investigated the effect of pharmacological inhibition of c-Abl on the processing of irradiation-induced DNA damage in Bcr-Abl-negative cells. Cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were treated with imatinib or dasatinib before c-irradiation. Inhibition of c-Abl caused an enhanced irradiationinduced mutation frequency and slowdown of DNA repair, whereas imatinib was ineffective in cells expressing a T315I variant of c-Abl. Mutation frequency and repair kinetics were also studied in c-AblÀ/À murine embryonic fibroblasts (MEFs) retransfected with wild-type c-Abl (wt-Abl) or a kinase-defect variant of Abl (KD-Abl). Enhanced mutation frequency as well as delayed DNA repair was observed in cells expressing KD-Abl. These data indicate that pharmacological inhibition of c-Abl compromises DNA-damage response.

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Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia

Cited by 547 publications

References 18 publications

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

The clinical relevance of imatinib plasma trough concentrations in chronic myeloid leukemia. A Belgian study

Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells

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