Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia

Cortés, Jorge E.; Egorin, Merrill J.; Guilhot, Joëlle; Molimard, Mathiéu; Mahon, François‐Xavier

doi:10.1038/leu.2009.88

Cited by 95 publications

(86 citation statements)

References 52 publications

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“…Studies have been conducted on IM metabolism (22,23), but the subject of intracellular accumulation in the malignant clone has been rarely addressed; indeed, the synthetic molecule is too small to be immunogenic; also, the reference technique for tracing its intracellular penetration is 14 C-labeled IM (15), which is difficult to manipulate and cannot be used to follow IM accumulation in patient cells.…”

Section: Discussionmentioning

confidence: 99%

Measurement of imatinib uptake by flow cytometry

Bourgne¹,

Bamdad²,

Janel³

et al. 2012

Cytometry Pt A

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One of the essential parameters of targeted therapy efficiency in cancer treatment is the amount of drug reaching the therapeutic target area. Imatinib (IM) was the first specifically targeted drug to be developed and has revolutionized the treatment of patients with chronic myeloid leukemia (CML). To evaluate cellular uptake of IM, we developed a method based on the chemical structure of the molecule and using the natural UV fluorescence that we quantified by flow cytometry. In two CML cell lines, we obtained a satisfactory relationship between intracellular IM (ICIM) levels and media concentrations, and we found a strong correlation between ICIM at 1 h and IM efficacy at 24 h, demonstrating that ICIM at 1 h might be a relevant predictive parameter of cell sensitivity. Our method was more sensitive than the standard physicochemical method. We applied our method to primary cells and found cell morphology-dependant IM accumulation. Moreover, in CML cells from patients at diagnosis, IM accumulation was heterogeneous. In all cases, ICIM at the single-cell level was much higher than in culture media arguing in favor of a predominantly active uptake process. We developed a simple method directly applicable to primary cells that has shown two major advantages: only a small number of cells are required, and cell subsets can be identified according to morphological criteria and/or the presence of particular antigenic sites. This method provides a new tool to assess CML cell sensitivity to IM, and ICIM levels in native CML cells could be used to monitor therapeutic response. ' 2012 International Society for Advancement of Cytometry

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Section: Discussionmentioning

confidence: 99%

Measurement of imatinib uptake by flow cytometry

Bourgne¹,

Bamdad²,

Janel³

et al. 2012

Cytometry Pt A

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“…However, Blanke et al; reported no significant difference in objective response for patients treated with high dose imatinib but, similar to our findings, a favorable outcome for female patients. The observations of side effects and treatment response in GIST patients may be compared to similar studies in chronic myeloid leukemi (CML) for which imatinib treatment is the golden standard [23]. In CML, increased plasma concentrations of imatinib have been associated with a higher rate of complete molecular response [24].…”

Section: Discussionmentioning

confidence: 99%

“…Adherence to medication is another factor contributing to reduced treatment response and event free survival in CML [25,26]. In a study of pharmacy records for 4,043 patients reduced adherence to imatinib treatment was observed in CML as well as GIST patients [23,27]. While it is well established that patients with advanced GIST benefit from imatinib treatment, knowledge of how to optimize the dosage to obtain maximal effectiveness with a minimum of side-effects is limited.…”

Section: Discussionmentioning

confidence: 99%

Side-effects from imatinib treatment of advanced GIST–associated with a better outcome

Åhlén

Westerdahl²,

Zedenius³

et al. 2012

J Cancer Ther Res

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“…on March 28, 2019. by guest www.bloodjournal.org From provided 2 advantages: (1) the high trough plasma level supported an adequate adherence to the treatment, which has been reported as a determining criterion of response 4 ; and (2) it raises the issue of the dose of treatment because retrospective analyses have determined the threshold of 1000 ng/mL of imatinib to be associated with an increased probability of achieving a major molecular response (MMR). 5 However, prospective trials are needed to further validate this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Blood consult: high Sokal risk chronic myeloid leukemia and suboptimal response

Roy

Tomowiak

Guilhot

2011

Blood

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A 49-year-old man with no previous medical history was admitted to Poitiers University Hospital in March 2007 with a 1-week history of headache, dizziness, and nausea.On examination, the patient described a moderate fatigue and a 3-kg weight loss over previous months. The neurologic, digestive, and respiratory examinations were normal. Abdominal palpation revealed a splenomegaly, 13 cm below the left costal margin.Results of laboratory tests showed a hyperleukocytosis of 486.0 ϫ 10 9 /L with an absolute neutrophil count of 37%, basophils 2%, eosinophils 2%, metamyelocytes 19%, myelocytes 28%, promyelocytes 4%, peripheral blasts 4%, anemia with a hemoglobin level of 9.4 g/dL, and a platelet count of 405.0 ϫ 10 9 /L. Coagulation and kidney and liver function tests were normal.

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Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia

Cited by 95 publications

References 52 publications

Measurement of imatinib uptake by flow cytometry

Measurement of imatinib uptake by flow cytometry

Side-effects from imatinib treatment of advanced GIST–associated with a better outcome

Blood consult: high Sokal risk chronic myeloid leukemia and suboptimal response

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