Early Switching From Imatinib to Nilotinib In CML Patients Failing to Achieve Early Molecular Targets May Not Be An Effective Approach In Patients with Very Low OCT-1 Activity: A TIDEL II Sub-Study
Authors: White Deborah L. , Saunders Verity , Frede Amity , GrootObbink Kelvin , Slader Cassandra , Yeung David T. , Osborn Michael , Mills Anthony K. , Grigg Andrew , Hughes Timothy 
Published: October 2019

Abstract
Abstract 356
We have previously demonstrated that CML patients with very low OCT-1 activity (Quartile 1 (Q1)<4 ng/200,000 cells) have significantly poorer outcomes with respect to response, mutation development, progression, and survival than patients with higher OCT-1 activity(OA). We have also demonstrated that the influx pump OCT-1 is associated with the active uptake of imatinib, but not nilotinib (NIL), into target CML cells. Hence, if the prognostic significance of OA primarily reflects IM transport we predicted that patients with very low OA who had poor initial responses to imatinib, should respond well when switched to NIL. In the Tidel II study CML-CP patients are treated with 600mg/day imatinib (IM) upfront and are dose escalated to 400mg BID or switched to NIL 400mg BID for either intolerance (Grade III/IV or persistent Grade II non-haematological toxicity) or failure to meet pre defined molecular targets. These targets are early markers of sub-optimal response, but not IM failure: failure to achieve <10% BCR-ABL IS by 3 months, <1% by 6 months and <0.1% by 12months. Hence this study is designed to enable early efficacious intervention in the case of poor response, to prevent frank therapeutic failure. In this study we examine the cohort of patients who have switched to NIL and compare their response on NIL to that achieved on IM. To date 63 patients on this trial have greater than 12 month molecular follow up, and OA quantified. 26/63 patients have OA<4ng/200,000 cells. As demonstrated in Table 1, and in keeping with previous findings, patients with low OA have significantly poorer rates of MMR by 12 months, and higher rates of study discontinuation when compared to patients with ≥4.0ng/200,000 (high OA). Importantly the study design of Tidel II has enabled the more careful assessment of therapeutic intervention. Of note 23% of patients with low OA had a dose increase and 42% switched to nilotinib because of failure to meet pre-stated milestones. This compares with only 8% of remaining patients being dose increased and 14% switching to NIL(p=0.007).
Table 1: Showing the response of patients within the two OCT-1 Activity Groups. MMR by 12 mo Mutations Off Study Increased dose 400mg BID IM MMR on 400mg BID IM Switched to NIL MMR on NIL <4.0ng/200,000 cells n=26 37% 19% 19% 23% 16.6% 42% 10% ≥4.0ng/200,000 cells n=37 81% 0% 2.7% 8.1% 100% 13.5% 100% p= <0.001 0.006 0.037 0.141 0.05 0.007 0.007
With a median follow up after switching to NIL of 12 months (Low OA R=6-21 high OA R=9-12 p=0.887) all patients with high OA, not previously in MMR (n=4), achieved MMR within 6 months. In contrast 1/10 low OA patients not previously in MMR achieved MMR on NIL. Interestingly, not all patients with low OA were switched to NIL because of sub-optimal IM response. Four of this cohort were intolerant to 600mg IM (one of these 4 achieved MMR), while all patients in the high OA cohort were switched because of intolerance. This implies that a low OA is not overcome with early switch to NIL, despite NIL transport being unrelated to OCT-1. This may be due to other intrinsic factors, possibly related to leukaemia biology and majority cell type for which the OA assay may be a surrogate measure. Alternatively, the poor response to imatinib in low OA patients has facilitated the activation of other resistance mechanisms, that in turn lead to a poor response after switching implying that patients with low OA may require upfront treatment with a TKI that is OCT-1 independent. Importantly only 1 of the patients on NIL had a mutation prior to switching, with another patient transforming to blast crisis with a T315I mutation while on NIL. Thus the presence of kinase domain mutations does not explain these findings.

Conclusions:
Low OA is associated with poor response to IM. Here we show that the MMR rate for patients with low OA was not substantially improved by the TIDEL II treatment strategy. This is despite the protocol allowing for early dose escalation or switch for suboptimal response. This preliminary data suggests that patients with low OA may have more generalized insensitivity to kinase inhibitor therapy which is not simply related to drug transport. These are important findings in the setting of multiple TKIs being available, and suggest that in patients with very low OA a regimen of selective TKI intensification may not be the optimal approach.

Disclosures:
White: Novartis: Honoraria, Research Funding; BMS: Research Funding. Slader:Novartis Pharmaceuticals: Employment, Equity Ownership. Osborn:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. Mills:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria.