Elsevier

Leukemia Research

Volume 70, July 2018, Pages 100-105
Leukemia Research

Research paper
Comparative analyses of nilotinib versus high-dose imatinib versus sustained standard-dose imatinib in patients with chronic phase chronic myeloid leukemia following suboptimal molecular response to first-line imatinib

https://doi.org/10.1016/j.leukres.2018.06.002Get rights and content

Highlights

  • Treatment options for suboptimal responders to first-line imatinib were compared.

  • The cumulative rate of MMR by 12 months was not different among treatment options.

  • Nilotinib 800 mg/day therapy showed better cumulative incidence of MMR by 36 months.

  • Different profile for adverse events was observed among treatment options.

Abstract

The aim of this study was to investigate the efficacy of nilotinib (NIL) versus high-dose imatinib (IM) versus sustained standard-dose IM for patients with chronic myeloid leukemia (CML) with suboptimal molecular response to first-line IM therapy. Patients with CML who achieved complete cytogenetic response (CCyR) but not major molecular response (MMR) after 18–24 months on first-line IM therapy were enrolled and divided into three treatment cohorts: NIL 800 mg/day (Cohort 1, n = 28) and IM 800 mg/day (Cohort 2, n = 28) in the RE-NICE study, and sustained IM 400 mg/day (Cohort 3, n = 52) in clinical practice. The primary efficacy variable of cumulative rate of MMR by 12 months was not different among the three cohorts. However, the cumulative incidence of MMR by 36 months was significantly higher in Cohort 1 than Cohort 3 (83.1% vs. 57.1%, P = 0.021), but there were no significant differences in Cohort 1 vs. 2 (P = 0.195) and Cohort 2 vs. 3 (P = 0.297). Different profile for adverse events was observed between NIL and high-dose IM therapy. In conclusion, our data suggested that switching to NIL may provide more effective long-term response than sustaining standard-dose IM for patients with suboptimal molecular response to first-line IM.

Introduction

Imatinib (IM) treatment is one of the standards of care for chronic phase (CP) chronic myeloid leukemia (CML). Its generic form is currently widely available as a cost-effective frontline treatment [1]. Although IM treatment has improved outcomes for CML patients, resulting in a 6-year progression-free survival of 93% [2], patients who experience treatment failure at milestones are at increased risk of disease progression to accelerated phase (AP), blast phase (BP), and death due to CML [[3], [4], [5], [6]].

The 2009 European Leukemia Net (ELN) recommendations suggest that some patients who do not achieve optimal responses to tyrosine kinase inhibitor (TKI) therapy may still sustain a suboptimal response, which that means a long-term benefit from continuing a specific treatment may be achieved but the chances of an optimal outcome are reduced [7]. Of note, patients who show treatment failure are unlikely to achieve a favorable long-term outcome and should receive a different treatment. This intermediate zone, which was previously referred to as suboptimal response, has been designated as warning the ELN recommendations in 2013 [8].

It has been reported that suboptimal responders to IM therapy have a less favorable prognosis with a reduced likelihood of achieving future optimal responses and poor outcomes compared with optimal responders to IM therapy [7,9,10]. However, there is insufficient evidence for the decision to change treatment for patients with suboptimal responses [11]. Several studies have shown that IM dose escalation may provide additional benefit in some patients with suboptimal response or treatment failure on standard-dose IM [[12], [13], [14]], but high-dose IM is associated with an increased risk of adverse events (AEs) [15,16] and poor tolerability [17]. The safety and efficacy of nilotinib (NIL) in patients with IM-resistant or IM-intolerant CML have been established [[18], [19], [20], [21], [22]]. A few studies have evaluated the benefits of switching patients with suboptimal response on front-line IM to NIL as a treatment strategy for patients with suboptimal response [21,23,24].

We conducted this study to compare the impact of switching to NIL, IM dose escalation, and sustaining standard-dose IM in patients in complete cytogenetic response (CCyR) with suboptimal molecular response to first-line IM therapy.

Section snippets

Patients and study design

Three cohorts of 108 patients in total were analyzed in this study. Patients in Cohort 1 and 2 were enrolled in a phase 3 multi-center, open-label, randomized study of the efficacy of NIL versus IM in adult patients with Philadelphia chromosome–positive CML in early CP who had a suboptimal molecular response to IM (RE-NICE study) between 2 April 2009 and 13 January 2014. Patients in Cohort 3 were selected from the Asia CML registry (ACR) database system using the same inclusion and exclusion

Patient characteristics

Patient characteristics are summarized in Table 1. A total of 108 patients were evaluated: 28 patients received 800 mg/day NIL (Cohort 1), 28 patients received high-dose IM group (Cohort 2), and 52 patients received sustained standard-dose IM (Cohort 3). Patient characteristics were balanced at baseline with respect to age, transcript type, and Sokal risk scores. There was no difference in time from initiation of first-line IM to enrollment between the three cohorts.

Treatment discontinuation and dosing information

Table 2 shows dose

Discussion

This study investigated the efficacy of NIL versus high-dose IM versus sustained standard-dose IM for patients who achieved CCyR but not MMR after first-line IM therapy with 400 mg daily for at least 18 months. Based on a comprehensive review of the relevant reports, the ELN defined optimal, suboptimal, and failure responses in 2009 [7]. Patients achieving optimal milestone responses show improved long-term outcomes, indicating a long-term benefit from continuing a frontline treatment [2,[25],

Acknowledgments

We thank the patients and investigators for their participation in the trial and the Korea Leukemia Bank for biomaterial banking and analysis (NRF-2013M3A9B8031236). This study was funded by Novartis Pharmaceuticals Corporation.

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      The results showed that the efficacy of switching to nilotinib was significantly better than maintaining imatinib. One study has reported on the treatment choice for patients with a warning response to first-line imatinib.22 The cumulative MMR rate for the imatinib group and converted nilotinib group after a follow-up of 24 months was 66.2% and 48.1%, respectively (P = .079).

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      Supporting the finding of García-Gutiérrez et al,5 in our patient cohort, approximately 90% of the patients with WR at 12 months (late WR), achieved MMR during imatinib treatment during the follow-up, and this maneuver surely saves at least some WR patients, who might achieve a “slow” OR during imatinib treatment, from switching to 2GTKIs, which are more potent than imatinib, but also are associated with toxicities that might lead to significant morbidities. A more recent study also did not show a clear benefit in switching to a more potent TKI therapy in patients with CCyR but not MMR at 18 months of standard-dose imatinib therapy.14 Because we did not switch patients with WR during imatinib 400 mg/d treatment to an alternative TKI, we cannot comment on whether switching to 2GTKIs would have resulted in superior long-term outcomes in our patient cohort, but we showed that a substantial number of patients who continued standard-dose imatinib treatment further achieved ORs, and the remaining still keeping their chances to switch to a more potent 2GTKI.

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