Early Switch to Nilotinib Does Not Overcome the Adverse Outcome for CML Patients Failing to Achieve Early Molecular Response On Imatinib, Despite Excellent Overall Outcomes in the TIDEL II Trial

We have previously reported promising results from the TIDEL-II trial, using imatinib (IM) treatment upfront in patients (pts) newly diagnosed with Philadelphia chromosome positive Chronic Myeloid Leukaemia in Chronic Phase (CML-CP), and switching selected pts to nilotinib (NIL) on the basis of failure to achieve time-dependent molecular response (MR). This strategy showed excellent rates of major molecular response (MMR; BCR-ABL ≤0.1% IS) at 12 months (mos) and transformation free survival.

To optimise molecular outcome and survival in treatment naïve CML-CP pts by selective dose escalation of IM for pts with low trough levels and early switching to NIL for pts with poor MR.

TIDEL-II enrolled 210 CML-CP pts across 23 Australasian centres in 2 equal and sequential cohorts. All pts started treatment with IM 600mg/d and dose escalated to IM 800mg/d if IM trough levels were <1000ng/mL. A series of time-dependent MR targets were set: BCR-ABL ≤10%, ≤1% and ≤0.1% (IS) at 3, 6 and 12 mos. Cohort 1 (C1) pts failing to meet these targets dose escalated to IM 800 mg/d. Pts who failed to improve molecular response, or were already on IM 800mg/d, switched to NIL 400mg BID. Pts in cohort 2 (C2) who failed these targets switched to NIL directly. Pts with grade III/IV or persistent grade II toxicity were also allowed to switch from IM to NIL.

Median follow up (f/u) for C1 and C2 pts were 42 & 24 mos respectively, and 31 mos for all pts (15–56 mos) – see table 1. The primary end-point, confirmed MMR at 12 mos, was achieved by 64%, with no difference between C1 and C2. This climbed to 75% at 24 mos. At 12 & 24 mos, the proportion of pts with confirmed MR4.5 (BCR-ABL ≤ 0.0032% IS) was 18% and 29% respectively.

Six pts progressed to blast crisis (BC) : 4 in their 1st year of treatment, and 1 each in the 2^nd and 3rd yrs, resulting in 2 deaths. Four other deaths were recorded, caused by stroke (1), pneumonia (1) and cardiac disease (2); 2 pts had NIL treatment before death. Eighteen mutations had been identified in 11 pts, including 4 pts with the highly resistant mutations T315I or E255K either singly or in combination with others. These were identified in the context of BC (3), loss of MMR (2), lack of MMR by 12 mos (4), and lack of CCR by 6 mos (2). One other pt lost MMR in the absence of a mutation and regained MMR with switching to NIL.

Thirty-one pts in C1 switched to NIL: 19 for intolerance and 12 for failure to achieve targets after a trial of IM 800mg/d. Of the latter, with median f/u of 26 mos on NIL, 5/12 reached MMR subsequently. In C2, 44 patients switched to NIL, 12 for intolerance and 32 for failing targets: of the latter, 9 reached MMR with median f/u of 14 mos. In contrast, in the 31 (C1+C2) pts switching for IM-intolerance, all but 2 reached MMR (including 12 patients already in MMR at time of switch).

Of the 25 pts with BCR-ABL ≥ 10% at 3mos, 3 pts progressed to BC (1 at 3.5mos), 6 more withdrew from study. Of the remainder, four pts achieved MMR, 9 more achieved BCR-ABL<1% but without MMR. None of these 25 pts have achieved MR4.5. (Table 2).

Overall, the TIDEL-II strategy compares well with other upfront studies of CML-CP pts with regard to MR, as well as risk of death and progression to BC. A small proportion of pts experience further falls in BCR-ABL when switching from IM to NIL for failure to achieve deep MR. In the 12% of pts who fail to achieve BCR-ABL ≤10% at 3 mos, there is greater risk of BC and so far no deep MR are seen, despite intensification in kinase inhibition instituted at as early as 3 mos. Alternative approaches are needed both to identify these pts early and protect them from disease transformation.

Yeung:Novartis Pharmaceuticals: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. White:Novartis Pharmaceuticals: Research Funding; BMS: Research Funding. Branford:Novartis : Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad : Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cepheid : Consultancy. Slader:Novartis Pharmaceuticals: Employment. Hiwase:CSL Ltd: Research Funding. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ross:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Grigg:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis Oncology: 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, Research Funding.