Evaluation of Molecular Response to Imatinib Mesylate Treatment in Iranian Patients With Chronic Myeloid Leukemia.
Nekoohesh Ladan,Rostami Shahrbano,Nikbakht Mohsen,Mohammadi Saeed,Babakhani Davood,Alimoghaddam Kamran,Ghahremani Mohammad H,Chahardouli Bahram
Clinical lymphoma, myeloma & leukemia
BACKGROUND:Imatinib mesylate has revolutionized the treatment of patients with chronic myeloid leukaemia (CML); however, some patients fail to respond and have a poor prognosis. Evaluation of molecular response to imatinib is a sensitive method can help physicians make better and quicker therapeutic decisions in the course of this disease. This study aims to evaluate the molecular response to generic imatinib in Iranian patients with CML. PATIENTS AND METHODS:This prospective study consisted of 255 newly diagnosed patients with CML who received imatinib. Molecular response was analyzed at 3 and 6 months from the start of the treatment and then every 6 months, and long-term outcomes, including overall survival (OS) and progression-free survival (PFS), were evaluated. RESULTS:At a median follow-up of 34.8 months (range, 3-84 months, (the OS and PFS at 7 years were 94.3% and 92.9%, respectively. Eighty-four-month PFS rates in patients with a BCR-ABLIS ≤ 10% at 3 months and BCR-ABLIS ≤ 1% at 6 months were significantly higher than patients who did not obtain these levels of BCR-ABL transcripts (P = .004 and P < .0001, respectively). The proportion of patients who achieved major molecular response (MMR) was 44.1%, 52.97%, and 60.75% at 12, 18, and 24 months, respectively. At 12, 18, and 84 months, the PFS rates in patients who achieved MMR were significantly higher than in patients who did not achieve MMR (P = .002, P < .0001, and P = .003, respectively). CONCLUSIONS:The data of this prospective study are highly comparable with that from clinical trials and prospective international studies.
10.1016/j.clml.2019.09.605
Association between C1236T Genetic Variant of ABCB1 Gene and Molecular Response to Imatinib in Indonesian Chronic Myeloid Patients.
Rinaldi Ikhwan,Nova Riki,Widyastuti Reni,Priambodo Rizky,Instiaty Instiaty,Louisa Melva
Asian Pacific journal of cancer prevention : APJCP
OBJECTIVE:Imatinib is the first-line drug used for the treatment of chronic myeloid leukemia (CML) patients due to high molecular response and overall survival rate. However, some patients develop resistance to imatinib even after attaining a response. Mutation in ABCB1 efflux transporters is one of the known mechanisms of resistance to imatinib in chronic myeloid leukemia patients. This study was aimed to investigate the association of ABCB1 C1236T polymorphism in Indonesian chronic myeloid patients with molecular response to imatinib treatment. METHODS:We analyzed 120 samples from chronic myeloid leukemia patients in the chronic phase, who had been on imatinib treatment for at least 12 months. We analyzed the C1236T variant of the ABCB1 gene using PCR, followed by direct sequencing, and associate them with the achievement of major molecular response (MMR). RESULTS:The major molecular response was achieved in 28% of patients. The frequencies of the SNPs were CC (40%), CT (46%), and TT (14%). Our result showed that there was a lack of association between polymorphism of ABCB1 C1236T and imatinib response in Indonesian patients, with OR = 0.646 (95% CI: 0.283, 1.471; p>0.05). CONCLUSION:There was no association between ABCB1 C1236T variants with the major molecular response in Indonesian chronic myeloid leukemia patients receiving imatinib treatment.
10.31557/APJCP.2019.20.11.3331
Towards a Personalized Treatment of Patients with Chronic Myeloid Leukemia.
Current hematologic malignancy reports
PURPOSE OF REVIEW:Treatment goals and ambitions have even been upwardly revised since demonstration was made that under certain conditions, treatment-free remission was possible. Herein, we will discuss on how to try tailoring treatment choices to the unique characteristics of each patient. RECENT FINDINGS:Since the first-generation ATP-competitive TKI imatinib was made available in the clinic in 2001, second-generation drugs such as dasatinib, nilotinib and bosutinib and the third-generation TKI ponatinib have broadened the therapeutic armamentarium, providing effective salvage against intolerance and different types of resistance, or as frontline options. Management and outcomes of patients with chronic myeloid leukemia have been revolutionized by the discovery, development, and approval of BCR-ABL tyrosine kinase inhibitors (TKIs). Most patients can now expect a near-to normal life expectancy and acceptable quality of life on life-long treatment, providing awareness and avoidance of harmful adverse events, which depend on each TKI safety profile and patient personal background.
10.1007/s11899-019-00546-4
Adverse effects of dasatinib on glucose-lipid metabolism in patients with chronic myeloid leukaemia in the chronic phase.
Yu Lu,Liu Jing,Huang Xiaojun,Jiang Qian
Scientific reports
To explore the differences in glucose-lipid metabolism profiles among the 3 TKIs, we designed a retrospective study to compare the onset of hyperglycaemia, hypertriglyceridemia, hypercholesterolemia and hyper-low density lipoprotein (LDL)-cholesterolemia in the patients with normal baseline glucose-lipid profiles and had no medical record of cardio- or cerebro-vascular diseases and/or metabolic syndrome diseases, and identify variables associated with them. 370 chronic myeloid leukaemia patients receiving dasatinib, nilotinib or imatinib therapy ≥3 months were retrospectively reviewed. During TKI-therapy, the mean fasting glucose, triglyceride, cholesterol, and LDL-cholesterol levels increased significantly in both dasatinib and nilotinib cohorts compared with the imatinib cohort. In multivariate analyses, dasatinib was the factor significantly associated with both poor hyperglycaemia- and hypertriglyceridemia-free survival. In addition, nilotinib was significantly associated with more occurrences of hyperglycaemia and hypercholesterolemia; increasing age was significantly associated with more occurrences of hyperglycaemia and hypertriglyceridemia. We concluded that dasatinib, similar to nilotinib, has the adverse impact on glucose-lipid metabolism compared with imatinib.
10.1038/s41598-019-54033-0
The predictive value of intracellular imatinib levels in newly diagnosed chronic myeloid leukemia.
Hillis Christopher M,Jackson Chornenki Nicholas L,Bence-Bruckler Isabelle,Busque Lambert,Cote Yvan,Hamm Caroline,Hasegawa Wanda,Kamel-Reid Suzanne,Savoie Lynn,Turner A Robert,Xenocostas Anargyros,Lipton Jeffrey H,Leber Brian
Leukemia research
10.1016/j.leukres.2019.106285
[Analysis of correlation between plasma trough level and response of generic imatinib in the treatment of Chinese patients with chronic myeloid leukemia].
You J H,Chen J,Zhou L,Du S H,Lu H Y,Sun S J,Li J M,Shen Z X
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi
To analyze the correlation between plasma trough level of generic imatinib and its metabolism and clinical outcomes in Chinese patients with chronic myeloid leukemia in chronic phase (CML-CP) . The 21 patients with CML-CP who enrolled in a clinical trial YMTN 1.0 from Oct 11(th), 2012 to May 8(th), 2013 and received generic imatinib were as study subjects. The correlation between steady plasma trough levels of imatinib and its metabolism with clinical response, age, weight and body surface area (BSA) were evaluated. ①The mean steady plasma trough level of generic imatinib and its metabolism was (1 185.07±417.91) μg/L and (251.53±76.50) μg/L, respectively. ②Age, weight and BSA has no significant effects on plasma trough level of generic imatinib and its metabolism (>0.05) . ③Patients with steady plasma trough level of generic imatinib more than 1 000 μg/L are possible to have higher major molecular response (MMR) /complete molecular response (CMR) rate than those below 1 000 μg/L (42% 0, <0.05) . Plasma trough levels of generic imatinib varied in CML patients. The steady plasma trough levels of generic imatinib is maybe related to molecular response in CML patients.
10.3760/cma.j.issn.0253-2727.2019.11.010
A Novel Inhibitor of STAT5 Signaling Overcomes Chemotherapy Resistance in Myeloid Leukemia Cells.
Brachet-Botineau Marie,Deynoux Margaux,Vallet Nicolas,Polomski Marion,Juen Ludovic,Hérault Olivier,Mazurier Frédéric,Viaud-Massuard Marie-Claude,Prié Gildas,Gouilleux Fabrice
Cancers
Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) are crucial downstream effectors of tyrosine kinase oncogenes (TKO) such as BCR-ABL in chronic myeloid leukemia (CML) and FLT3-ITD in acute myeloid leukemia (AML). Both proteins have been shown to promote the resistance of CML cells to tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM). We recently synthesized and discovered a new inhibitor (17f) with promising antileukemic activity. 17f selectively inhibits STAT5 signaling in CML and AML cells by interfering with the phosphorylation and transcriptional activity of these proteins. In this study, the effects of 17f were evaluated on CML and AML cell lines that respectively acquired resistance to IM and cytarabine (Ara-C), a conventional therapeutic agent used in AML treatment. We showed that 17f strongly inhibits the growth and survival of resistant CML and AML cells when associated with IM or Ara-C. We also obtained evidence that 17f inhibits STAT5B but not STAT5A protein expression in resistant CML and AML cells. Furthermore, we demonstrated that 17f also targets oncogenic STAT5B N642H mutant in transformed hematopoietic cells.
10.3390/cancers11122043
Comprehensive analyses of safety and efficacy toward individualizing imatinib dosage in patients with chronic myeloid leukemia.
Shin Hyejin,Choi Soo Young,Kee Kyung-Mi,Kim Soo-Hyun,Yang Seon-Young,Jung Su Young,Noh Hayeon,Zang Dae Young,Kim Dong-Wook,Lee Jangik I
International journal of hematology
Safety and efficacy outcomes of imatinib treatment were evaluated using extensive clinical data collected from a total of 1003 patients with newly diagnosed chronic myeloid leukemia in chronic phase between 2001 and 2018. By 12 months of imatinib treatment at a fixed dose of 400 mg/day, 45.4% of patients experienced at least one type of dose-limiting toxicities (DLTs). The DLTs that frequently occurred first were thrombocytopenia (40.0%), neutropenia/leukopenia (14.3%) and dermatological reactions (12.1%). Patients with lighter body weight (≤ 64 kg) and older age (> 43 years) experienced a markedly higher occurrence of first DLTs by 12 months than heavier and younger patients (57.9% vs. 30.1%, p < 0.001). On the other hand, 38.9% of patients achieved major molecular response (MMR) at 12 months at the fixed dose. Female patients achieved a greater rate of MMR than male patients (45.6% vs. 35.5%, p = 0.028). In conclusion, patients with light weight and old age are more vulnerable to DLTs, whereas female patients gain more efficacy benefit at the fixed dose. The authors suggest that the initial dose of imatinib should be reduced to 300 mg/day or lower for patients vulnerable to DLTs to diminish the risk of DLTs without compromising the achievement of MMR.
10.1007/s12185-019-02805-9
Longer Hydroxyurea Administration Prior to Imatinib Mesylate is Risk Factor for Unsuccessful Major Molecular Response in Chronic-Phase Chronic Myeloid Leukemia: Possibility of P-Glycoprotein Role.
Rinaldi Ikhwan,Reksodiputro Ary Harryanto,Jusman Sri Widia,Harahap Alida,Setiabudy Rianto,Wanandi Septelia Inawati,Tambunan Karmel,Suharti Catharina
Asian Pacific journal of cancer prevention : APJCP
OBJECTIVE:This study aimed to identify the association between duration of HU administration prior to IM treatment and MMR achievement in chronic-phase CML while evaluating the role of MDA, HIF-1α and P-gp. METHODS:The study was conducted at Dr. Cipto Mangunkusumo National General Hospital and Dharmais Cancer Hospital, Jakarta using retrospective cohort design to analyse the association between the duration of HU before IM and its MMR achievement and cross-sectional design to analyse the association between MDA, HIF-1α and P-gp expressions with MMR achievement. Main subjects were chronic-phase CML patients treated by HU prior to IM for ≥ 12 months and HU only. The subjects were divided into four main groups: (1) chronic-phase CML patients treated with HU ≤ 6 months + IM ≥ 12 months and (2) HU > 6 months + IM ≥ 12 months (3) HU only (≤ 6 months), (4) HU only ( >6 months). Subjects were obtained from January 2015 to May 2016. Data were gathered through history taking, physical examination, medical record evaluation, and blood sample analysis. Bivariate analysis was conducted using chi square, independent T-test, and Mann-Whitney according to the variables. RESULTS:Administration of HU for more than 6 months prior to IM was associated with unsuccessful MMR achievement (RR 1.60; 95%CI 1.29-2.00). MDA level, HIF-1α, P-glycoprotein expression were not associated with MMR achievement but the mean MDA level (0.63±0.31 vs 0.75±0.41 p=0.461) and median P-glycoprotein expressions {16,92 (0,04 - 43,86) vs. 5,15 (0,02-39,64); p=0.311} were found to be higher in patients receiving HU for > 6 months group than in HU ≤ 6 months group consecutively. CONCLUSION:Administration of HU for more than 6 months prior to IM was associated with unsuccessful MMR achievement in chronic-phase CML. The study suggested that P-glycoprotein overexpression as the predictor for unsuccessful MMR achievement.
10.31557/APJCP.2019.20.12.3689
Determination of Anlotinib, a Tyrosine Kinase Inhibitor, in Rat Plasma by UHPLC-MS/MS and Its Application to a Pharmacokinetic Study.
Wang Zhe,Lian Le-Jing,Dong Yan-Yan,Cui Xiao,Qian Jian-Chang,Huang Cheng-Ke,Chen Rui-Jie,Sun Wei
Journal of analytical methods in chemistry
Anlotinib is a novel inhibitor of receptor kinase tyrosine with multitargets and has a broad spectrum of inhibitory action on tumor angiogenesis and growth. A simple and rapid UHPLC-MS/MS bioanalytical method was validated for the determination of anlotinib in rat plasma, using imatinib as an internal standard. An Acquity BEH C18 column was used to separate analytes. The eluents consisted of formic acid/water (0.1 : 100, v/v) and acetonitrile with a mobile phase. A triple quadrupole mass spectrometer was operated for the quantification with multiple reaction monitoring (MRM) to determine transitions: 408.2 ⟶ 339.1 for anlotinib, and 494.3 ⟶ 394.1 for imatinib. The validated range was 0.1-50 ng/mL for anlotinib. Mean recovery rate of anlotinib in plasma was ≥99.32% and reproducible. Also, the intra- and interday precisions were both below 15%. This robust method was successfully applied to support the pharmacokinetic study of anlotinib in rats.
10.1155/2019/5016757
Decreased expression of microRNA-214 contributes to imatinib mesylate resistance of chronic myeloid leukemia patients by upregulating ABCB1 gene expression.
Jin Jing,Yao Jia,Yue Fang,Jin Zhaoying,Li Dan,Wang Shan
Experimental and therapeutic medicine
The aim of the present study was to determine the expression of adenosine triphosphate binding cassette subfamily B member 1 (ABCB1) gene and its protein P-glycoprotein (PGP) in bone marrow mononuclear cells from chronic myeloid leukemia (CML) patients with imatinib mesylate (IM) resistance, or IM-resistant CML K562 cells. In addition, the molecular mechanism of action of microRNA (miR)-214 on ABCB1 in IM resistance was investigated. A total of 26 CML patients with IM resistance were included in the present study. In addition, 31 CML patients who did not have IM resistance were included as the control group. Bone marrow was collected from all subjects. The K562R cell line, which is a K562 cell line with IM resistance, was used for cellular studies. Reverse transcription-quantitative polymerase chain reaction was used to determine the expression of ABCB1 mRNA and miR-214 in cells. Western blotting was employed to determine the expression of PGP. Dual luciferase reporter assay was carried out to identify interactions between ABCB1 mRNA and miR-214. MTT assay was used to determine the survival rate of cells. ABCB1 mRNA and PGP expression was upregulated in bone marrow mononuclear cells from CML patients with IM resistance. K562R cells had higher ABCB1 and PGP expression than K562 cells, potentially due to their different sensitivity to IM. Expression miR-214 was decreased in bone marrow mononuclear cells from patients with IM resistance and K562R cells. Notably, miR-214 was able to bind with the 3'-untranslated region, seed region of ABCB1 mRNA to regulate its expression. In addition, elevated expression of miR-214 restored IM sensitivity to K562R cells potentially by affecting ABCB1 expression. The present study demonstrated that upregulated expression of ABCB1 mRNA and PGP in bone marrow mononuclear cells from CML patients with IM resistance may be associated with the downregulation of miR-214. In addition, miR-214 may participate in the IM resistance of CML patients by regulating ABCB1 expression.
10.3892/etm.2018.6404
Evaluation of oxidative stress responses in human circulating blood cells after imatinib mesylate treatment - Implications to its mechanism of action.
Gajski Goran,Gerić Marko,Domijan Ana-Marija,Golubović Ivana,Garaj-Vrhovac Vera
Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society
Imatinib mesylate (IM) is the first developed protein kinase inhibitor and recently it has topped consumption rates among targeted and total anticancer drugs. Although there are indications that IM possesses cyto/genotoxic activities against normal non-target cells as well, there is a lack of information regarding the underlying mechanism involved in those actions. Therefore, we aimed to evaluate the response of human circulating blood cells towards oxidative stress after IM treatment (0.0001-10 µg/mL) . Based on the results, IM had an influence on all of the oxidative stress parameters tested. Lower concentrations of IM induced an increase of glutathione level, following its decrease at higher IM concentrations indicating impairment in oxidative stress defences. Concomitant to a glutathione decrease, an increase of malondialdehyde and protein carbonyls level was observed indicating oxidative damage of lipids and proteins. The observed effects overlapped with the observed formation of oxidative base damage detected by formamidopyrimidine-DNA glycosylase modified-comet assay indicating that IM managed to induce oxidative DNA damage. Our results provide novelty in their mechanistic approach to IM-induced toxicity in non-target cells and suggest that IM can affect blood cells and induce oxidative stress.
10.1016/j.jsps.2019.10.005
Pharmacology and pharmacokinetics of imatinib in pediatric patients.
Suttorp Meinolf,Bornhäuser Martin,Metzler Markus,Millot Frédéric,Schleyer Eberhard
Expert review of clinical pharmacology
INTRODUCTION:The tyrosine kinase inhibitor (TKI) imatinib was rationally designed to target BCR-ABL1 which is constitutively activated in chronic myeloid leukemia (CML). Following the tremendous success in adults, imatinib also became licensed for treatment of CML in minors. The rarity of pediatric CML hampers the conduction of formal trials. Thus, imatinib is still the single TKI approved for CML treatment in childhood. Areas covered: This review attempts to provide an overview of the literature on pharmacology, pharmacokinetic, and pharmacogenetic of imatinib concerning pediatric CML treatment. Articles were identified through a PubMed search and by reviewing abstracts from relevant hematology congresses. Additional information was provided from the authors' libraries and expertise and from our own measurements of imatinib trough plasma levels in children. Pharmacokinetic variables (e.g. alpha 1-acid glycoprotein binding, drug-drug/food-drug interactions via cytochrome P450 3A4/5, cellular uptake mediated via OCT-1-influx variations and P-glycoprotein-mediated drug efflux) still await to be addressed in pediatric patients systematically. Expert commentary: TKI response rates vary among different individuals and pharmacokinetic variables all can influence CML treatment success. Adherence to imatinib intake may be the most prominent factor influencing treatment outcome in teenagers thus pointing towards the potential benefits of regular drug monitoring.
10.1080/17512433.2018.1398644
Differential effects of hepatic cirrhosis on the intrinsic clearances of sorafenib and imatinib by CYPs in human liver.
Murray Michael,Gillani Tina B,Ghassabian Sussan,Edwards Robert J,Rawling Tristan
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
The tyrosine kinase inhibitors sorafenib and imatinib are important in the treatment of a range of cancers but adverse effects in some patients necessitate dosage modifications. CYP3A4 has a major role in the oxidation of sorafenib to its N-oxide and N-hydroxymethyl metabolites and also acts in concert with CYP2C8 to mediate imatinib N-demethylation. CYP3A4 expression and function are impaired in patients with advanced liver disease, whereas the functions of CYP2C enzymes are relatively preserved. We evaluated the biotransformation of sorafenib and imatinib in well-characterized microsomal fractions from 17 control subjects and 19 individuals with hepatic cirrhosis of varying severity. The principal findings were that liver disease impaired the microsomal oxidation of sorafenib to its major metabolites to 40-44% of control (P<0.01), whereas the N-demethylation of imatinib was relatively unimpaired. The impairments in sorafenib biotransformation were correlated with decreased serum albumin concentrations and increased serum bilirubin concentrations in patients with liver disease, but not with the overall grade of liver disease according to the Child-Pugh system. In contrast, there was no relationship between imatinib N-demethylation and clinicopathologic factors in liver disease patients. These findings were accounted for in terms of the differential roles of CYPs 3A4 and 2C8 in the intrinsic clearance of the drugs. CYP3A4 has the major role in the intrinsic clearance of sorafenib but plays a secondary role to CYP2C8 in the intrinsic clearance of imatinib. In agreement with these findings CYP2C protein expression and CYP2C8-mediated paclitaxel 6α-hydroxylation were unimpaired in cirrhotic livers. This information could be adapted in individualized approaches such as in vivo CYP3A4 phenotyping to optimize sorafenib safety and efficacy in cancer patients with liver dysfunction.
10.1016/j.ejps.2017.12.003
Effect of imatinib on plasma glucose concentration in subjects with chronic myeloid leukemia and gastrointestinal stromal tumor.
Gómez-Sámano Miguel Ángel,Baquerizo-Burgos Jorge Enrique,Coronel Melissa Fabiola Coronel,Wong-Campoverde Buileng Daniela,Villanueva-Martinez Fernando,Molina-Botello Diego,Avila-Rojo Jose Alonso,Palacios-Báez Lucía,Cuevas-Ramos Daniel,Gomez-Perez Francisco Javier,Zentella-Dehesa Alejandro,Aguayo-González Álvaro,Gulias-Herrero Alfonso
BMC endocrine disorders
BACKGROUND:Type 2 diabetes mellitus has become one of the most important public health concerns worldwide. Due to its high prevalence and morbidity, there is an avid necessity to find new therapies that slow the progression and promote the regression of the disease. Imatinib mesylate is a tyrosine kinase inhibitor that binds to the Abelson tyrosine kinase and related proteins. It enhances β-cell survival in response to toxins and pro-inflammatory cytokine. The aim of this study is to evaluate the effect of imatinib on fasting plasma glucose in subjects with normal fasting glucose, subjects with impaired fasting glucose and in subjects with type 2 diabetes mellitus. METHODS:We identified 284 subjects diagnosed with chronic myeloid leukemia or gastrointestinal stromal tumors from the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran database. 106/284 subjects were treated with imatinib. We compared the effect of imatinib on fasting plasma glucose after 1 and 6 months of treatment. We used ANOVA test of repeated samples to determine statistical significance in fasting plasma glucose before imatinib treatment and the follow-up. Statistical analysis was performed with Statistical Package for the Social Sciences v22. RESULTS:We included a total of 106 subjects: 76 with fasting plasma glucose concentrations < 100 mg/dL (normal FG), 19 subjects with fasting plasma glucose concentrations ≥100 mg/dL (impaired fasting glucose), and 11 subjects with ≥126 mg/dL (type 2 diabetes mellitus). We found a significant increase in fasting plasma glucose concentration in the normal fasting glucose group (p = 0.048), and a significant decrease in fasting plasma glucose concentration in the type 2 diabetes mellitus group (p = 0.042). In the impaired fasting glucose group, we also found a tendency towards a decrease in fasting plasma glucose (p = 0.076). We identified 11 subjects with type 2 diabetes mellitus, of whom, 7 (64%) had a reduction in their fasting plasma glucose concentrations after 6 months. A significant glycosylated hemoglobin reduction (p = 0.04) was observed. CONCLUSION:Subjects with chronic myeloid leukemia or gastrointestinal stromal tumor with type 2 diabetes mellitus had a significant reduction in fasting plasma glucose and glycosylated hemoglobin at 1 and 6 months while using imatinib.
10.1186/s12902-018-0303-x
Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib. PATIENTS AND METHODS:Patients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). RESULTS:At the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5% and 7% of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms. CONCLUSION:These final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long-term treatment of CML-CP.
10.1200/JCO.2015.64.8899
Imatinib, sunitinib and pazopanib: From flat-fixed dosing towards a pharmacokinetically guided personalized dose.
Westerdijk Kim,Desar Ingrid M E,Steeghs Neeltje,van der Graaf Winette T A,van Erp Nielka P,
British journal of clinical pharmacology
Tyrosine kinase inhibitors (TKIs) are anti-cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure-treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs. In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib.
10.1111/bcp.14185
Effective quantification of 11 tyrosine kinase inhibitors and caffeine in human plasma by validated LC-MS/MS method with potent phospholipids clean-up procedure. Application to therapeutic drug monitoring.
Koller Dora,Vaitsekhovich Viktoryia,Mba Cecile,Steegmann Juan L,Zubiaur Pablo,Abad-Santos Francisco,Wojnicz Aneta
Talanta
Therapeutic drug monitoring (TDM) help to improve treatment efficacy and safety. Therefore, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous monitoring of 11 tyrosine kinase inhibitors (TKIs) in human plasma. TKIs included in the assay are used in the treatment of chronic myeloid leukemia (CML: imatinib, dasatinib, nilotinib, bosutinib, ponatinib), polycythemia vera (ruxolitinib), chronic lymphocytic leukemia (ibrutinib) and rheumatoid arthritis (filgotinib, tofacitinib, baricitinib, peficitinib). Caffeine was also included in the method. Caffeine increases the acidity of the stomach and decreases its pH as well as is a competitive inhibitor of cytochrome P450 isoenzymes. Thus, it may influence absorption and metabolism of some TKIs, by modifying their plasma levels. The analytes of interest and their stable isotope-labeled internal standards were extracted from 200 μL of human plasma. Microelution-solid phase extraction (μ-SPE) was optimized for method validation and compared to simple protein precipitation (PPT). A gradient elution on a Poroshell 120 EC-C18 column at 60 °C and a flow rate of 0.5 mL/min was applied for analyte separation. The analytical run lasted 8 min and it was followed by a re-equilibration time of 4 min. Dynamic multiple reaction monitoring scan in the positive ionization mode was applied to improve method sensitivity. Endogenous plasma phospholipids can strongly affect MS analysis. Hence, the monitoring of endogenous phospholipids was included in the assay. Full validation of the method was achieved, including tests of precision, accuracy, trueness, linearity, extraction recovery, matrix effect, process efficiency, stability, sensitivity (with excellent LLOQs), selectivity, identity confirmation and carry-over effect. Regarding sample cleanup, more than 91% of early eluting and more than 96% of late eluting endogenous phospholipids were eliminated by μ-SPE when compared to PPT. This method enables the simultaneous plasma monitoring of 11 TKIs and caffeine and ensures high effectiveness in phospholipids elimination. The present approach is currently used in our clinical practice, being applied to TDM of dasatinib, imatinib, nilotinib and ponatinib. TKIs plasma monitoring helps to individualize dose adjustment and manage adverse effects in CML patients.
10.1016/j.talanta.2019.120450
Imatinib mesylate inhibits STAT5 phosphorylation in response to IL-7 and promotes T cell lymphopenia in chronic myelogenous leukemia patients.
Thiant S,Moutuou M M,Laflamme P,Sidi Boumedine R,Leboeuf D M,Busque L,Roy J,Guimond M
Blood cancer journal
Imatinib mesylate (IM) therapy has been shown to induce lower T cell counts in chronic myelogenous leukemia (CML) patients and an interference of IM with T cell receptor (TCR) signaling has been invoked to explain this observation. However, IL-7 and TCR signaling are both essential for lymphocyte survival. This study was undertaken to determine whether IM interferes with IL-7 or TCR signaling to explain lower T cell counts in patients. At diagnosis, CML patients have typically lower CD4 counts in their blood, yet CD8 counts are normal or even increased in some. Following the initiation of IM treatment, CD4 counts were further diminished and CD8 T lymphocytes were dramatically decreased. In vitro studies confirmed IM interference with TCR signaling through the inhibition of ERK phosphorylation and we showed a similar effect on IL-7 signaling and STAT5 phosphorylation (STAT5-p). Importantly however, using an in vivo mouse model, we demonstrated that IM impaired T cell survival through the inhibition of IL-7 and STAT5-p but not TCR signaling which remained unaffected during IM therapy. Thus, off-target inhibitory effects of IM on IL-7 and STAT5-p explain how T cell lymphopenia occurs in patients treated with IM.
10.1038/bcj.2017.29
[Expression Levels of JARID1B, Hes1 and MMP-9 Genes in CML Patients Treated with Imatinib Mesylate].
He Zhi-Kai,Xue Seng,Zhang Yong-Hong,Li Lin,Xia Yun-Jin,Wang Xiang,Shi Xin,Liu Yu,Xu Zheng,Li Chen,Zhang Jing-Xuan
Zhongguo shi yan xue ye xue za zhi
OBJECTIVE:To explore the relationship between the expression levels of JARID1B,Hes1 and MMP-9 genes and the stages of chronic myelogenous leukemia(CML) and the curative effect of imatinib mesylate (IM). METHODS:Peripheral blood samples of 15 cases of CML in chronic phase and 10 cases of CML in progressive phase were collected from the Hematology Department of Taihe Hospital affiliated to Hubei University of Medicine and 15 cases of healthy people in the Physical Examination Center. CML patients were divided into effective group and ineffective group based on the efficacy after treatment with IM, then real-time PCR was used to detect the expression levels of JARID1B, Hes1 and MMP-9 mRNA, finally, the differences in the level of gene expression and their correlations with CML stages and IM curative efficacy were analysed. RESULTS:The expression levels of Hes1 and MMP-9 in initially diagnosed patients in chronic and progressive phase without IM treatment were significantly higher than those of health people（P＜0.05）. There was no significant difference in the expression level of JARID1B between chronic phase patients and health people（P＞0.05）, but the expression level of JARID1B in the progressive phase patients was higher than that of health people （P＜0.05）. The expression levels of JARID1B and Hes1 in the IM-effective group were not significantly different from those in the IM-ineffective group (P=0.85,P=0.82）, while the expression level of MMP-9 in the IM-effective group [JP2]was significantly lower than that in the IM-ineffective group（P＜0.05）. CONCLUSION:The expression levels of JARID1B Hes1 and MMP-9 relate with the different phase of CML; The expression levels of JARID1B and Hes1 have not significant relationship with IM curative efficacy, the MMP-9 gene expression level relates with IM curative efficacy.
10.19746/j.cnki.issn.1009-2137.2019.04.013
Association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with clinical response to imatinib mesylate treatment among Malaysian chronic myeloid leukaemia patients.
Makhtar Siti Maziras,Husin Azlan,Baba Abdul Aziz,Ankathil Ravindran
Journal of genetics
The detoxifying activity of glutathione S-transferases (GST) enzymes not only protect cells from the adverse effects of xenobiotics, but also alters the effectiveness of drugs in cancer cells, resulting in toxicity or drug resistance. In this study, we aimed to evaluate the association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with treatment response among Malaysian chronic myeloid leukaemia (CML) patients who everyday undergo 400 mg of imatinib mesylate (IM) therapy. Multiplex polymerase chain reaction (multiplex-PCR) was performed to detect GSTM1 and GSTT1 polymorphisms simultaneously and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was conducted to detect the GSTP1 Ile195Val polymorphism. On evaluating the association of the variant genotype with treatment outcome, heterozygous variant (AG) and homozygous variant (GG) of GSTP1 Ile105Val showed significantly a higher risk for the development of resistance to IM with OR: 1.951 (95% CI: 1.186-3.209, P = 0.009) and OR: 3.540 (95% CI: 1.305-9.606, P = 0.013), respectively. Likewise, GSTT1 null genotype was also associated with a significantly higher risk for the development of resistance to IM with OR = 1.664 (95% CI: 1.011-2.739, P = 0.045). Our results indicate the potential usefulness of GST polymorphism genotyping in predicting the IM treatment response among CML patients.
Concurrent effects of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp genetic polymorphisms with risk of cancer, clinical output, and response to treatment with imatinib mesylate in patients with chronic myeloid leukemia.
Salimizand Hana,Amini Sabrieh,Abdi Mohammad,Ghaderi Bayazid,Azadi Namam-Ali
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine
There are a paucity and contradicted data about the impact of concurrent heredity of polymorphic genes and risk of chronic myeloid leukemia (CML). In the present study, the concurrent effects of three polymorphisms affecting the integrity of DNA consist of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp on development of chronic myeloid leukemia were studied. Furthermore, the role of these polymorphisms in clinical and laboratory outcomes of patients was evaluated. In this case-control study, 70 CML patients and 140 healthy individuals were enrolled in the study. The clinical features of patients such as phase of disease and response to treatment and laboratory data before and after treatment with imatinib mesylate were collected. ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp single nucleotide polymorphisms were evaluated by restriction fragment length polymorphism-polymerase chain reaction. The T allele of ABCB1 C3435T, T allele of XRCC1 Arg194Trp, and C allele of ABCG2 C421A polymorphisms were significantly higher in patients than controls. TT genotype of ABCB1 and TT genotype of XRCC1 were associated with higher risk of chronic myeloid leukemia development. CC421 ABCG2/TT3435 ABCB1 and CC421 ABCG2/TT27157 XRCC1 were also correlated with a higher risk of CML. Patients with C allele of ABCB1 had poor cytogenetic response, and correlation of CC421 ABCG2/TT3435 ABCB1 diplotype with accelerated phase of CML was significant. Patients with CC421 ABCG2/TT3435 ABCB1 and CC421 ABCG2/TT27157 XRCC1 diplotypes might be at higher risk to rapid and severe development of CML and have weaker response to treatments with imatinib.
10.1007/s13277-015-3874-4
Mutations Associated with Imatinib Mesylate Resistance - Review.
Linev Alexandar J,Ivanov Hristo J,Zhelyazkov Ivan G,Ivanova Hristina,Goranova-Marinova Veselina S,Stoyanova Vili K
Folia medica
Chronic myeloid leukemia (CML) arises from the fusion of the BCR and the ABL1 genes. The BCR gene (chromosome 22q11.2) and the ABL1 gene (chromosome 9q34) fuse together due to reciprocal chromosome translocation forming the Philadelphia chromosome (Ph). This fusion gene codes tyrosine kinase which accelerates the cell division and reduces DNA repair. Imatinib mesylate is a selective inhibitor of this tyrosine kinase. It is the first-line treatment for CML-patients. However, it became clear that Philadelphia-positive (Ph+) cells could evolve to elude inhibition due to point mutations within the BCR-ABL kinase domain. To date more than 40 mutations have been identified and their early detection is important for clinical treatment. With the development of the new tyrosine kinase inhibitors (TKIs), associated with these mutations, the resistance problem seems to diminish, as some of the new drugs are less prone to resistance. The aim of this review is to focus on the diff erent mutations leading to resistance.
10.2478/folmed-2018-0030
Genetic variations in influx transporter gene are associated with clinical responses to imatinib mesylate among Malaysian chronic myeloid leukaemia patients.
Makhtar Siti Maziras,Husin Azlan,Baba Abdul Aziz,Ankathil Ravindran
Journal of genetics
Imatinib mesylate (IM), a well-established gold standard drug in the treatment of chronic myeloid leukaemia (CML), is a synthetic tyrosine kinase inhibitor. Despite excellent efficacy, a significant number of patients on IM therapy develop resistance to IM. Currently, great focus has been laid on the effect of interindividual pharmacogenetic variability on IM treatment responses. IM uptake is mediated by the hOCT1 protein encoded by the solute carrier 22 gene (). The current study investigated the impact of few single-nucleotide polymorphisms (SNPs) of on mediating resistance and/or good response to IM among 278 Malaysian CML patients (146 IM-resistant group and 132 IM good response group) undergoing IM therapy on 400 mg daily. Our results showed that the allelic frequencies of heterozygous (CG) and homozygous variant (GG) genotypes of C480G were significantly higher in the IM-resistant group compared with the IM good response group (41.8% versus 30.3% and 10.9% versus 4.5% with values of 0.047 and 0.048, respectively). On evaluating the association of genotypes with risk of IM resistance development, heterozygous (CG) and homozygous (GG) variant genotypes showed significantly higher risk for developing resistance to IM treatment with odds ratio (OR): 1.901 (95% confidence interval (CI): 1.142-3.163, = 0.013) and 3.324 (95% CI: 1.235-8.947, = 0.017), respectively. Two SNPs and two insertions/deletions were detected in exon 7 of . For exon 7, 1222AA carriers together with the presence of both the 8-bp insertion and 3-bp deletion, and M420del alleles showed higher possibility of developing resistance towards IMtreatment. Our results warrant the need of genotyping this SNP in terms of modulating IM treatment in CML patients.
Genetic Polymorphisms Contribute to the Individual Variations of Imatinib Mesylate Plasma Levels and Adverse Reactions in Chinese GIST Patients.
Liu Jing,Chen Zhiyu,Chen Hanmei,Hou Yingyong,Lu Weiqi,He Junyi,Tong Hanxing,Zhou Yuhong,Cai Weimin
International journal of molecular sciences
Imatinib mesylate (IM) has dramatically improved the outcomes of gastrointestinal stromal tumor (GIST) patients. However, the clinical responses of IM may considerably vary among single individuals. This study aimed to investigate the influences of genetic polymorphisms of drug-metabolizing enzyme (CYP3A4), transporters (ABCB1, ABCG2), and nuclear receptor (Pregnane X Receptor (PXR, encoded by )) on IM plasma levels and related adverse reactions in Chinese GIST patients. A total of 68 Chinese GIST patients who have received IM 300-600 mg/day were genotyped for six single nucleotide polymorphisms (SNPs) (; ; ; , , ), and the steady-state IM trough plasma concentrations were measured by a validated HPLC method. There were statistically significant variances in the steady-state IM trough plasma concentrations (from 272.22 to 4365.96 ng/mL). Subjects of in , allele carriers in and in had significantly higher steady-state IM dose-adjusted trough plasma concentrations. Subjects of in had significantly higher incidence rate of edema. The genetic polymorphisms of , , were significantly associated with IM plasma levels, and the genetic variations of were significantly associated with the incidence rate of edema in Chinese GIST patients. The current results may serve as valuable fundamental knowledge for IM therapy in Chinese GIST patients.
10.3390/ijms18030603
Cysteine-rich protein 61 regulates the chemosensitivity of chronic myeloid leukemia to imatinib mesylate through the nuclear factor kappa B/Bcl-2 pathway.
Song Yanfang,Lin Qing,Cai Zhaolian,Hao Taisen,Zhang Yaohan,Zhu Xianjin
Cancer science
Although the targeted tyrosine kinase inhibitor imatinib mesylate (IM) has achieved significant responses against CML in the clinical setting, a small proportion of patients fail to respond to IM treatment and their disease continues to progress, indicating resistance to IM therapy. As a secreted extracellular matrix protein, cysteine-rich protein 61 (Cyr61) plays an important role in the resistance of solid tumors to chemotherapy, but its role in CML is unclear. In the present study, we observed that Cyr61 levels were upregulated in the plasma and bone marrow (BM) of patients with CML as well as in K562 cells. This upregulation of Cyr61 significantly decreased IM-induced cellular apoptosis of K562 cells through nuclear factor kappa B/B-cell lymphoma 2 pathways. Inhibition of Cyr61 restored the chemosensitivity of K562 cells to IM both in vitro and in vivo. Thus, our results showed for the first time that Cyr61 plays an important role in regulating the chemosensitivity of CML cells to IM, suggesting that selectively targeting Cyr61 directly or its relevant effector pathways may provide potential value in improving the clinical response of patients with CML to IM treatment.
10.1111/cas.14083
A study to explore the correlation of ABCB1, ABCG2, OCT1 genetic polymorphisms and trough level concentration with imatinib mesylate-induced thrombocytopenia in chronic myeloid leukemia patients.
Francis Jose,Dubashi Biswajit,Sundaram Rajan,Pradhan Suresh Chandra,Chandrasekaran Adithan
Cancer chemotherapy and pharmacology
PURPOSE:Imatinib mesylate is presently the first-line treatment for chronic myeloid leukemia (CML). Therapeutic drug monitoring (TDM) and pharmacogenetic screening is warranted for better management of imatinib therapy. The present study was framed to explore the influence of common drug transporter gene polymorphisms of ABCB1, ABCG2, OCT1 and trough level concentration on commonly occurring adverse events in CML patients treated with imatinib mesylate. METHODS:A total number of 111 patients in chronic phase (Philadelphia chromosome +ve) were included in the study. The plasma drug concentration of imatinib was estimated using LC-MS/MS method. RESULTS:The mean ± SD trough level concentration of imatinib mesylate was found to be 1430.7 ± 438.7 ng/ml. The trough level concentration at steady state (Cmin.ss) was significantly higher in patients with grade 2-4 thrombocytopenia compared with patients without the adverse event (P value 0.033). CONCLUSION:The drug level of imatinib in plasma correlates with the severity of thrombocytopenia, which adds to the utility of TDM in the management of CML patients.
10.1007/s00280-015-2905-6
Aberrant DNA Methylation of SOCS1 Gene is Not Associated with Resistance to Imatinib Mesylate among Chronic Myeloid Leukemia Patients.
Elias Marjanu Hikmah,Azlan Husin,Baba Abdul Aziz,Ankathil Ravindran
Cardiovascular & hematological disorders drug targets
BACKGROUND:In exploring the cause of Imatinib Mesylate (IM) resistance among Chronic Myeloid Leukemia (CML) patients who do not harbor BCR-ABL dependent mechanism, BCR-ABL independent pathways are the most probable pathways that should be explored. In BCR-ABL independent pathway, SOCS1 plays an important role as it helps in regulating optimal JAK/STAT activity. OBJECTIVE:To identify the association of SOCS1 gene hypermethylation in mediating IM Resistance. METHOD:The SOCS1 promoter methylation level of 92 BCR-ABL non mutated IM resistant CML patients, 83 IM good response CML patients and 5 normal samples from healthy individuals were measured using Methylation Specific-High Resolution Melt (MS-HRM) analysis. RESULTS:Both primers used to amplify promoter region from -333 to -223 and from -332 to -188 showed less than 10% methylation in all CML and normal samples. Consequently, there was no significant difference in SOCS1 promoter methylation level between IM resistant and IM good response patients. CONCLUSION:SOCS1 promoter methylation level is not suitable to be used as one of the biomarkers for predicting the possibility of acquiring resistance among CML patients treated with IM.
10.2174/1871529X18666180419101416