ABSTRACT
OBJECTIVE: To study the effect of MDR1 and CYP3A5 gene polymorphisms on the outcomes of imatinib treatment in patients with chronic myeloid leukemia (CML). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
ABSTRACT
Influence of polymorphisms in the genes coding for imatinib transporters and metabolizing enzymes on cytogenetic relapse in patients with chronic myeloid leukemia (CML) is not known. One hundred and four patients (52 cases with cytogenetic relapse and 52 controls without relapse) with chronic-phase CML on imatinib therapy and have completed 5 years of follow-up were enrolled. The following single nucleotide polymorphisms (SNPs) were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene, using PCR-RFLP method and validated by direct gene sequencing. Imatinib trough levels were measured using LC-MS/MS. Patients with CC genotype for MDR1-C1236T polymorphism were at significantly higher risk for cytogenetic relapse [OR =4.382, 95% CI (1.145, 16.774), p = .022], while those with TT genotype for MDR1-C3435T polymorphism had significantly lower risk of relapse [OR =0.309, 95% CI (0.134, 0.708), p = .005]. Imatinib trough levels were lower in patients with relapse compared to those without relapse (1551.4 ± 1324.1 vs. 2154.2 ± 1358.3 ng/mL; p = .041). MDR1-C3435T genotype [adjusted-OR: 0.266; 95% CI (0.111, 0.636); p = .003] and trough levels (p = .014) were independent predictors of relapse in multivariate analysis. To conclude, C1236T and C3435T polymorphisms in MDR1 gene and trough levels significantly influence the risk of cytogenetic relapse. MDR1-C3435T genotype might emerge as a potential biomarker to predict the risk of cytogenetic relapse in patients with CML.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Cytochrome P-450 CYP3A/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Polymorphism, Single Nucleotide , Adult , Alleles , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Case-Control Studies , Cytogenetics , Female , Gene Frequency , Genotype , Humans , Imatinib Mesylate/pharmacology , Imatinib Mesylate/therapeutic use , Kaplan-Meier Estimate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Male , Middle Aged , Molecular Targeted Therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Recurrence , Young AdultABSTRACT
Objective To study the effect of decitabine treating elderly patient with myelodysplastic syndrome-ring sideroblastic refractory anemia (MDS-RAS) and review the literatures. Methods Decitabine treated a patient with MDS-RAS four courses, at the dose of 25 mg everyday for 5 days per course. Observed the change of symptoms, peripheral blood cell counts, myelogram, T cell polarization, cellular immunity,chromosome. Determined the curative effect combined with efficiency standard of WHO 2008. Results The clinical symptoms got better after two courses. Peripheral blood cell counts began to get better after one course. The number of leukocyte, hemoglobin and platelet got nearly normal after four courses. After two courses, T cell polarization state got normal, the number of iron ring promyelocyticin bone marrow declined from 16 % to 0 and chromosome changed from complex karyotype to normal. Conclusion Decitabine is an effective drug to the old patient with MDS-RAS. But it needs to increase the number of cases and follow up long-term to observe the effective rate and long-term efficacy.
