Original StudyComparative Effectiveness of Newer Tyrosine Kinase Inhibitors Versus Imatinib in the First-Line Treatment of Chronic-Phase Chronic Myeloid Leukemia Across Risk Groups: A Systematic Review and Meta-Analysis of Eight Randomized Trials
Introduction
The BCR-ABL1 oncoprotein plays an essential role in chronic myeloid leukemia (CML) leukemogenesis.1 Imatinib, which targets the ABL1 kinase domain, significantly improved the survival outcomes for patients with chronic phase (CP)-CML,2, 3 and subsequent newer generation tyrosine kinase inhibitors (NG-TKIs; nilotinib, dasatinib, bosutinib, ponatinib, and radotinib) demonstrated greater potency in newly developed and imatinib-resistant CML.4, 5, 6, 7, 8, 9 Among these, 3 NG-TKIs have been approved as first-line therapy for patients with CP-CML based on recent randomized trials that showed better cytogenetic and molecular responses compared with imatinib (nilotinib and dasatinib has been approved by the U.S. Food and Drug Administration [FDA], and radotinib by the Korea FDA).10, 11, 12 The prognostic effect of a complete cytogenetic response (CCyR) and major molecular response (MMR) on survival outcomes in patients with CP-CML has been well studied in previous trials.13, 14, 15 However, the variability in the CCyR and MMR to NG-TKIs seems to be significant, and no NG-TKI has demonstrated a clear survival advantage compared with imatinib.10, 11, 12, 16, 17, 18, 19, 20 Nilotinib or dasatinib has been preferably selected as the first-line agent for patients with CP-CML with high risk scores in the expectation of a deeper molecular response to minimize the risk of disease progression.21, 22 However, a paucity of data is available to support that the degree of benefit from first-line approved NG-TKIs compared imatinib in high-risk patients is greater than that in those with intermediate- or low-risk scores.
Therefore, we performed a systematic review and meta-analysis to compare the efficacy of NG-TKIs as a category versus imatinib in patients with CP-CML as first-line treatment and to indirectly compare the efficacy of NG-TKIs because no head-to-head or comprehensive multiagent comparison has been performed. Furthermore, we assessed the prognostic effect of risk stratification on the cytogenetic and molecular response outcomes. The primary outcomes of the present study included the CCyR and MMR rates at 12 months of TKI treatment. The secondary outcomes included progression to acute phase (AP)/blast crisis (BC), ABL1 kinase domain (KD) mutation, progression-free survival (PFS), and overall survival (OS) at 12 months.
Section snippets
Study Selection
The following criteria were used to select the eligible randomized controlled trials: (1) assessment of the efficacy of any NG-TKIs versus imatinib; (2) inclusion of adult patients aged ≥ 18 years with newly diagnosed CP-CML according to the European LeukemiaNet criteria23 and naive to any TKI; (3) CCyR and/or MMR outcomes reported at 12 months of TKI treatment; and (4) published as peer-reviewed reports or abstracts.
Data Sources
The main key words for the literature search included CML, TKI, imatinib
Search Results
Our initial literature search yielded a total of 184 relevant abstracts. Of the 184 studies, 143 were excluded as being irrelevant according to the abstract review, and the full text of 41 studies was assessed. Of the 41 studies, 13 imatinib studies, 2 retrospective studies, and 3 meta-analyses were excluded. Also, 4 studies of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia and 11 duplicates or follow-up studies were excluded. After a careful eligibility review, 8
Discussion
The survival of patients with newly diagnosed CP-CML has significantly improved with the advent of imatinib, with the 8-year OS rate approaching 85%.2, 3 Preclinical and clinical studies have demonstrated NG-TKIs to have greater potency in vitro and to result in deeper and faster cytogenetic and molecular responses. However, most NG-TKIs have not shown a significant survival advantage compared with imatinib in either the short or long term.28, 29, 30 Consistently, our pooled analyses
Conclusion
In our meta-analysis of randomized controlled trials of patients with CP-CML, the NG-TKIs nilotinib, dasatinib, bosutinib, ponatinib, and radotinib were associated with greater MMR rates and lower rates of progression to AP/BC but not with significant differences in CCyR, PFS, OS, or KD mutation rates relative to imatinib at 12 months of TKI treatment. However, the NG-TKIs approved for first-line treatment (nilotinib, dasatinib, and, in Korea, also radotinib) were associated with greater CCyR
Disclosure
I.A. has designed, implemented, and disseminated studies related to imatinib as an employee of Matrix45, which was under contract with Novartis for such services. By company policy, employees of Matrix45 are prohibited from owning equity and/or providing services independently to Matrix45 sponsor organizations. Matrix45 provides scientific services to various (bio-) pharmaceutical companies under nonexclusivity conditions. D.W.K. received research fund from Il-Yang Pharmaceutical. The remaining
Acknowledgments
We gratefully acknowledge the comments and suggestions from B. D. Smith (Johns Hopkins). This work was supported by predoctoral fellowships to N.D.V. from the Mayo Foundation for Education and Research and a Bressler Alpert Society Research Grant to S.Y. from the University of Arizona.
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A unique case of chronic myeloid leukemia presenting as monocular vision loss with unilateral retinopathy
2019, American Journal of Ophthalmology Case ReportsCitation Excerpt :Clinical decisions are often guided by the Sokal and Hasford prognostic scoring systems, which utilize their respective validated algorithms based upon patient age, spleen size, platelet count, and several peripheral cell counts to stratify patients into low, intermediate, and high risk disease categories.5,6 NG-TKIs have been shown to be superior to Imatinib in high-risk CML patients.4 To date, nine cases have been reported in which the ocular manifestations of CML were the only presenting signs of the disease, however, in all of these cases, ocular involvement was described bilaterally.7–11
POINT Imatinib is still recommended for frontline therapy for CML
2018, Blood AdvancesCitation Excerpt :Although early surrogate end points such as CCyR, MMR, and early molecular response (EMR, defined as a transcript level <10% at 3 months) were emphasized in registration trials, long-term follow-up has not yet translated into improved PFS or OS. A recent meta-analysis of next-generation TKIs did not show differences in these measures when compared with imatinib.19 Survival is arguably most important to the patient, and these data remain as robust for imatinib as for other agents.
Comparative efficacy and safety of tyrosine kinase inhibitors for chronic myeloid leukaemia: A systematic review and network meta-analysis
2018, European Journal of CancerCitation Excerpt :In general, analysis of therapeutic monitoring showed that patients treated with nilotinib reached the highest rates of efficacy outcomes when compared with the other representatives of this pharmacological class. These findings are in agreement with previous published studies [4,16,17,69–77] and with the recent recommendations of the current NCCN, and ELN guidelines, considering nilotinib as an option for first-line treatment [8,9]. In addition, when comparing nilotinib with the other first-line treatment options, nilotinib 600 mg has an 81.0% chance of achieving MMR compared with imatinib 400 mg (24.4%), imatinib 600 mg (24.7%) and dasatinib 100 mg (61.9%).
Risk of Atrial Fibrillation and Bleeding Diathesis Associated With Ibrutinib Treatment: A Systematic Review and Pooled Analysis of Four Randomized Controlled Trials
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