Research paperComparative 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
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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2022, Leukemia ResearchCitation Excerpt :However, there was no significant difference observed between groups 3 and 4. In previous studies, assessments of EMR or ECyR at 3 months have been used to predict long-term response and outcome in newly diagnosed CML-CP patients treated with various first-line TKIs [7–9,13,21–23]. However, current ELN 2020 recommendations suggest that molecular testing can replace cytogenetic monitoring in most situations because of the worldwide availability of reliable qRT-PCR assays [20].
Feasibility Study of Switching to Nilotinib After First-line Imatinib in the Chronic Phase of Chronic Myeloid Leukemia
2020, Clinical Lymphoma, Myeloma and LeukemiaCitation Excerpt :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).
The Outcomes of Chronic Myeloid Leukemia Patients With Molecular Warning Responses During Imatinib Treatment According to the European LeukemiaNet 2013 Recommendations
2019, Clinical Lymphoma, Myeloma and LeukemiaCitation Excerpt :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.