Original Study
Comparative 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

https://doi.org/10.1016/j.clml.2016.03.003Get rights and content

Abstract

Background

BCR-ABL1 tyrosine kinase inhibitors (TKIs) have significantly improved the survival outcomes for patients with chronic myeloid leukemia (CML). In addition to imatinib, 3 newer generation TKIs (NG-TKIs) have been approved as first-line treatment of chronic phase (CP)-CML. These have been preferably used in patients with CP-CML with a high Sokal or Hasford risk score. We performed a systematic review and meta-analysis to compare the outcomes with NG-TKIs as a category versus imatinib in patients with newly diagnosed CP-CML and to indirectly compare the efficacy of NG-TKIs among each other. Furthermore, we assessed the effect of the risk scores on the complete cytogenetic response (CCyR) and major molecular response (MMR).

Materials and Methods

The eligible studies were limited to randomized controlled trials comparing the efficacy of first-line treatment using NG-TKIs versus imatinib in adult patients (aged ≥ 18 years) with CP-CML.

Results

The differences in the CCyR, progression-free survival, and overall survival between the NG-TKIs and imatinib were not statistically significant. NG-TKI-treated patients showed a significantly greater likelihood of MMR (relative risk [RR], 0.76; 95% confidence interval, 0.63-0.91; P = .003) and lower likelihood of progression to an accelerated phase/blast crisis (RR, 0.37; 95% confidence interval, 0.20-0.67; P = .001) than did imatinib-treated patients. Nilotinib, dasatinib, and radotinib showed significantly greater CCyR rates compared with bosutinib and ponatinib. All risk groups showed statistically equivalent benefits from NG-TKIs for the CCyR and MMR.

Conclusion

In first-line treatment, the NG-TKIs as a category showed greater effectiveness in MMR and prevention of accelerated phase/blast crisis progression. Risk stratification was not found to affect the RR of CCyR and MMR.

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.

References (39)

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