Abstract

We have previously demonstrated in CML patients enrolled to the Australian TIDEL trial, (600mg imatinib upfront in newly diagnosed patients) that patients with high OCT-1 activity, measured in patient blood mononuclear cells prior to imatinib start, achieve a superior molecular response, compared to those with low OCT-1 activity 11. Furthermore, the impact of low OCT-1 activity could be partially overcome with increased imatinib dose. We now prospectively test the predictive value of OCT-1 activity on the achievement of a major molecular response (<0.1 BCR-ABL IS) by 12 months, in CML patients enrolled to the TOPS trial (randomised 400 vs 800 mg imatinib). A subset of 131 TOPS22 patients had OCT-1 activity measured prior to the start of therapy, as part of the Global Novartis Correlative Science Studies. 41 had high OCT-1 activity (>7.2ng/200,000 cells) as defined in our original study. Patients with high OCT-1 activity had a markedly superior rate of MMR, on either standard or high dose imatinib (table 1). Significantly, a greater proportion of patients with low OCT-1 activity achieved MMR on the high dose arm compared to those on standard dose. This finding was not evident in the high OCT-1 activity group.

 The % of patients achieving MMR by 12 months (n) 
 Total Low OCT-1 Activity High OCT-1 Activity p- value 
Total  48% (90) 90% (41) <0.001 
400mg 59% (34) 24% (17) 94% (17) <0.001 
800mg 62% (97) 53% (73) 87% (24) 0.044 
p-value 0.27 0.012 0.64  
 The % of patients achieving MMR by 12 months (n) 
 Total Low OCT-1 Activity High OCT-1 Activity p- value 
Total  48% (90) 90% (41) <0.001 
400mg 59% (34) 24% (17) 94% (17) <0.001 
800mg 62% (97) 53% (73) 87% (24) 0.044 
p-value 0.27 0.012 0.64  

Table 1: The % of patients achieving MMR based on OCT-1 activity and Randomised dose.

The median OCT-1 activity for those patients achieving a MMR (n=80) was 6.05ng/200,000 cells compared to 3.9 for those patients failing to achieve MMR (n=51:p=0.003). Of the 131 patients, trough imatinib levels were available on 61. A greater proportion of patients with a trough imatinib plasma level of >1000ng/ml 33 (n=50) at 1 month achieved MMR (88%) compared to those with plasma levels of <1000ng/ml (n=11:45%: p=0.032). Importantly, OCT-1 activity is not significantly different comparing those patients with trough levels >1000ng/ml (5.6ng/200,000 cells) at 1 month to those with lower trough levels (7.3ng/200,000 cells: p=0.117). This indicates that OCT-1 activity is not providing a surrogate marker of imatinib PK. Dividing the imatinib PK data into quartiles, there is no significant difference in the % of patients achieving MMR based on trough imatinib levels, in patients with high OCT-1 activity. In contrast significantly fewer patients with low OCT-1 activity and low trough levels achieve MMR by 12 months. (Table 2)

 The % of patients achieving MMR by 12 months (n) 
Imatinib PK (ng/ml) Total Low OCT-1 Activity High OCT-1 Activity P value 
Quartile 1 <1600 47% (15) 12% (8) 86% (7) 0.013 
Quartile 2 >1600 < 2500 80% (15) 67% (6) 89% (9) 0.469 
Quartile 3 >2500 < 3500 80% (15) 77% (13) 100% (2) 0.654 
Quartile 4 >3500 75% (16) 60% (10) 91% (6) 0.559 
 The % of patients achieving MMR by 12 months (n) 
Imatinib PK (ng/ml) Total Low OCT-1 Activity High OCT-1 Activity P value 
Quartile 1 <1600 47% (15) 12% (8) 86% (7) 0.013 
Quartile 2 >1600 < 2500 80% (15) 67% (6) 89% (9) 0.469 
Quartile 3 >2500 < 3500 80% (15) 77% (13) 100% (2) 0.654 
Quartile 4 >3500 75% (16) 60% (10) 91% (6) 0.559 

Table 2: The percentage of patients achieving MMR based on quartile analysis of imatinib PK at day 29

In the Australian cohort of 60 patients where detailed molecular response data is available the median molecular response in the 4 subgroups at 12 months shows a significant difference between the 400 mg group with low and high OCT-1 activity (Median BCR-ABL 0.2% IS v 0.02% IS p=0.03) but no difference in the 800 mg groups (low OCT-1 activity v high Median BCR-ABL 0.05% IS v 0.03% IS p=0.139). These analyses support our original proposal that OCT-1 activity defined at diagnosis has a major impact on molecular response and raises the possibility of patient-specific dosing. Patients with low OCT-1 activity are likely to achieve superior molecular responses if they receive imatinib at doses greater than 400 mg, whereas we could not find evidence of a molecular benefit to high dose imatinib for patients with high OCT-1 activity. The clinical value of monitoring trough imatinib drug levels remains to be clearly defined but it is likely to be greatly enhanced if it assessed in the context of the patient’s OCT-1 activity.

Disclosures: White:Novartis: Honoraria, Research Funding; BMS: Research Funding. Kim:Novartis: Research Funding. Pane:Novartis: Research Funding. Martinelli:Novartis: Research Funding. Radich:Novartis: Research Funding. Kalebic:Novartis: Employment. Saglio:Novartis: Research Funding. Hughes:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau.

1
White DL, et al
Blood
.
2007
;
110
:
4064
–4072.
2
Cortez J et al
EHA
2008
3
Picard S, et al.
Blood
.
2007
;
109
:
3496
–3499

Author notes

Corresponding author