The Strategy of Early Nilotinib Switch Based on Failure to Achieve Optimal Molecular Targets on Imatinib May Not Overcome the Negative Impact of a Low OCT-1 Activity in De-Novo CP-CML Patients
Authors: White Deborah L. , Saunders Verity A , Frede Amity , GrootObbink Kelvin , Slader Cassandra , Yeung David T. , Osborn Michael , Mills Anthony K. , Grigg Andrew , Hughes Timothy P 
Published: October 2019

Abstract 1690

Background:

We have previously identified that low OCT-1 activity (OA) is a poor prognostic indicator in CP-CML patients treated with imatinib (IM). Importantly, a very low OA (OA≤4ng/200,000 cells) is associated with a significant risk of poor molecular response, kinase domain mutations and transformation. The TIDEL II strategy of early intervention, via dose escalation and/or switch to nilotinib (NIL) may reduce the incidence of poor response/therapeutic failure in CP-CML patients, particularly those with very low OA.

Methods:

Patients in Cohort I (n=105) of the TIDEL II trial were switched to NIL for either IM intolerance, or failure to demonstrate a clinical benefit from IM dose escalation which was triggered by failure to achieve time dependent molecular targets: ≤10% BCR-ABL by 3 m, ≤1% BCR-ABL by 6 m or ≤0.1% BCR-ABL by 12 m. In Cohort II (n=105) patients failing to achieve these molecular targets were switched directly to NIL without prior IM dose intensification. All patients, where possible, had OA measured at diagnosis. Only therapeutic changes prior to 24 months, and patients with a minimum of 6 months exposure to NIL are considered in this analysis.

Results:

(Table 1) Cohort I: Median follow-up 30 months. The overall rate of major molecular response (MMR) by 12 months was 66%. There was a significant difference in the rate of MMR between patients with low OA (n=49) compared to those with higher OA (n= 54): 49% vs 76%, p=0.007. The overall rate of MMR by 24 months was 81%. Again, patients with low OA (n=46) achieved MMR at a significantly lower rate compared to those with higher OA (n=54): 65% vs 91%, p= 0.003. Thirty patients have switched to NIL, 19/30 because of IM intolerance (av. time on IM 8.5m.) and 11/30 because of molecular target failure (av. time on IM 12.8m). 14/14 intolerant patients not in MMR at the time of switch have achieved MMR on NIL with an average log reduction of 2.8, and 9/18 have achieved CMR. In contrast, 1/9 patients switched for molecular target failure has achieved MMR on NIL, with an average log reduction of 0.65. Importantly, 3/19 withdrew from study due to CML related events.

Cohort II: Median follow-up 12 months. To date, 22/105 patients have switched to NIL and have a minimum of 6 months follow-up: 11 for intolerance and 11 for molecular target failure. All patients switched for intolerance achieved and/or maintained MMR on nilotinib, with an average log reduction of 2.89. In contrast, 1/11 patients switched for molecular target failure achieved MMR, with an average log reduction of 0.95 and CCyR has been achieved in 5/10 patients not previously in CCyR. 2/11 of these patients have withdrawn from study.

There was a significant difference in the time of switch to NIL, and the length of imatinib exposure between the 2 cohorts for intolerance, and a significant difference between the cohorts in the length of IM exposure for patients with target failure. However, this did not translate to a significant difference in molecular response between the 2 cohorts, suggesting the length of prior IM exposure is not a determinant of subsequent NIL response.

Importantly in both cohorts, the OA of those patients switched to NIL based on molecular target failure was significantly lower than that of those who switched for intolerance (p=0.007 and p=0.003) and those patients remaining on IM (p=0.004).

Conclusion:

Switch to NIL significantly improves response in IM intolerant patients. The majority of patients who switch for molecular target failure on IM do not subsequently achieve MMR on NIL. This suggests that a low OA may delineate a group of CP-CML patients intrinsically insensitive to TKI therapy, for whom switch to NIL either following IM dose intensification (Cohort 1) or as a primary strategy (Cohort II) may not result in an improvement in response. A different first-line strategy may be more effective for this poor risk subgroup.

Disclosures:

White: Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Slader:Novartis Pharmaceuticals: Employment, Equity Ownership. Yeung:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Osborn:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Mills:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Sponsorship to professional meetings; BMS Oncology:. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Honoraria, Membership on an entity's Board of Directors or advisory committees.