Abstract 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).

Months61224
Incidence of CCyR (%) Overall 28 53 84  
 OCT-1/GUS <0.94 27 54 83 0.0049/0.002 
 OCT-1/GUS >0.94 50 76 90  
 MDR1/GUS <1.7 28 52 83 0.07/0.02 
 MDR1/GUS >1.7 45 72 91  
Incidence of MMR (%) Overall 10 30 66  
 OCT-1/GUS <0.94 10 25 61 0.036/0.018 
 OCT-1/GUS >0.94 11 46 78  
 MDR1/GUS <1.7 22 61 0.0047/0.0011 
 MDR1/GUS >1.7 16 48 76 
Months61224
Incidence of CCyR (%) Overall 28 53 84  
 OCT-1/GUS <0.94 27 54 83 0.0049/0.002 
 OCT-1/GUS >0.94 50 76 90  
 MDR1/GUS <1.7 28 52 83 0.07/0.02 
 MDR1/GUS >1.7 45 72 91  
Incidence of MMR (%) Overall 10 30 66  
 OCT-1/GUS <0.94 10 25 61 0.036/0.018 
 OCT-1/GUS >0.94 11 46 78  
 MDR1/GUS <1.7 22 61 0.0047/0.0011 
 MDR1/GUS >1.7 16 48 76 
Risk Group Stratification
Incidence of CCyR (%) Poor Risk 19 58 0.5/0.2 0.0001/<0.0001 
 Intermediate Risk 16 34 69   
 Good Risk 16 68 89   
Incidence of MMR (%) Poor Risk 25 50 82 0.089/0.032 0.0001/<0.0001 
 Intermediate Risk 45 62 86   
 Good Risk 76 94 100   
Risk Group Stratification
Incidence of CCyR (%) Poor Risk 19 58 0.5/0.2 0.0001/<0.0001 
 Intermediate Risk 16 34 69   
 Good Risk 16 68 89   
Incidence of MMR (%) Poor Risk 25 50 82 0.089/0.032 0.0001/<0.0001 
 Intermediate Risk 45 62 86   
 Good Risk 76 94 100   
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.

Author notes

*

Asterisk with author names denotes non-ASH members.