Relationship of serum imatinib trough level and response in CML patients: Long term follow-up

Awidi, Abdalla; Ayed, Ayed O.; Bsoul, Nazzal; Magablah, Ahmad; Mefleh, Razan; Dweiri, Mohammad; Ramahi, Mohammad; Arafat, Eyad; Bishtawi, M.; Marie, Lena

doi:10.1016/j.leukres.2010.07.014

Cited by 35 publications

(23 citation statements)

References 10 publications

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“…In contrast to other studies [15,19,20], trough plasma concentration of imatinib did not reflect clinical response in chronic CML. Our results showed higher imatinib levels in CCyR, but no significant difference was found.…”

Section: Discussioncontrasting

confidence: 99%

“…In patients who do not respond to initial imatinib treatment as expected, measurement of trough plasma concentration can assist in making decisions regarding dose increases. Blood level testing may also be helpful in other clinical scenarios: for example, when poor adherence or drug-drug interaction is suspected, or in case of unusually severe adverse reactions [14,15]. …”

Section: Introductionmentioning

confidence: 99%

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CD117 (c-kit) Expression on CD34+ Cells Participates in the Cytogenetic Response to Imatinib in Patients with Chronic Myeloid Leukemia in the First Chronic Phase

Dybko¹,

Haus²,

Jaźwiec³

et al. 2014

Acta Haematol

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Background: Chronic myeloid leukemia (CML) biology seemed to be perfectly explored especially at the beginning of the tyrosine kinase inhibitors era. Later years with imatinib and second-generation tyrosine kinase inhibitors showed a variety of resistance mechanisms and it became obvious that the bcr-abl chimeric gene is not the only enemy to fight. Some studies assumed the decreased rate of programmed cell death (apoptotic) to be the primary mechanism by which BCR-ABL affects expansion of the leukemic clone in CML. Therefore, the aim of this study was to investigate the role of c-kit inhibition in treatment response. Methods: Cytogenetic analysis, real-time quantitative reverse-transcriptase polymerase chain reaction, flow-cytometric analysis and imatinib serum level quantification were applied. Results: The percentage of CD34+ cells expressing c-kit (CD117) isolated from bone marrow samples of 54 CML patients treated with standard-dose imatinib was significantly lower among imatinib responders. The fraction of apoptotic CD34+CD117+ cells in this patient group was significantly higher than in nonresponders. Conclusion: To achieve optimal treatment response in CML patients, the elimination of CD34+CD117+ may be necessary through an apoptotic pathway.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD117 (c-kit) Expression on CD34+ Cells Participates in the Cytogenetic Response to Imatinib in Patients with Chronic Myeloid Leukemia in the First Chronic Phase

Dybko¹,

Haus²,

Jaźwiec³

et al. 2014

Acta Haematol

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“…[21][22][23][24][25] Several studies have investigated whether the imatinib C 0 reflects the clinical response of patients taking imatinib, namely exposure-response relationships. 11,12,[20][21][22][25][26][27][28][29][30] In Japanese CML patients, we have reported that the imatinib C 0 was significantly higher in patients with a MMR than in those without a MMR; the mean values were 1107±594 ng/ mL and 873±529 ng/mL, respectively (p=0.002). 21) Picard et al first reported that a steady-state imatinib C 0 measured after at least 12 months of treatment with a standard imatinib dose correlated with the MMR, and the threshold for the imae-mail: m-miura@hos.akita-u.ac.jp tinib C 0 should be set above 1002 ng/mL.…”

Section: Imatinib Tdmmentioning

confidence: 89%

Therapeutic Drug Monitoring of Imatinib, Nilotinib, and Dasatinib for Patients with Chronic Myeloid Leukemia

Miura

2015

Biological & Pharmaceutical Bulletin

136

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Imatinib, nilotinib, and dasatinib are tyrosine kinase inhibitors (TKIs) that have become first-line treatments for Philadelphia chromosome-positive chronic myeloid leukemia (CML). According to European LeukemiaNet recommendations, the clinical response of CML patients receiving TKI therapy should be evaluated after 3, 6, and 12 months. For patients not achieving a satisfactory response within 3 months, the mean plasma concentration for the three months of TKI administration must be considered. In TKI therapy for CML patients, therapeutic drug monitoring is a new strategy for dosage optimization to obtain a faster and more effective clinical response. The imatinib plasma trough concentration (C 0 ) should be set above 1000 ng/mL to obtain a response and below 3000 ng/mL to avoid serious adverse events such as neutropenia. For patients with a UGT1A1*6/*6, *6/*28, or *28/*28 genotype initially administered 300-400 mg/d, a target nilotinib C 0 of 500 ng/mL is recommended to prevent elevation of bilirubin levels, whereas for patients with the UGT1A1*1 allele initially administered 600 mg/d, a target nilotinib C 0 of 800 ng/mL is recommended. For dasatinib, it is recommended that a higher C max or C 2 (above 50 ng/mL) to obtain a clinical response and a lower C 0 (less than 2.5 ng/mL) to avoid pleural effusion be maintained by once daily administration of dasatinib. Although at present clinicians consider the next pharmacotherapy from clinical responses (efficacy/ toxicity) obtained by a fixed dosage of TKI, the TKI dosage should be adjusted based on target plasma concentrations to maximize the efficacy and to minimize the incidence of adverse events.

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“…TDM, recently, has become an essential tool for the management of CML patients, particularly for patients taking imatinib [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39], which efficacy threshold in terms of plasma concentrations is clearly defined. In order to manage primary or acquired resistance to imatinib, clinical studies using dasatinib or nilotinib as second line therapy or combination of therapies with different TKIs, in sequential or simultaneous administration, are currently under evaluation [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. Sub-inhibitory intracellular drug concentrations, probably, and sequential treatment with multiple tyrosine kinase inhibitors promote the selection of BCR-ABL kinase domain mutations in CML patients [51][52].…”

Section: Discussionmentioning

confidence: 99%

HPLC–MS method for the simultaneous quantification of the antileukemia drugs imatinib, dasatinib and nilotinib in human peripheral blood mononuclear cell (PBMC)

D’Avolio¹,

Simiele²,

Francia

et al. 2012

Journal of Pharmaceutical and Biomedical Analysis

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A new method using high performance liquid chromatography coupled with electrospray mass spectrometry is described for the quantification of PBMC concentration of tyrosine kinase inhibitors imatinib, dasatinib and nilotinib. A simple PBMC isolation and extraction procedure were applied on 10-14 mL of blood aliquots. Chromatographic separation of drugs and Internal Standard (quinoxaline) was achieved with a gradient (acetonitrile and water + formic acid 0.05%) on a C18 reverse phase analytical column with 25 min of analytical run, at flow rate of 0.25 mL/min. Mean intra-and inter-day precision for all compounds were 8.76 and 12.20%; mean accuracy was -3.86%; extraction recovery ranged within 79 and 91%. Calibration curves ranged from 50.0 to 0.25 ng. The limit of quantification was set at 0.25 ng for all the analyzed drugs.This novel developed methodology allows a specific, sensitive and reliable simultaneous intracellular determination of the three tyrosine kinase inhibitors imatinib, dasatinib and nilotinib in a single chromatographic run, useful for drugs estimation in PBMC of patients affected by chronic myeloid leukemia.

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Relationship of serum imatinib trough level and response in CML patients: Long term follow-up

Cited by 35 publications

References 10 publications

CD117 (c-kit) Expression on CD34+ Cells Participates in the Cytogenetic Response to Imatinib in Patients with Chronic Myeloid Leukemia in the First Chronic Phase

CD117 (c-kit) Expression on CD34+ Cells Participates in the Cytogenetic Response to Imatinib in Patients with Chronic Myeloid Leukemia in the First Chronic Phase

Therapeutic Drug Monitoring of Imatinib, Nilotinib, and Dasatinib for Patients with Chronic Myeloid Leukemia

HPLC–MS method for the simultaneous quantification of the antileukemia drugs imatinib, dasatinib and nilotinib in human peripheral blood mononuclear cell (PBMC)

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