Cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia are correlated with Sokal risk scores and duration of therapy but not trough imatinib plasma levels

Forrest, Donna L.; Trainor, Shannon; Brinkman, Ryan R.; Barnett, Michael J.; Hogge, Donna E.; Nevill, Thomas J.; Shepherd, John; Nantel, Stephen H.; Toze, Cynthia L.; Sutherland, Heather J.; Song, Kevin; Lavoie, Julye C.; Power, Maryse; Abou-Mourad, Yasser; Smith, Clayton A.

doi:10.1016/j.leukres.2008.07.015

Cited by 71 publications

(70 citation statements)

References 11 publications

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“…It suggests that taking imatinib as soon as possible helps to achieve CMR. Our data agree with the conclusion that imatinib C mins are not correlated with molecular response [12] . An odd result was that the mean imatinib C mins in our patients were a littler higher in the no-CMR group than in the CMR group (P=0.237).…”

Section: Discussionsupporting

confidence: 92%

“…Singh et al [11] also reported that the mean C mins of imatinib responders were significantly higher than those of non-responders. However, it was also reported that there was no correlation between mean C mins and CCyR or MMR [12] . The pharmacokinetics of imatinib has been extensively studied in Caucasian CML patients, and very recently Sakai et al [13] found that a lower dose of imatinib could maintain enough imatinib C mins and provided excellent results for the treatment of CML in a Japanese registry.…”

Section: Introductionmentioning

confidence: 97%

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Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

Chen

et al. 2010

Acta Pharmacol Sin

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Aim: To investigate the pharmacokinetics of imatinib in Chinese chronic myelogenous leukemia (CML) patients. Methods: Fourty-six naïve Chinese CML patients treated with imatinib (400 and 600 mg daily, n=36 and 10, respectively) were recruited. The correlations of imatinib (400 mg) trough plasma concentrations (C mins ) with the patients' characteristics and responses were analyzed. Results: The overall mean (±SD, CV%) steady-state C mins for imatinib at 400 mg (n=36) and 600 mg (n=10) daily was 1325.61 ng/mL (±583.53 ng/mL; 44%) and 1550.90 ng/mL (±462.63 ng/mL; 30%), respectively, and no statistically significant differences were found between them (P=0.267). At 400 mg daily, female patients had significantly higher C mins than the male patients (P=0.048), and molecular responses were not correlated with imatinib C mins , but they were correlated with time elapsed before imatinib therapy. Conclusion:The results suggest that Chinese CML patients have higher imatinib C mins than their Caucasian counterparts and that the optimal initial imatinib dose for them requires further investigation.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 97%

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

Chen

et al. 2010

Acta Pharmacol Sin

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“…Maintaining trough plasma IM levels at or above the mean population concentration of approximately 1000 ng/ mL may be important for achieving improved CCyR and MMR rates [16,17]. However, Forrest et al [18] reported no correlation between mean plasma trough IM levels and CCyR at 1 year (CCyR ¼ 1010 ng/mL vs. noCCyR ¼ 1175 ng/mL, p ¼ 0.29) or MMR (MMR ¼ 1067 ng/mL vs. no-MMR ¼ 1063 ng/mL, p ¼ 0.74) after a median of 1298 days of IM therapy. However, they suggested that further prospective studies were needed to establish the utility of trough plasma IM level monitoring in order to determine the most appropriate timing of the test, because their study may have been limited by patient numbers (n ¼ 78) and heterogeneous sampling times [18].…”

Section: Discussionmentioning

confidence: 99%

Trough plasma imatinib levels are correlated with optimal cytogenetic responses at 6 months after treatment with standard dose of imatinib in newly diagnosed chronic myeloid leukemia

Sohn

Kim³

et al. 2011

Leukemia & Lymphoma

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To investigate the correlation of trough imatinib mesylate (IM) levels with cytogenetic or molecular responses, we measured trough IM levels in patients with chronic myeloid leukemia, chronic phase (CML-CP), at 6 months of treatment with a standard dose of IM. Eighty-seven newly diagnosed patients with CML-CP were prospectively enrolled. Seventy-eight patients (89.7%) showed an optimal response (complete or partial cytogenetic response) at 6 months. Trough IM levels were 1378 + 725 ng/mL. When categorized into two groups, there was a statistically significant difference in numbers of patients with optimal and suboptimal responses at 6 months (group with 51000: 80.6% vs. 19.4%; 1000: 94.6% vs. 5.4%; p ¼ 0.032), and in numbers of patients with early major molecular response (early-MMR) and without MMR at 6 months (group with 51000: 3.2% vs. 96.8%; 1000: 21.4% vs. 78.6%; p ¼ 0.047). In conclusion, the incidence of optimal cytogenetic response or early-MMR in patients with CML-CP treated with IM for 6 months was significantly higher in those with a trough level of 1000 compared with those with a level of 51000. Dose escalation of IM can be one option in patients with CML showing suboptimal response or resistance to the standard dose of IM, especially with low trough plasma IM levels (51000 ng/mL).

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“…However, a recent single institution study failed to identify a difference in trough imatinib concentrations in those patients obtaining and those failing to obtain a CCyR or an MMR. 71 As no prospective data exist on the impact of dose intensification in those failing to obtain an optimal imatinib plasma level, the importance of drug-level monitoring will require further validation.…”

Section: Drug Concentrationmentioning

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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Cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia are correlated with Sokal risk scores and duration of therapy but not trough imatinib plasma levels

Cited by 71 publications

References 11 publications

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

Trough plasma imatinib levels are correlated with optimal cytogenetic responses at 6 months after treatment with standard dose of imatinib in newly diagnosed chronic myeloid leukemia

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

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