Imatinib Trough Levels Research Articles

Relationship of body mass index and plasma imatinib levels in CML patients and mitigation of clinical impact using PK-guided dosing strategy.

e18522 Background: Imatinib is a mainstay of treatment for patients with chronic myeloid lymphoma (CML). Exposure-response relationships have been demonstrated and trough levels between 800 and 1000 ng/ml are usually associated with Major Molecular Response (MMR), prolonged survival and acceptable safety. The extent to which body mass index (BMI) might influence drug pharmacokinetics (PK) and clinical outcome remains to be investigated. Methods: Therapeutic drug monitoring was performed in 60 adult patients (56 years, M33/27F) starting imatinib (400 mg QD) for CML, and baseline deviation from target Cmin was used to subsequently adjust dosing using Monolix software. Baseline BMI was calculated and collected along with other patient characteristics and comedications likely to alter imatinib PK. Response (MMR at 3 months) and drug-related toxicity (CTCAE grading) were recorded. Patients were divided into three subgroups: BMI<18.5; 18.5<BMI<24.5, and BMI>24.5. The association between BMI and trough imatinib levels at baseline, further differences in toxic events and response rate between cohorts, as well as differences in dosing after PK-guided dose adjustment, were all tested using appropriate statistical analysis. Results: Mean imatinib trough levels at baseline were 1172 (754-4737), 870 (276-1767) and 820 (334-2217) ng/ml for patients with BMI<18.5, 18.5<BMI<24.5 and BMI>24.5, respectively. Patients with BMI<18.5 were statistically overexposed (p<0.01, ANOVA). Conversely, there was a trend towards lower exposure in patients with BMI>24.5, but this was not statistically significant. Multivariate analysis confirmed that low BMI was an independent factor for overexposure with imatinib. After PK-guided dosing, a statistically significant difference in dosing after correction was observed, as overexposed patients had their dose reduced to an average of 330 mg QD, whereas underexposed patients had their dose increased to an average of 500 mg QD (p<0.01, paired t-test). Consequently, when comparing in the three different cohorts the incidence of both response and toxic events, no difference was observed among patients (p=0.33 and p=0.911 for efficacy and toxicity respectively, Chi-2 test). Conclusions: Low BMI (<18.5) puts patients at risk of significant overexposure to imatinib, whereas there is a trend towards lower exposure in patients with high BMI (>24.5). This could potentially lead to either increased toxicity or lack of efficacy is no adjustment in dosing is performed. Here, TDM with subsequent adaptive dosing helps to correct the dose according to the initial deviation from target, thus smoothing the clinical impact of the differences in exposure observed at the start of treatment.

Impact of CYP3A4 rs2242480 polymorphisms on Imatinib HPLC determined trough concentration and response in Chronic Myeloid Leukaemia in Pakistani patients

Objective To ascertain the impact of CYP3A4 polymorphism on the therapeutic outcome of imatinib and its trough concentration Study design Descriptive analytical study Place and duration of the study This study was conducted in the Department of Pharmacology & Therapeutics, Islamic International Medical College, between December 2020 and February 2022, in collaboration with the Institute of Biomedical Genetic Engineering, KRL Hospital Islamabad. Methods Patients with Chronic Myeloid Leukaemia age range–18-70 years were included in this study. One group comprised responders and the other group comprised non-responders. Imatinib trough levels in both groups were determined using High-performance Liquid Chromatography and compared, and the association was determined with therapeutic outcomes. DNA was extracted, and the PCR restriction fragment length polymorphism technique was used to identify the alleles. The results were analyzed using Statistical Package for Social Sciences (SPSS) version 22.0. Results The imatinib concentration in patients with the homozygous wild allele CC of rs2242480 was higher(1298ng/ml) as compared with the mutant homozygous TT allele (489ng/ml) or heterozygous allele CT(873ng/ml) Conclusion There was a significant association between imatinib trough levels and CYP3A4 polymorphism, and trough concentration was found to be lower in patients with the TT or CT variant of rs2242480 than in patients with the CC genotype.

CO-RELATION OF P-GLYCOPROTEIN AND PLASMA IMATINIB IN IMATINIB RESPONDERS AND NON-RESPONDERS PATIENTS WITH CHRONIC MYELOID LEUKAEMIA

Objective: To measure and compare P-glycoprotein (P-gp) expressions in imatinib responders and non-responders with chronic myeloid leukemia-chronic phase (CML-CP) and correlate with plasma imatinib levels. Methods: Patients were classified into two groups based on their haematological and cytogenetic responses to imatinib: responders and non-responders. Liquid chromatography-mass spectrometry was used to measure plasma imatinib levels, while flow cytometry was used to evaluate leucocyte P-gp expression. Results: The median plasma imatinib trough levels in non-responders were 496 (217-3150) ng/ml compared to 2245 (454-4270) ng/ml in the responders, which was statistically significant (p=0.0003). The proportion of patients expressing P-gp in granulocytes was higher in the non-responder group than in the responder group (75% vs. 62.5%). The ratio of mean fluorescence intensity (RFI) revealed that non-responders had higher median P-gp expression than did respondents MFI (1.16(1.06-1.50) and 1.12(1.01-1.38), respectively; p = 0. 2307). In both groups, there was a negative correlation between P-gp expression and plasma imatinib trough levels (-0.4384 vs.-0.2848). Conclusion: Imatinib median plasma trough levels in non-responders were considerably lower. This was highly supported by P-gp expression in granulocytes, which is inversely related to imatinib plasma trough levels; however, the difference was not statistically significant, which could be attributed to the small number of patients. This could be the cause of imatinib resistance in non-responder CML-CP patients, and P-gp levels should be evaluated to optimize treatment in patients who do not achieve hematologic or cytogenetic response.

Analysis of correlation between plasma trough level and response of generic imatinib in the treatment of Chinese patients with chronic myeloid leukemia

目的评价我国慢性髓性白血病慢性期（CML-CP）患者接受国产伊马替尼（商品名：格尼可）治疗后伊马替尼及其代谢物血浆谷浓度水平与疗效的关系。方法以2012年10月11日至2013年5月8日入组编号为YMTN1.0临床研究的21例接受国产伊马替尼治疗的CML-CP患者为研究对象，评价其血浆药物谷浓度与疗效、年龄、体重、体表面积的关系。伊马替尼及其代谢物浓度检测采用高效液相色谱-串联质谱法。结果①伊马替尼及其代谢物血浆谷浓度分别为（1 185.07±417.91）µg/L和（251.53±76.50）µg/L。②伊马替尼及其代谢物血浆谷浓度与患者年龄、体重和体表面积均无明显相关性（P值均>0.05）。③伊马替尼稳态血浆谷浓度高于1 000 µg/L的患者其完全及主要分子学反应率显著高于未达1 000 µg/L的患者（42%对0，P<0.01）。结论接受国产伊马替尼治疗的CML-CP患者中，伊马替尼及其代谢产物稳态血浆谷浓度存在较大个体差异，伊马替尼血浆谷浓度与患者获得分子学疗效有一定的相关性。

270O - Imatinib induced toxicity and its influence on cytogenetic and molecular response in newly diagnosed patients with chronic myeloid leukemia

BackgroundIncidence of imatinib-induced toxicity and its influence on clinical outcomes in Indian patients with CML is not well-studied. We investigated the influence of imatinib-induced toxicity on therapeutic outcomes in newly diagnosed patients with CML. We also studied the effect of drug levels on imatinib-induced hematological toxicity. MethodsTwo hundred and fifty newly diagnosed patients with chronic-phase CML, started on imatinib therapy, were enrolled and followed-up for 24 months. Toxicity due to imatinib were assessed and graded as per CTCAE. Cytogenetic and molecular responses were assessed by conventional bone-marrow cytogenetics and qRTPCR using international scale, respectively, based on which patients were categorized as imatinib responders and non-responders. Imatinib trough levels were measured using LC-MS/MS. Multivariate analysis was done to find the influence of various covariates on imatinib response. ResultsA total of 719 adverse reactions due to imatinib occurred among 250 enrolled patients. Hematological toxicity was the most common imatinib-induced toxicity and its incidence was significantly higher in non-responders than responders (65% vs. 35%; P < 0.001). Patients with thrombocytopenia [RR = 1.768; 95%CI (1.357, 2.302); P < 0.001] and neutropenia [RR = 1.654; 95%CI (1.322, 2.070); P < 0.001] were at high risk of imatinib failure. Patients without any hematological toxicity were at lower risk for failure of imatinib therapy [RR = 0.520; 95%CI (0.388, 0.698); P < 0.001]. Although patients with hematological toxicity had higher imatinib levels than those without (2039.1±1361.6 vs. 1833.8±1335.3 ng/mL), the difference was not statistically significant [mean difference 205.2; 95% CI (590.4, -180); P = 0.295]. Hematological toxicity requiring dose interruption or reduction emerged as an independent factor predicting cytogenetic and molecular response to imatinib in multivariate analysis. ConclusionsImatinib induced hematological toxicities significantly influence cytogenetic and molecular response in patients with CML. Active monitoring and prompt management of imatinib induced adverse events is indispensable to achieve optimal therapeutic outcomes. Clinical trial identificationNot Applicable. Editorial acknowledgementNot Applicable. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Effect of MDR1 and CYP3A5 gene polymorphisms on outcomes of patients receiving imatinib treatment for chronic myeloid leukemia

To study the effect of MDR1 and CYP3A5 gene polymorphisms on the outcomes of imatinib treatment in patients with chronic myeloid leukemia (CML). A total of 100 patients with CML treated with imatinib were enrolled in this study, including 50 patients with cytogenetic relapse (study group) and 50 without cytogenetic relapse (control group) during the follow-up for 45 months. For all the patients, single nucleotide polymorphisms (SNPs) of C1236T, C3435T, and G2677T/A loci in the MDR1 gene and A6986G locus in CYP3A5 gene were genotyped and the trough levels of imatinib was measured using LC-MS/MS. The relationship between SNPs of the loci and the risk of cytogenetic relapse were analyzed. The risk of cytogenetic recurrence was significantly higher in patients with CC genotypes of MDR1-C1236T and MDR1-C3435T than in those with CT + TT genotypes (P < 0.05). The median survival time of the patients with TT genotypes of MDR1-C3435T and MDR1-C1236T was significantly higher than that of patients with CC genotypes and CT genotypes (P < 0.05). The incidences of hematologic toxicity and neutropenia were significantly higher in patients with cytogenetic relapse than in those without cytogenetic relapse (P < 0.05). MDR1-C3435T genotype and imatinib concentration were independent predictors of cytogenetic relapse of CML. The risk of cytogenetic relapse of CML was significantly affected by SNPs of C1236T and C3435T loci of MDR1 gene and blood imatinib concentration. MDR1-C3435T genotype can be used as a potential biomarker for predicting cytogenetic relapse in CML patients.

Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in newly diagnosed patients with chronic myeloid leukemia

Polymorphisms in genes coding for imatinib transporters and metabolizing enzymes may affect imatinib pharmacokinetics and clinical response. Aim of this study was to assess the influence of polymorphisms in MDR1 and CYP3A5 genes on imatinib trough levels, cytogenetic and molecular response in patients with CML. Newly diagnosed patients with chronic-phase CML started on imatinib therapy were enrolled and followed up prospectively for 24 months. The following single nucleotide polymorphisms were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene. Genotyping was done using PCR-RFLP method and validated by direct gene sequencing. Trough levels of imatinib were measured using LC–MS/MS. Cytogenetic response was assessed by conventional bone-marrow cytogenetics. Molecular response was assessed by qRTPCR using international scale. A total of 173 patients were included, out of which 71 patients were imatinib responders, while 102 were non-responders. Marked inter-individual variability in trough levels of imatinib was seen. Patients with GG genotype for CYP3A5-A6986G (P=0.016) and TT genotype for MDR1-C3435T (P=0.013) polymorphisms had significantly higher trough levels of imatinib. Patients with AA genotype for CYP3A5-A6986G [RR=1.448, 95% CI (1.126, 1.860), P=0.029] and CC genotype for MDR1-C1236T [RR=1.397, 95% CI (1.066, 1.831), P=0.06] &MDR1-C3435T [RR=1.508, 95% CI (1.186, 1.917), P=0.018] polymorphisms were at high risk for failure of imatinib therapy. Patients with CGC haplotype for MDR1 polymorphisms had significantly lower imatinib trough levels and were at a higher risk of imatinib failure [RR=1.547, 95% CI (1.324, 1.808), P<0.001]. GG vs. non-GG genotype for CYP3A5-A6986G [adjusted OR: 0.246; 95% CI (0.116, 0.519); P<0.001] and TT vs. non-TT genotype for MDR1-C1236T [adjusted OR: 0.270; 95% CI (0.110, 0.659); P=0.004] &MDR1-C3435T [adjusted OR: 0.289; 95% CI (0.135, 0.615); P=0.001] polymorphisms were independent factors predicting imatinib response in multivariate analysis. To conclude, MDR1 and CYP3A5 genetic polymorphisms significantly influence plasma trough levels and therapeutic response of imatinib in patients with CML. Genotyping of these polymorphisms could be of value to individualize the therapy and optimize the clinical outcomes.

Serial monitoring of imatinib pharmacokinetics (PK) in perioperative imatinib treatment in patients (pts) with gastrointestinal stromal tumors (GISTs): Results from the multinational phase II trial.

118 Background: Imatinib plasma levels may be affected by the duration of exposure to imatinib and resection of the stomach. Therefore, we performed PK study to monitor imatinib plasma levels serially in the multinational phase II trial of perioperative imatinib for pts with large ( ≥ 10 cm) gastric GISTs without distant metastasis. Methods: In this trial conducted in Japan and Korea, 53 pts received neoadjuvant imatinib 400 mg daily and 40 pts received adjuvant imatinib after surgery. Blood samples for imatinib trough levels (Cmin) were collected after 1, 3, 6 months of each neoadjuvant and adjuvant imatinib and measured by using liquid chromatography-tandem mass spectrometry. For the comparison of imatinib Cmin between different time points, values were dose-adjusted and log-transformed. Results: During the neoadjuvant treatment, imatinib Cmin (mean ± standard deviation) was 2253.0 ± 1148.0 ng/mL (n = 49), 1623.3 ± 832.4 ng/mL (n = 47), and 1852.0 ± 1572.4 ng/mL (n = 45) after 1, 3, and 6 months of imatinib, respectively. During the postoperative treatment, imatinib Cmin was 1436.1 ± 852.8 ng/mL (n = 31), 1357.8 ± 646.4 ng/mL (n = 33), and 1084.2 ± 360.8 ng/mL (n = 31) after 1, 3, and 6 months of imatinib, respectively. In the neoadjuvant setting, imatinib Cmin was significantly reduced after 3 months (p = 0.0001) and 6 months (p = 0.004) compared to the value at 1 month. In 36 patients that imatinib Cmin was measured at both preoperative and postoperative setting, imatinib Cmin was significantly reduced after surgery (1732.4 ± 997.9 ng/mL vs 1282.8 ± 557.3 ng/mL; p = 0.04). The magnitude of changes in imatinib Cmin after surgery was greatest in patients who underwent total gastrectomy (10.6%, n = 2) followed by proximal gastrectomy (8.4%, n = 3), and wedge resection (3.3%, n = 30). There were no significant relationships between imatinib Cmin and toxicity or objective response. Conclusions: Imatinib exposure was reduced until approximately 3 months after imatinib treatment. It was also significantly reduced after surgery and the magnitude of changes might be affected by the extent of surgical resection of stomach.

Influence of CYP2C8 polymorphisms on imatinib steady-state trough level in chronic myeloid leukemia and gastrointestinal stromal tumor patients.

Imatinib trough levels have been associated with its clinical effects. During chronic use of imatinib, CYP2C8 becomes an important metabolizing enzyme because of cytochrome P450 3A4 (CYP3A4) autoinhibition. Single nucleotide polymorphisms (SNPs) in CYP2C8 may affect imatinib trough levels. This study investigates the effect of common CYP2C8 polymorphisms [*1B (rs7909236), *1C (rs17110453), *3 (rs11572080 and rs10509681), and *4 (rs1058930)] on steady-state trough levels imatinib during chronic imatinib use in 43 patients with chronic myeloid leukemia or gastrointestinal stromal tumors. Standardized imatinib trough levels did not show a significant difference between wild-type and variant groups for any of the tested SNPs, but an association with age was found, with older patients having higher trough levels. This suggests that common CYP2C8 SNPs have no effect on the pharmacokinetics of imatinib.

Upfront Imatinib with Selective Early Switching to Nilotinib Leads to Excellent Achievement of Deep Molecular Response in Chronic Phase CML: 5 Year (Final) Analysis of the TIDEL-II Study

Upfront Imatinib with Selective Early Switching to Nilotinib Leads to Excellent Achievement of Deep Molecular Response in Chronic Phase CML: 5 Year (Final) Analysis of the TIDEL-II Study

335O Imatinib trough levels: A potential biomarker to predict cytogenetic and molecular response in newly diagnosed patients with chronic myeloid leukemia

Background A good pharmacokinetic/pharmacodynamic correlation between imatinib exposure and therapeutic outcome has been reported. However, therapeutic drug monitoring (TDM) of imatinib in patients with Chronic Myeloid Leukemia (CML) is an ongoing debate. We studied the influence of imatinib trough levels on cytogenetic and molecular response in patients with CML. Methods Newly diagnosed patients with chronic-phase CML, started on Imatinib therapy, were enrolled and followed-up prospectively for 24 months. Plasma trough levels of imatinib were measured using LC-MS/MS. Cytogenetic response was assessed by conventional bone-marrow cytogenetics. Molecular response was assessed by qRTPCR using international scale. Multivariate analysis was done to find the influence of various covariates on imatinib response. Results A total of 206 newly diagnosed patients with CML were enrolled in this study. The mean age at diagnosis was 35.2614 years. Marked inter-individual variability was seen in imatinib trough levels (Coefficient of variation= 69%). Mean imatinib trough level was 190161305 ng/mL. Trough levels were significantly higher in patients who attained complete cytogenetic response than those who didn't (2213.961101 vs. 1648.661403.4ng/mL;P<0.001). Patients with major molecular response(MMR) had higher trough levels than those without MMR (2333.461112 vs. 1643.461383.9 ng/mL; P = 0.001). Patients with trough levels <1002 ng/mL were at a high risk for failure of imatinib therapy[RR=1.926;95%CI(1.562,2.374);P <0.001]. Trough levels of imatinib emerged as an independent predict or of cytogenetic [adjusted OR: 10.488; 95%CI(4.136,26.594);P <0.001] and molecular response [adjustedOR:14.407;95%CI (3.414,60.791);P<0.001]in multivariate analysis. No significant correlation of trough levels with imatinib induced hematological toxicity was seen. Conclusions Trough level so fimatinib significantly influence thecy to genetic and molecular response in patients with CML and might emerge as a potential biomarker to predict therapeutic response. TDM is recommended for individualizing the dosage of imatinib, especially in patients with suboptimal response. Legal entity responsible for the study All India Institute of Medical Sciences, New Delhi, India Funding All India Institute of Medical Sciences, NewDelhi, India Disclosure All authors have declared no conflicts of interest.

335O Imatinib trough levels: A potential biomarker to predict cytogenetic and molecular response in newly diagnosed patients with chronic myeloid leukemia

335O Imatinib trough levels: A potential biomarker to predict cytogenetic and molecular response in newly diagnosed patients with chronic myeloid leukemia

Abstract 2040: Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in patients with chronic myeloid leukemia

Abstract Introduction: Genetic polymorphisms in the genes coding for imatinib transporters &amp; metabolizing enzymes might be responsible for marked inter-individual pharmacokinetic variability seen with imatinib &amp; might result in altered therapeutic response. Methodology: Newly diagnosed patients with chronic phase CML started on imatinib therapy were enrolled &amp; followed up for 24 months. The following single nucleotide polymorphisms (SNPs) were genotyped - C1236T, C3435T, G2677T &amp; G2677A in MDR1 gene and A6986G in CYP3A5 gene. Genotyping was done using PCR-RFLP method &amp; validated by direct gene sequencing. Plasma trough levels of imatinib were measured using LC-MS/MS. Patients who attained complete cytogenetic response by 12 months after imatinib therapy were called responders while those who failed to do so were called non-responders. Molecular response was assessed by quantitative RTPCR using international scale. Results: A total of 173 chronic phase CML patients were included in this study, out of which 71 were responders. Mean age at diagnosis was 35.9±14.3 years. All the alleles, except those for MDR1-C1236T, followed Hardy-Weinberg equilibrium. Marked variability in trough levels of imatinib was seen in patients with different genotypes (table1). The frequency of GG genotype for CYP3A5-A6986G and TT genotype for MDR1-C1236T, C3435T &amp; G2677T/A was higher in responders; while the frequency of AA genotype for CYP3A5-A6986G, CC genotype for MDR1-C1236T &amp; C3435T and GG genotype for MDR1-G2677T/A was higher in non-responders (table1). Conclusions: Genetic polymorphisms in MDR1 &amp; CYP3A5 genes have a significant role in determining imatinib levels &amp; therapeutic response in patients with CML. Genotyping of CPY3A5 &amp; MDR1 genes may be considered in patients with CML to individualize the therapy &amp; optimize the outcomes. Table 1:Trough levels of Imatinib in patients with different genotypes and frequency of different genotypes in imatinib responders and non-respondersSNPGenotypeTrough levels (mean±SD) of Imatinib (ng/mL)P valueImatinib responseP valueResponders (n = 71)Non-responders (n = 102)CYP3A5-A6986GAA1415.1 ± 1036.30.0164 (19%)17 (81%)&amp;lt; 0.001AG1610 ± 1161.120 (28%)51 (72%)GG2229 ± 1524.647 (58%)34 (42%)MDR1-C1236TCC1559.8 ± 990.40.2014 (21%)15 (79%)0.005CT1819.6 ± 1450.242 (37%)71 (63%)TT2178.4 ± 1246.725 (61%)16 (39%)MDR1-C3435TCC1418 ± 865.90.0133 (16%)16 (84%)&amp;lt; 0.001CT1695 ± 1318.928 (32%)60 (68%)TT2249.6 ± 1470.140 (61%)26 (39%)MDR1-G2677T/AGG1570.8 ± 1181.20.2974 (22%)14 (78%)0.019GT1726.5 ± 1489.323 (31%)51 (69%)TT2133.7 ± 1338.437 (54%)32 (46%)TA1840.5 ± 754.26 (60%)4 (40%)GA1450.2 ± 743.51 (50%)1 (50%) Citation Format: Natarajan Harivenkatesh, Lalit Kumar, Sameer Bakhshi, Atul Sharma, Madhulika Kabra, Thirumurthy Velpandian, Ajay Gogia, Shivaram Shastri, Yogendra Kumar Gupta. Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in patients with chronic myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2040.

Distinct predictive factors influence on achievement of early molecular response by frontline imatinib in chronic phase chronic myeloid leukemia

To explore the factors for achieving early molecular responses (EMR; BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months) by imatinib (IM), baseline characteristics including individual BCR-ABL1 transcript level, dose intensity, and IM trough level on day 29 were analyzed in 286 chronic phase chronic myeloid leukemia patients. Distinct predictive factors for achieving EMR at 3 months and 6 months were noted. Blast count at diagnosis and IM trough level on day 29 were significantly associated with an achievement of 3-month EMR. Early decline of BCR-ABL1 transcript, low Sokal risk, and mean daily dose (≥350mg/day) by 6 months were associated with an achievement of 6-month EMR. Understanding the predictive factors for EMR may provide additional information to guide clinical decisions on the changing therapies at each landmark.

Association of ABCG2 polymorphism with clinical efficacy of imatinib in patients with gastrointestinal stromal tumor.

Imatinib is a substrate of drug transporters and metabolizing enzymes, including members of the cytochrome P450 (CYP) system. Differences in imatinib pharmacokinetics among individuals might be influenced by genetic polymorphisms and be associated with variable clinical imatinib efficacy. This study sought to test how genetic polymorphisms can affect the clinical efficacy of imatinib and its blood levels in GIST patients. A total of 209 GIST patients who had received imatinib 400 mg daily were genotyped for six single-nucleotide polymorphisms in three genes (CYP3A5 6986A>G; ABCB1 1236C>T, 2677G>A/T, and 3435C>T; and ABCG2 34G>A and 421C>A) via blood samples. Progression-free survival (PFS) and imatinib plasma trough levels were evaluated and compared according to genotypes. With a median follow-up of 39.6 months (range 16.7-97.5 months), the estimated 5-year PFS rate was 67.5 % (95 % CI 59.9-75.1). Among the CYP3A5, ABCB1, and ABCG2 genotypes, ABCG2 421C>A was associated with PFS. The 5-year PFS rate in patients with the AA variant of ABCG2 421C>A (92.3 %; 95 % CI 77.8-100.0) was significantly superior to that of patients with CC/CA genotypes (65.0 %; 95 % CI 56.9-73.1; p = 0.047). For the imatinib trough levels, there were no statistically significant differences when comparing polymorphisms among all genotypes, even after adjusting for clinical factors, including sex, age, body surface area, hemoglobin, albumin, and creatinine clearance. The ABCG2 421C>A genetic variation could influence clinical efficacy in terms of PFS in patients with advanced GIST undergoing imatinib therapy.

Polymorphisms in the human organic cation transporter and the multidrug resistance gene: correlation with imatinib levels and clinical course in patients with chronic myeloid leukemia

The optimal tyrosine kinase inhibitor for any individual patient with chronic myeloid leukemia (CML) is not predictable. Pharmacogenetic parameters and trough levels of imatinib (IM) have each been independently correlated with response. We therefore studied the human organic cation transporter (hOCT1) and multidrug resistance (MDR1) single nucleotide polymorphisms (SNPs) and correlated these with IM levels and major molecular response (MMR) (3-log reduction) in 84 patients with CML, the first such study performed in Caucasians. We studied MDR1 G2677T and C3435T, and for hOCT1, C480G and A1222G. IM levels varied significantly with dose (< or > 400 mg/day) (p = 0.038) and were significantly lower in 20 patients who lost MMR (p = 0.042). Adjusting for dose, trough IM levels were not significantly correlated with SNPs. Patients with MDR1 3435 TT had significantly longer times to MMR compared to CC/CT genotypes (p = 0.047). Genotypes did not predict treatment failure when controlling for IM levels. We conclude that IM levels, but not the SNPs studied here, determine IM failure.

Correlation of plasma trough levels of imatinib with molecular response in patients with chronic myeloid leukemia

The present study looked at the correlation between mean trough Imatinib plasma levels and molecular response in 131 CML patients on imatinib. Patients receiving Glivec versus generic Imatinib were also compared. A ROC curve was constructed to estimate a threshold level that correlates with a favourable response. Patients were grouped into Responders (bcr/abl ration by RQ-PCR less than 1) and Non Responders (ration ≥ 1). The mean trough imatinib plasma level in the responders was significantly higher than in the non responders (p = 0.001). The area under ROC curve was 0.733, with best sensitivity (51.85%) and specificity (89.42%) at a plasma threshold of 0.988 g/ml [1.675 M]. Levels in the patients on Glivec versus generic drug (p > 0.05) were comparable. Trough Imatinib plasma levels may be a marker for suboptimal response and may identify patients in whom increase of drug dose or change in therapy may be indicated.

Demonstration of gender-specific variability in a pharmacokinetic (PK) analysis of the PERSIST-5 trial of adjuvant imatinib (IM) for patients with primary gastrointestinal stromal tumor (GIST) at significant risk of recurrence.

10538 Background: ThePERSIST-5 phase II trial is evaluating 5 years of adjuvant IM therapy in patients with resected GIST at significant risk of recurrence. This analysis studied the effect of chronic therapy on steady-state trough levels in patients who received IM for up to 24 months to evaluate potential PK variations. Methods: Eligible patients were adults with KIT+ primary GIST who were considered to be at significant risk for recurrence (primary tumor any site ≥2 cm andmitotic rate ≥5/50 high-power fields, or non-gastric primary GIST ≥5 cm) without metastases. R0 resection of primary GIST was performed ≤12 weeks prior to the first IM dose. Patients are to receive oral IM 400 mg/day for up to 5 years or until progression, relapse, or intolerance. Plasma samples for PK analysis were collected at 1, 4, 12, and 24 months. IM plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. Results: In-study assay performance (%CV) was ≤9.6% and bias was -1.3% to 5.2%. IM concentrations ranged from below quantifiable limits to 4798 ng/mL. After daily IM doses for up to 12 months (or 24 months in 3 patients), IM trough levels remained constant over time. The range of IM trough levels (mean ± SD) was 957 ± 750 ng/mL to 1219 ± 822 ng/mL at month 1, and 727 ± 430 ng/mL to 996 ± 405 ng/mL at month 12. Inter-patient variability was 40.7-78.4%. There was no significant difference in IM trough levels between months 1 and 4, 1 and 12, or 4 and 12. Trough levels did not significantly differ by location of GIST. Most notably, mean IM trough concentrations were on average ~33% higher in females vs males. Conclusions: In this study,IM trough levels remained relatively unaltered in patients with high-risk GIST who received adjuvant IM for 1 year. The 33% higher mean trough levels in females warrants further study for clinical decision making. Clinical trial information: NCT00867113. [Table: see text]

Plasma trough imatinib levels and molecular response in patients of chronic myeloid leukemia (CML): A single institution study from India.

7079 Background: One of the reasons proposed for suboptimal responses in Chronic Myeloid Leukemia (CML) patients receiving standard-dose Imatinib has been low blood levels of the drug. Our study aimed to determine the correlation between mean trough Imatinib plasma levels and molecular response in CML chronic phase patients at our centre. We also attempted to compare imatinib plasma levels in patients receiving Gleevec (Novartis) versus patients who were on the generic version of the drug. Methods: One hundred and thirty one (131) CML Chronic phase patients were included in this study. All patients had received 400 mg of imatinib for more than 2 year. Plasma Imatinib trough levels were estimated by high-performance liquid chromatography (HPLC). In order to estimate a threshold for plasma imatinib level that correlates with a favorable response, a receiver operating characteristic (ROC) curve was constructed. Patients were divided into two groups: those with Major Molecular Response (MMR) [bcr/abl : abl ratio &lt;1% as assessed by RQ-PCR] or better (Responders) and those without MMR (bcr/abl : abl ratio =/&gt; 1% as assessed by RQ-PCR) [Non Responders]. Imatinib plasma levels were also compared in patients who were on Gleevec versus those who were on the generic version of the drug. Results: The mean trough imatinib plasma level in the responders was significantly higher (2.10±1.18µg/ml) than in the non responders (1.31±0.72µg/ml) with p value of 0.001. The area under ROC curve was 0.733, with best sensitivity (51.85%) and specificity (89.42%) at a plasma threshold of 0.988 µg/ml. There was no significant difference between the mean trough plasma imatinib levels of the patients who were on Gleevec as compared to those who were on generic Imatinib (p value &gt; 0.05). Conclusions: Plasma Imatinib trough levels were statistically similar in the Gleevec and generic Imatinib groups. These levels showed a statistically significant correlation with molecular response. Trough plasma imatinib levels may be a marker for suboptimal response to Imatinib and may identify patients in whom increase of drug dose or change to second generation tyrosine kinase inhibitors may be indicated.

Sustained Long-Term MMR to a Reduced Dose of Imatinib in Chronic-Phase CML: A Pilot Study of SLC22A1 Gene Polymorphisms

AbstractAbstract 4449 Background:Recently, The efficacy of reduced dose of imatinib for the patients with small BSA was reported by our group and Japanese group. Also, therapeutic drug monitoring to maintain a plasma threshold level of about 1,000ng/ml would be beneficial during imatinib therapy in practical setting. But, we sometimes see a discrepancy between imatinib trough level and clinical efficacy. Observed inter-patient pharmacokinetic variability may be due to patients' genetics. Method:We investigated a panel of 9 polymorphisms in 4 genes (ABCG2, SLC22A1, ABCB1, CYP3A5), potentially associated with the pharmacogenetics of imatinib in a subset of 7 patients with sustained MMR. The DNAs from peripheral blood samples were genotyped. Imatinib trough levels were tested between 21 and 27 hours from the last dose of imatinib. Result:All patients were reduced dose to 300mg/day within six months after starting imatinib therapy with 400mg/day. The main reasons for dose reduction were severe neutropenia or thrombocytopenia (≥ grade 3) (62.9%). They couldn’t increase a standard imatnib dose due to severe adverse effect. Although relatively small BSA (mean BSA; 1.53), 4 of seven patients showed lower imatinib trough level than 1,000ng/ml. After median follow-up period of 66.2 months (18.4∼150.7), all patients have sustained MMR. Allele frequencies of rs683369, rs2282143, rs628031and rs2282143 polymorphisms of SLC22A1 gene were 0%, 78.5% and 8.3%, respectively. Interethnic differences in the genotype and allele frequencies of SLC22A1 gene polymorphism were observed when compared with other previous major populations. The SNPs rs2282143, T allele and rs628031, G allele were more common in Asians (5.5–16.8% and 76.2–81%) and African Americans (8.2% and 73.5%) than in Caucasians (0–2% and 57.4–60%). Conclusion:In our pilot study, we found interethnic differences in the genotype and allele frequencies of SLC22A1 gene in spite of very small cases. These findings might be explained a discrepancy between imatinib trough level and clinical efficacy in practical setting with reduced dose and further studies with larger scale will be needed to clarify the effect of these results. Disclosures:No relevant conflicts of interest to declare.