Detection Of ABL Kinase Domain Point Mutations In Chronic Myeloid Leukemia Patients Receiving Imatinib Treatment And Research On The Clinical Correlation Of Imatinib Plasama Concentration

Objective To explore the occurrence of ABL kinase domain mutation in chronic myelogenous leukemia (CML) patients with resistant to imatinib (Gleevec, IM); Detecting the imatinib plasma concentrations of CML patients, further exploring its clinical significance.Method 1.51 bone marrow samples of CML patients were collected including 28 cases with imatinib resistant and 10 cases with newly diagnosed during Different periods. ABL kinase domain of BCR-ABL allele was amplified by reverse tmnscription polymerase chain reaction(RT-PCR), followed by direct sequencing and sequence homology analysis to determine the existance of mutation.2. Imatinib plasma concentrations of the 153 CML patients taking regular treatment of imatinib were detected with liquid chromatography-mass-spectrometry (LC-MS/MS), and the correlation between imatinib plasma concentrations and general characteristics of patients were analyzed.Results 1.The point mutations were found in 12 of 38 patients, and all the 12 ones progressed to advanced disease or death.2 patients showed Met351Thr mutation,7 Glu252His and 2 Glu279Lys, the other types were Glu255Val and Glu356Gly, each of which was tested in one patient. The incidence of the point mutation was 17.6%,45.5% and 44.4% in chronic,accelerated and blast phase, respectively. The incidence of hematologically and genetically resistant patients is 50%(5/10) and 44.4%(8/18) and the 95%CI was 12.3%-87.7% and 19%-69.9%.2. Imatinib in patients with plasma concentration levels and gender (t=0.9988, P> 0.05), age (r=-0.09687), height (r=-0.0663), body weight (r=-0.1881), body surface area (r =-0.1427), and taking IM time (r=0.0023) There was no significant correlation between the.3. 111 cases of standard-dose imatinib in treatment of CML patients,86 cases achieved complete cytogenetic response (CCyR), In Q1, Q2-3, and Q4 group were 18 cases (67.7%,18/27),50 cases (87.7%,50/57) and 18 cases (67.7%,18/27),χ2= 7.04 among the three groups, P<0.05; 86 cases received CCyR plasma trough concentrations in patients with the level of [(1643.45±594.10) ng/ml] than 25 cases of patients without the CCyR Valley plasma concentrations [(830.48±117.35) ng/ml] (P<0.05, t=6.78); 86 cases received CCyR plasma trough concentrations in patients with the level of [(1643.45±594.10) ng/ml] than 25 cases of patients without the CCyR Valley plasma concentrations [(830.48±117.35) ng/ml] (P<0.05, t=6.78);Conclusion 1.ABL kinase point mutation is an important mechanism of imatinib resistance, monitoring of the ABL kinase domain point mutation is helpful to estimate the prognosis and for therapeutic strategy adjustment. ABL kinase domain point mutations in imatinib treatment of CML is a major reason for failure. Occurs in patients with imatinib-resistant BCR/ABL gene ABL kinase domain point mutations with high frequency, regular monitoring of ABL kinase domain point mutations contribute to the early intervention measures to raise the treatment level, to avoid the loss of great significance to the treatment time.2. Accelerated, blastic phase CML patients with a higher detection rate of mutation, there mutation prompted poor prognosis, should shorten the observation period, and promptly adjust treatment programs; late mutation detection rate in patients with chronic phase chronic phase in patients with higher than the standard should be regularly carried out mutation test and to closely observe the patient's condition changes in order to be able to take early steps to intervene.3. Imatinib plasma concentration levels and patient sex, age, height, weight, body surface area independent of the general characteristics.4. Taking standard dose (400mg) treatment of chronic phase CML patients, Q2-3 group of patients was significantly more than the number of cases of CCyR patients with Ql and Q4 group, access to CCyR plasma trough concentrations in patients with IM were higher than that without the CCyR patients with Tip within a certain range the higher the level of blood concentration help improve CCyR rate, to achieve better therapeutic effect, but the high blood concentration level may be a negative impact on patient care.5. Taking standard dose (400mg) of IM for the treatment of chronic phase CML patients, among the three groups of molecular biology remission rate (MMR) no significant difference, but access to MMR in patients with IM of plasma trough concentrations higher than those of patients without the MMR, suggesting that the higher the blood drug concentration may be beneficial to patients with access to MMR, but the optimal concentration range of yet to be further clarified.