Molecular Response to Imatinib Is Dependent on Dose in CML Patients with Low OCT-1 Influx Activity. Patients with High Activity May Respond Equally Well to Standard or Increased Dose Imatinib.
Authors: White Deborah , Saunders Verity , Dang Phuong , Venables Amity , Zrim Steph , Reynolds John , Quinn Steven , Zannettino Andrew , Hughes Timothy 
Published: April 2020

We have shown that IC50 is predictive of molecular response in newly diagnosed CML patients treated with 600mg of imatinib (TIDEL). OCT-1 is an influx transporter for imatinib and key determinant of interpatient variation in the IC50 assay. Using 14C imatinib we have performed an intracellular uptake and retention (IUR) assay and RQ-PCR for OCT-1 mRNA expression on blood cells from 42 patients at diagnosis, enrolled to TIDEL. Using the OCT-1 inhibitor Prazosin, we determined OCT-1 in-vitro activity to be the difference in IUR between assays performed with and without Prazosin. The median OCT-1 activity was 6.1ng (range of -3.6 to 27ng). Grouping patients about the median, into low and high OCT-1activity, we found a significant difference between the two groups in molecular response.

Log Reduction BCR-ABL based on OCT-1 Activity Months 6M 12M 18M 24M Low OCT-1 Activity n=19 1.9 2.4 2.6 2.5 High OCT-1 Activity n=23 2.07 2.9 3.6 3.8 p value 0.05 0.05 0.003 0.007 Low OCT-1 Activity &lt;600mg n=10 1.4 1.7 1.7 2.4 600mg n=9 2.7 2.6 2.9 3.6 p value 0.01 0.023 0.046 0.042 High OCT-1 Activity &lt;600mg n=11 2.4 2.9 3.3 3.7 600mg n=12 2.4 2.8 3.3 3.9 p value 0.63 0.69 0.82 0.66

Dividing groups into patients receiving 600mg imatinib and those receiving &lt;600mg over the first 12 months of therapy revealed patients with high OCT-1 activity generally achieved excellent molecular response regardless of dose, whereas the response of patients with low OCT-1 activity was highly dose dependent. There was a significant difference in molecular response between the low and high OCT-1 activity groups on &lt;600 mg (p=0.004 at 24 months) but no difference in the 600mg cohort, further indicating dose sensitivity of low OCT-1 activity patients. The level of OCT-1 mRNA (n=30) as determined by RQ-PCR correlated with the in-vitro OCT-1 activity (r=0.381 p=0.04). However, in this smaller cohort, OCT-1 mRNA level was not predictive of molecular response (low OCT-1 3.5 log(n=15); high OCT-1 3.9 log(n=16) p=0.169). The IC50 is predictive of molecular response to 12 months (low IC50 log reduction 3.0 (n=20) high IC50 2.5 (n=15) p=0.02), but not in this smaller cohort to 24 months (p=0.15). TIDEL mandated dose increase to 800mg where tolerable. We assessed the log reduction from 12 to 24 months based on dose.

Log reduction from 12 to 24 months. Dose increase Yes No p value Low OCT-1 activity 0.33 n=12 0 n=7 0.002 High OCT-1 activity 0.59 n=14 0.46 n=9 0.637 p value 0.703 0.034

There was no statistical difference between the low and high OCT-1 activity groups when dose was escalated, however with constant dose, patients with low OCT-1 activity performed less well (Table 2). We conclude that OCT-1 influx activity is an important determinant of molecular response to imatinib, but its predictive value is closely linked to the dose received. This functional assay of OCT-1 activity performed at diagnosis may identify patients most likely to benefit from higher doses of imatinib or second generation ABL kinase inhibitors, and a cohort who are likely to respond well to standard dose imatinib.