The IC50 Assay Is Predictive of Molecular Response, and Indicative of Optimal Dose in De-Novo CML Patients.

Abstract

We have previously demonstrated significant interpatient variability in the IC50imatinib, a measure of the intrinsic sensitivity of a patient to imatinib induced kinase inhibition. Furthermore, this measure is predictive of the achievement of major molecular response (MMR > 3 log reduction in BCR-ABL) in de-novo CML patients treated with imatinib (n=60)1. In an expanded patient pool (n=116) we now perform an evaluation of the IC50 as a predictor of response, and address the IC50imatinib as a guide to dose selection. Samples were obtained with informed consent from de novo CML patients enrolled to either the TIDEL (600mg imatinib) or TOPS (randomised 400mg vs 800mg imatinib) trials. Blood was collected pre therapy, and the IC50 was performed as previously1. Outcome data was assessed using Kaplan Meier Analysis and the log rank test was used to assess statistical significance. In our previous analysis the IC50imatinib was divided about the median value for the cohort (0.6μM) into low and high IC50, with a significantly greater proportion of patients with low IC50imatinib achieving MMR by 12 months. In this expanded patient pool, we confirm this finding (<median of 0.7μM for this patient group) (low IC50 65% of patients achieve MMR by 12 mo vs high IC50 39% of patients p=0.014) Dividing the IC50's into quartiles we now demonstrate that the IC50imatinib is a continuous variable with a greater proportion of patients in the lower quartile achieving MMR than those in the higher (Table 1 Total). Addressing the issue of dose we demonstrate that no patients with IC50>0.95uM achieve MMR on 400mg, and that this is statistically significantly when compared to all other groups. At 600mg while there is no overall significant difference there is a statistically relevant difference between groups 1, 2 and 4 as indicated. In contrast, at 800 mg the effect of IC50imatinib is overcome.MMR by 12 monthsTotal400mg600mg800mgp valueGroup1 <0.5μM67% (27)83% (12)*50% (8)*86% (7)0.470Group 2 >0.5<0.7μM63% (30)67% (6)*53% (17)*71% (7)0.337Group 3 >0.7<0.95μM45% (31)40%(5)*30% (10)56% (16)0.139Group 4>0.95μM32% (28)0% (7)*22% (9)*58% (12)0.016P value0.0420.0180.1080.778Table 1: Dividing the patients into quartile based on the IC50imatinib and assessing the Impact of dose on the achievement of MMR by 12 month. *p value <0.05 between groups (n).The failure to achieve a Complete Cytogenetic Response by 12 months is considered a suboptimal response. Assessing the molecular equivalent (≥2 log reduction in BCR-ABL) we demonstrate that a significantly greater proportion of patients with IC50imatinib>0.7μM fail to achieve a 2 log reduction when treated with 400mg (IC50 <0.7μM 11%: >0.7μM 33% p=0.034), and 600mg (IC50 <0.7μM 12%: >0.7μM 22% p=0.036). However, there is no significant difference in the 800mg patient cohort (IC50 <0.7μM 7%: >0.7μM 14% p=0.79). This analysis confirms that the IC50imatinib, is predictive of imatinib response. Patients with an IC50imatinib <0.7μM are likely to respond well to doses of 400mg imatinib, as suggested by evaluation of statistically relevant outcome benefit. In contrast patients with higher IC50imatinib (>0.7μM) may benefit from higher dosing regimens (p=0.012). Thus, the accurate assessment of IC50imatinib could support dose optimization strategy for patients with a suboptimal response.