Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years

Rousselot, Philippe; Huguet, Françoise; Réa, Delphine; Legros, Laurence; Cayuela, Jean Michel; Maarek, Odile; Blanchet, Odile; Marit, Gérald; Gluckman, Éliane; Reiffers, Josy; Gardembas, Martine; Mahon, François‐Xavier

doi:10.1182/blood-2006-03-011239

Cited by 485 publications

(364 citation statements)

References 9 publications

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“…The pharmacokinetics of imatinib has been extensively studied in Caucasian CML patients [17][18][19][20][21] . However, few studies have been reported on naïve Chinese.…”

Section: Discussionmentioning

confidence: 99%

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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“…The pharmacokinetics of imatinib has been extensively studied in Caucasian CML patients [17][18][19][20][21] . However, few studies have been reported on naïve Chinese.…”

Section: Discussionmentioning

confidence: 99%

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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“…Despite this indication, several interruption studies showed that it is possible to safely interrupt imatinib treatment without experiencing progression of disease [13][14][15]. The STIM trial, the largest interruption study so far, showed that approximately 40% of patients maintained CMR [16,17].…”

Section: Introductionmentioning

confidence: 99%

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

et al. 2015

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Imatinib is effective for the treatment of chronic myeloid leukemia (CML). However even undetectable BCR-ABL1 by Q-RT-PCR does not equate to eradication of the disease. Digital-PCR (dPCR), able to detect 1 BCR-ABL1 positive cell out of 10 7 , has been recently developed. The ISAV study is a multicentre trial aimed at validating dPCR to predict relapses after imatinib discontinuation in CML patients with undetectable Q-RT-PCR. CML patients under imatinib therapy since more than 2 years and with undetectable PCR for at least 18 months were eligible. Patients were monitored by standard Q-RT-PCR for 36 months. Patients losing molecular remission (two consecutive positive Q-RT-PCR with at least 1 BCR-ABL1/ABL1 value above 0.1%) resumed imatinib. The study enrolled 112 patients, with a median follow-up of 21.6 months. Fifty-two of the 108 evaluable patients (48.1%), relapsed; 73.1% relapsed in the first 9 months but 14 late relapses were observed between 10 and 22 months. Among the 56 not-relapsed patients, 40 (37.0% of total) regained Q-RT-PCR positivity but never lost MMR. dPCR results showed a significant negative predictive value ratio of 1.115 [95% CI: 1.013-1.227]. An inverse relationship between patients age and risk of relapse was evident: 95% of patients <45 years relapsed versus 42% in the class 45 to <65 years and 33% of patients 65 years [P(v 2 ) < 0.0001]. Relapse rates ranged between 100% (<45 years, dPCR1) and 36% (>45 years, dPCR-). Imatinib can be safely discontinued in the setting of continued PCR negativity; age and dPCR results can predict relapse.

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“…Nonetheless second and third generation TKIs have been developed in response to BCR-ABL mutations inferring resistance to treatment (for review see O'Hare 21 ). Despite continued TKI therapy in CML patients, the minimal effect of TKIs on primitive CML haemopoietic cells results in the persistence of minimal residual disease (MDR) which causes disease relapse upon drug withdrawal [22][23][24][25][26][27] . Given that CML is a stem-cell-driven disease, any new potentially curative therapies must be tested on primary stem cells, which are only available in finite quantities.…”

Section: Introductionmentioning

confidence: 99%

Antibody-based detection of protein phosphorylation status to track the efficacy of novel therapies using nanogram protein quantities from stem cells and cell lines

et al. 2014

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This protocol describes a highly reproducible antibody-based method providing protein level and phosphorylation status information from nanogram quantities of protein cell lysate. Nanocapillary isoelectric focusing (cIEF) combines with UV activated linking chemistry to detect changes in phosphorylation status. We describe how to detect changes in response to tyrosine kinase inhibitors (TKIs) in the phosphorylation status of the adapter protein CrkL a major substrate of the oncogenic tyrosine kinase BCR/ABL in chronic myeloid leukaemia (CML), using highly enriched CML stem cells and mature cell populations in vitro. This protocol provides a 2.5pg/nL limit of protein detection (<0.2% of a stem cell sample containing <10 4 cells). Additional assays are described for pTyr207-CrkL and PTPRC/CD45, developed using this protocol and applied to CML patient samples. This method is high throughput and can act as a screen for in vitro cancer stem cell response to drugs and novel agents. SummaryThis protocol uses a highly sensitive and reproducible antibody-based capillary isoelectric focusing approach to establish protein phosphorylation status from nanogram quantities of protein cell lysate from cell line or primary stem cell material. Is-protocol-to

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Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years

Abstract: In the present study, we address the issue of the discontinuation of imatinib mesylate (Gleevec) in chronic myelogenous leukemia with undetectable residual disease for more than 2 years. Twelve patients were included.

Cited by 485 publications

References 9 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

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

Antibody-based detection of protein phosphorylation status to track the efficacy of novel therapies using nanogram protein quantities from stem cells and cell lines

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