Larson RA, Druker BJ, Guilhot FA, O’Brien SG, Riviere GJ, Krahnke T, Gathmann I, Wang YImatinib pharmacokinetics and its correlation with response and safety in chronic phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 111(8): 4022-4028

University of Chicago, MC-2115, 5841 S Maryland Ave, Chicago, IL 60637, USA.
Blood (Impact Factor: 10.45). 05/2008; 111(8):4022-8. DOI: 10.1182/blood-2007-10-116475
Source: PubMed

ABSTRACT Imatinib at 400 mg daily is standard treatment for chronic myeloid leukemia in chronic phase. We here describe the correlation of imatinib trough plasma concentrations (C(mins)) with clinical responses, event-free survival (EFS), and adverse events (AEs). Trough level plasma samples were obtained on day 29 (steady state, n = 351). Plasma concentrations of imatinib and its metabolite CGP74588 were determined by liquid chromatography/mass spectrometry. The overall mean (+/- SD, CV%) steady-state C(min) for imatinib and CGP74588 were 979 ng/mL (+/- 530 ng/mL, 54.1%) and 242 ng/mL (+/- 106 ng/mL, 43.6%), respectively. Cumulative estimated complete cytogenetic response (CCyR) and major molecular response (MMR) rates differed among the quartiles of imatinib trough levels (P = .01 for CCyR, P = .02 for MMR). C(min) of imatinib was significantly higher in patients who achieved CCyR (1009 +/- 544 ng/mL vs 812 +/- 409 ng/mL, P = .01). Patients with high imatinib exposure had better rates of CCyR and MMR and EFS. An exploratory analysis demonstrated that imatinib trough levels were predictive of higher CCyR independently of Sokal risk group. AE rates were similar among the imatinib quartile categories except fluid retention, rash, myalgia, and anemia, which were more common at higher imatinib concentrations. These results suggest that an adequate plasma concentration of imatinib is important for a good clinical response. This study is registered at as NCT00333840.

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Available from: Yanfeng Wang, Sep 27, 2015
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    • "Significant correlations between imatinib trough plasma levels (Cmin) and cytogenetic and molecular responses of Caucasian patients with CML have been found.32–34 In a pharmacokinetics/pharmacodynamics (PK/PD) analysis from the IRIS study, imatinib plasma Cmin levels higher than 1,000 ng/mL correlated significantly with improved cytogenetic and molecular response rates.33 In the Tyrosine Kinase Dose Optimization Study (TOPS), evaluation of the effects of imatinib 400 mg twice daily compared with imatinib 400 mg daily in previously untreated patients with newly diagnosed CML cells in Chronic Phase (CML-CP) showed that imatinib trough plasma levels were proportional to dose and stable over time.35 "
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    ABSTRACT: Imatinib mesylate is considered the standard first-line systemic treatment for patients with chronic myeloid leukemia (CML) and functions by targeting BCR-ABL tyrosine kinases. Imatinib has substantially changed the clinical management and improved the prognosis of CML and Philadelphia chromosome-positive acute lymphocytic leukemia (Ph(+) ALL). Here, we review the pharmacology, mode of action, and pharmacokinetics of imatinib; Chinese efficacy studies in CML and Ph(+) ALL; safety and tolerability; patient-focused perspectives, such as quality of life, patient satisfaction, acceptability, and adherence; and uptake of imatinib.
    OncoTargets and Therapy 03/2014; 7:395-404. DOI:10.2147/OTT.S38846 · 2.31 Impact Factor
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    • "Another study reported 5-year event-free survival (EFS) of only 63% (de Lavallade et al, 2008; Marin et al, 2012a) and a population-based report found that only half of newly diagnosed CP-CML patients were in CCyR and receiving imatinib at 2 years after starting therapy (Lucas et al, 2008). Reasons to consider imatinib doses >400 mg daily include the fact that no maximum tolerated dose was established in the initial phase 1 study (Druker et al, 2001), that higher plasma imatinib concentrations are associated with improved responses (Larson et al, 2008) and that dose escalation induces responses in some patients failing IM400 (Kantarjian et al, 2003). In 2004, four North American cooperative groups [Southwest Oncology Group (SWOG), Eastern Cooperative Oncology Group (ECOG), Cancer and Leukemia Group B (CALGB), National Cancer Institute (NCI) Canada Clinical Trials Group] initiated study S0325 (ClinicalTrials .gov "
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    ABSTRACT: The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukaemia (CP-CML) is 400 mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematological and cytogenetic response to IM400 vs. imatinib 400 mg twice daily (IM800) in 153 adult patients with CP-CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4-log reduction of BCR-ABL1 mRNA: 25% vs. 10% of patients, P = 0·038; 3-log reduction: 53% vs. 35%, P = 0·049). During the first 12 months BCR-ABL1 levels in the IM800 arm were an average 2·9-fold lower than in the IM400 arm (P = 0·010). Complete haematological response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P = 0·040). Grade 3-4 toxicities were more common for IM800 (58% vs. 31%, P = 0·0007), and were most commonly haematological. Few patients have relapsed, progressed or died, but both progression-free (P = 0·048) and relapse-free (P = 0·031) survival were superior for IM800. In newly diagnosed CP-CML patients, IM800 induced deeper MRs than IM400, with a trend for improved progression-free and overall survival, but was associated with more severe toxicity.
    British Journal of Haematology 01/2014; 164(2):223-32. DOI:10.1111/bjh.12618 · 4.71 Impact Factor
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    • "The activity of CYP enzyme exhibits intrinsic variability, which could be the cause of high interpatient unevenness in imatinib exposure.18,19 Drugs that are inhibitors or inductors of the CYP3A4 isoenzyme have been shown to alter imatinib pharmacokinetic activity.20 "
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    ABSTRACT: Imatinib was the first signal transduction inhibitor (STI), used in a clinical setting. It prevents a BCR-ABL protein from exerting its role in the oncogenic pathway in chronic myeloid leukemia (CML). Imatinib directly inhibits the constitutive tyrosine kinase activity. Imatinib binds to BCR-ABL kinase domain by preventing the transfer of a phosphate group to tyrosine on the protein substrate and the subsequent activation of phosphorylated protein. As the result, the transmission of proliferative signals to the nucleus is blocked and leukemic cell apoptosis is induced. The FDA has approved imatinib as first-line treatment for newly diagnosed CML in December 2002 following an International Randomized Study (IRIS), initiated in June 2000, comparing imatinib at a single daily dose 400 mg to IFN alpha plus cytarabine in newly diagnosed patients with CML in CP. Results from this study show the outstanding effectiveness of imatinib and its superiority with respect to the rates of complete hematological response (CHR), major and complete cytogenetic response (MCyR, CCyR). Patients randomized to imatinib arm at 8 - year data cut off continue to have a durable hematologic and cytogenetic responses, low progression rates to AP or BC, and remarkable survival outcomes. An overall survival (OS) rate is 85% for patients receiving imatinib (93% when only CML-related deaths and those prior to stem cell transplantation are considered). The results have been confirmed in the last years by several groups. According these cumulative results the rates of CCyR achieved after one year of therapy with imatinib at standard dose ranged from 49% to 77%, and the proportion of patients who achieved major molecular response (MMR) after one year ranged between 18% and 58%. Discontinuation of imatinib has been also tried in patients in MMR, a molecular relapse occurs in about one third of patients, generally within 6 months from imatinib cessation.
    Mediterranean Journal of Hematology and Infectious Diseases 01/2014; 6(1):e2014007. DOI:10.4084/MJHID.2014.007
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