Pretreatment Expression Levels of MDR1 and OCT-1 Predict Response to First Line Imatinib Treatment In Chronic Phase CML Patients

Abstract

AbstractAbstract 671 Introduction:The goal of imatinib therapy in newly diagnosed CML patients is the rapid achievement of cytogenetic and molecular responses. However, suboptimal response or resistance occur in a significant proportion of patients. BCR-ABL kinase domain mutations and various BCR-ABL independent mechanisms, such as clonal evolution are considered as leading causes of resistance and progression. It has been shown that imatinib efficacy depends on intracellular drug levels which are influenced by the activity of the human organic cation transporter 1 (OCT-1) influx protein and the multidrug resistance 1 (MDR1) efflux transporter protein. We therefore assessed the predictive significance of MDR1 and OCT-1 expression levels for molecular and cytogenetic response of chronic phase CML patients on first line imatinib treatment. Methods:A cohort of 170 newly diagnosed chronic phase CML patients (68 female, median age 53 years, range 19–79) treated with imatinib 400 mg/day in the German CML-Study IV were investigated. Multidrug resistance 1 efflux transporter protein (MDR1) and human organic cation transporter 1 (OCT-1) mRNA expression levels were determined by quantitative reverse transcription PCR using LightCycler™ technology and normalized against beta-glucuronidase (GUS) expression. Cytogenetic response was determined by G-banding metaphase analyses. Cut-off levels were defined by minimizing p-values. The Log-rank test (LR) and Gehan-Breslow-Wilcoxon test (GB) were performed to compare the time to major molecular remission (MMR) and complete cytogenetic remission (CCyR). Results:CCyR was achieved after a median of 6 months (range 3–42), MMR (BCR-ABL levels ≤0.1% on the International Scale) was achieved after a median of 13 months (range 3–43). Further, a significantly higher MMR and CCyR rates were observed in patients with high MDR1 and OCT-1 expression compared to patients with low MDR1 and OCT-1 expression. In addition, a prognostic score resulting in a three group stratification: Good risk, high MDR1 and high OCT-1 expression; intermediate risk, high MDR1 or high OCT-1 expression; poor risk, low MDR1 and low OCT-1 expression was also determined. MMR and CCyR rates were significantly higher in good risk compared to poor risk patients (Table).Months61224Incidence of CCyR (%)Overall285384OCT-1/GUS <0.942754830.0049/0.002OCT-1/GUS >0.94507690MDR1/GUS <1.72852830.07/0.02MDR1/GUS >1.7457291Incidence of MMR (%)Overall103066OCT-1/GUS <0.941025610.036/0.018OCT-1/GUS >0.94114678MDR1/GUS <1.7622610.0047/0.0011MDR1/GUS >1.7164876Risk Group StratificationIncidence of CCyR (%)Poor Risk519580.5/0.20.0001/<0.0001Intermediate Risk163469Good Risk166889Incidence of MMR (%)Poor Risk2550820.089/0.0320.0001/<0.0001Intermediate Risk456286Good Risk7694100 Conclusions:Pretreatment expression levels of MDR1 and OCT-1 appear to predict the achievement of MMR and CCyR under imatinib therapy in chronic phase CML patients over a period of 2 years of therapy. These findings might allow risk stratification in order to tailor the individualized first line therapy in CML. Disclosures:Erben:Novartis: Honoraria, Research Funding. Hochhaus:Novartis, BMS: Consultancy, Honoraria, Research Funding. Mueller:Novartis, BMS: Honoraria, Research Funding.