Selective Escalation of Imatinib Therapy and Early Switching to Nilotinib In De Novo Chronic Phase CML Patients: Interim Results From the TIDEL-II Trial

Although the majority of chronic phase (CP) Philadelphia positive (Ph+) chronic myelogenous leukemia (CML) patients (pts) achieve good disease control with imatinib, some pts demonstrate suboptimal responses. Early dose escalation or switching to nilotinib, a more potent BCR-ABL kinase inhibitor, as soon as suboptimal molecular response is recognised may improve response and disease outcome.

To optimise clinical and molecular outcomes in Ph+ CML using imatinib (IM) as frontline therapy with selective IM dose escalation based on pharmacokinetic (PK) results and switching to nilotinib (NIL) in case of suboptimal response, or IM-intolerance.

TIDEL-II is a multicentre, single arm prospective ALLG trial in de novo CP-CML pts with 2 separate sequential cohorts. In Cohort I, pts are treated with IM 600mg/d up-front, aiming for BCR-ABL RQ-PCR target values of ≤ 10%, 1%, and 0.1% IS (major molecular response, MMR) at 3, 6, and 12 months respectively. Pts who do not reach these treatment targets are classified as suboptimal responders. Dose escalation to 800mg/d or maximal tolerated dose occurs if trough IM level is <1000ng/mL at day 22, or for suboptimal response. A switch to NIL (400mg bid) is triggered if molecular targets are still not met 3 months after IM escalation, or for loss or response, or for IM intolerance (Grade III/IV or persistent Grade II non-haematological toxicity).

105 pts were assessed with median follow up of 18.9 months (range: 9–33) in cohort I. For pts with a minimum of 12 months follow up (n=80), complete cytogenetic response (CCR), MMR and complete molecular response (CMR)^# rates at 12 months were 92%, 66% and 11% respectively. BCR-ABL levels at 3 months were predictive of MMR at 12 months, but not for CMR due to small pt numbers (Table 1). For pts who failed to achieve BCR-ABL of ≤10% at 3 months, the 12 month MMR rate was 25% (vs 5% in TIDEL-I where pts were also started on IM 600mg/d and suboptimal responders were dose escalated to IM 800mg/d). Of the 105 pts, 16 pts dose escalated IM due to a day 22 IM blood level <1000ng/mL, after which 2/16 switched to NIL (1 suboptimal, 1 intolerant); all achieved CCR. Twelve pts dose escalated for suboptimal response, 7 subsequently switched to NIL for again failing treatment targets. In all, 21/105 pts (20%) switched to NIL: 7 for suboptimal response and 14 for intolerance. The median time to switching and the median pre-switch prescribed IM dose were 468 days & 800mg/d for the suboptimal group; and 183 days & 600mg/d for the intolerant group respectively. Of these, 20/21 achieved or remained in CCR. At the time of switching to NIL, 19/21 pts were not in MMR. With a median follow-up of 295 days post switch to NIL, 9/12 intolerant pts (75%) achieved MMR, whereas 1/7 suboptimal IM responders (14%) achieved MMR (median follow up after switching: 286 days). Only 7/105 pts (7%) discontinued treatment: 4 for non-compliance, 1 pt with a T315I mutation and 2 pts with blast crisis (BC). Progression to BC was associated with detectable mutations: 1 pt with 4 different mutations including T315I and 1 pt with H396P mutation. The progression rate to AP/BC was 2%. The overall mutation rate was 5/105 (5%). The 2 pts who progressed and the pt who discontinued when a T315I mutation was detected were among the 28 pts with BCR-ABL values >1.0% at 3 months. In contrast, no resistant mutations were detected or transformations occurred in the 49 pts with BCR-ABL values ≤1.0% at 3 months. Conclusion: A strategy of selective intensification of BCR-ABL inhibitor therapy based on molecular response and PK values resulted in a 66% MMR rate by 12 months. Despite a minority of pts (20%) requiring a switch to NIL, this has enhanced the rate of MMR by 12 months when compared to IM intensification alone as seen in TIDEL-I where the rate of MMR and CMR by 12 months was 47% and 9% respectively. The IM intolerant pts demonstrated excellent response rates after switching to NIL. To date, the results from TIDEL-II compare favourably with other frontline strategies with regards to response and transformation rates.

Yeung:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. Osborn:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. White:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Slader:Novartis Pharmaceuticals: Employment, Equity Ownership. Ross:Novartis Pharmaceuticals: Honoraria, 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-Meyers Squibb: Honoraria, Research Funding; Ariad: Honoraria.