BCR-ABL Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A Systematic Review and Meta-Analysis on the Risk of Cardiovascular Events, Major Molecular Response and Overall Survival
Authors: Douxfils Jonathan , Haguet Hélène , Chatelain Christian J. , Graux Carlos , Dogné Jean-Michel 
Published: October 2019

Abstract
Introduction:
Ponatinib is a BCR-ABL tyrosine kinase inhibitor (TKI) indicated in adult patients suffering from chronic myeloid leukemia (CML) or “Philadelphia-chromosome positive” (Ph+) acute lymphoblastic leukemia resistant or intolerant to dasatinib or nilotinib. A high incidence of arterial events including peripheral artery occlusive diseases has been observed with ponatinib during the clinical development. A similar risk was also suspected with nilotinib, another BCR-ABL TKI used in CML. To date, no signal of increased risk of vascular thrombosis and embolism was found in clinical trials with imatinib and dasatinib. However, some cases were reported post-marketing.
Aim:
To perform a meta-analysis to assess the risk of vascular occlusive events (VOE) with novel generation BCR-ABL TKI (i.e. bosutinib, dasatinib, nilotinib and ponatinib) in CML patients compared with standard of care (i.e. imatinib). Stratifications by BCR-ABL TKI are performed to provide product specific risk assessment. Data on the overall survival and the major molecular response were also extracted to provide global benefit-risk evaluation.
Methods:
Study selection was performed in two stages. Initially, two independent reviewers screened abstracts and titles against inclusion and exclusion criteria (see protocol at PROSPERO 2014:CRD42014014147). Then, both reviewers assessed potentially relevant papers in their entirety, deciding on inclusion. Studies included all randomized controlled trials (RCT), comparing BCR-ABL TKI versus the reference therapy. Data on major molecular response, overall survival and VOE were extracted. The meta-analysis was performed using a fixed-effect model. Odds ratios (OR) with 95% confidence intervals (CI) were computed using the Peto method. Statistical heterogeneity across the various trials was tested using the Cochran's Q statistic and quantified by the I2 value. Funnel plot asymmetry was assessed by the method of Egger's linear regression, the Begg and Mazumbar rank correlation and the Owrin's fail safe N tests.
Results:
Among the 10 studies included, 3 studies did not report overall survival and 9 studies reported VOE and the major molecular response. Risk of VOE was increased with dasatinib (OR 3.86; 95%CI: 1.33 to 11.18), nilotinib (OR: 3.45; 95%CI: 2.07 to 5.63) and ponatinib (OR: 3.47; 95%CI: 1.23 to 9.78) compared to imatinib in patients with Ph+ CML (Figure 1). No significant difference was found with bosutinib (OR: 2.77; 95%CI: 0.39 to 19.77) probably due to a lack of power, but a trend was also demonstrated (Figure 1). Novel generation TKI increased the rate of major molecular response at 1 year compared to imatinib (overall OR: 2.22; 95%CI: 1.87 to 2.63) (Figure 2). No statistical difference in term of overall survival at one year was found (overall OR: 1.23; 95%CI: 0.67 to 2.23) (Figure 3). Unfortunately, the inaccessibility to individual data and to the time-to-event along with the fact that the evaluation criteria were not similar between studies can introduce a bias in the analysis. However, neither heterogeneity nor publication bias were found, supporting the robustness of our results.
The risk of VOE is likely to be dose-related; however, currently available data on dose-efficacy and dose-toxicity relationship are not sufficient to make a formal recommendation on dose reduction, since there is a risk that lower doses might have reduced efficacy. However, safety and efficacy data concerning dose reduction following major cytogenetic response have been included in the EU-SmPC of Iclusig¨ (ponatinib) as a risk minimization measure.
Conclusion:
Dasatinib, nilotinib and ponatinib increase VOE. Novel generation TKI improve major molecular response but not the overall survival at one year. Further dose-ranging studies are required to define the dose regimen of each BCR-ABL TKI that will provide the best benefit-risk profile. Monitoring the response at the individual level might be of utmost importance to reduce the risk of VOE while keeping the benefit in term of major molecular response.
Figure 1. Forest plot of the risk of VOE in patients with Ph+ leukemia treated with new generation TKIs versus imatinib. Figure 1. Forest plot of the risk of VOE in patients with Ph+ leukemia treated with new generation TKIs versus imatinib. Figure 2. Forest plot of the major molecular response in patients with Ph+ leukemia treated with new generation TKIs versus imatinib. Figure 2. Forest plot of the major molecular response in patients with Ph+ leukemia treated with new generation TKIs versus imatinib. Figure 3. Forest plot of the overall survival in patients with Ph+ leukemia treated with new generation TKIs versus imatinib. Figure 3. Forest plot of the overall survival in patients with Ph+ leukemia treated with new generation TKIs versus imatinib.

Disclosures
Graux: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.