Jonathan Douxfils1, Hélène Haguet1, François Mullier2, Christian Chatelain3, Carlos Graux3, Jean-Michel Dogné1. 1. Department of Pharmacy, Namur Thrombosis and Hemostasis Center, Namur Research Institute for Life Sciences, University of Namur, Namur, Belgium. 2. Hematology Laboratory, Namur Thrombosis and Hemostasis Center, Namur Research Institute for Life Sciences, CHU UCL Namur, Belgium. 3. Department of Hematology, Namur Thrombosis and Hemostasis Center, Namur Research Institute for Life Sciences, CHU UCL Namur, Belgium.
Abstract
IMPORTANCE: A phase 3 trial with ponatinib in patients with chronic myeloid leukemia (CML) was interrupted due to an important increase of vascular occlusive events. A similar risk was also suspected with nilotinib, another BCR-ABL tyrosine kinase inhibitor (TKI) used in patients with CML. OBJECTIVE: To assess the risk of vascular occlusive events in patients with CML treated by new generations of TKIs and provide an overall assessment of the clinical benefit. DATA SOURCES: Two independent reviewers selected studies from PubMed, Scopus, and the Cochrane library database from their inception to October 21, 2014. Abstracts published during the past 3 years at international congresses and a trial register were also searched. STUDY SELECTION: Two independent reviewers screened abstracts and titles against inclusion and exclusion criteria published previously in the PROSPERO 2014 protocol: CRD42014014147. Among the 249 abstracts identified, 10 studies fulfilled the established criteria. DATA EXTRACTION AND SYNTHESIS: Two investigators independently extracted data using a standard form. MAIN OUTCOMES AND MEASURES: Information extracted included study and patients characteristics, type of intervention and data on vascular occlusive events, overall survival, and major molecular response (MMR). The meta-analysis was performed using a fixed-effects model. Odds ratios (ORs) with 95% CIs were computed using the Peto method. RESULTS: Ten randomized clinical trials (3043 patients) were analyzed. Risk of vascular occlusive events was increased with dasatinib (OR, 3.86; 95% CI, 1.33-11.18), nilotinib (OR, 3.42; 95% CI, 2.07-5.63), and ponatinib (OR, 3.47; 95% CI, 1.23-9.78) compared with imatinib in patients with CML. No significant difference was found with bosutinib (OR, 2.77; 95% CI, 0.39-19.77). New-generation TKIs increased the rate of MMR at 1 year compared with imatinib (overall OR, 2.22; 95% CI, 1.87 to 2.63). No statistical difference in overall survival at 1 year was found (overall OR, 1.20; 95% CI, 0.63-2.29). Inaccessibility to individual data and time-to-event data and differences in evaluation criteria between studies could have introduced bias. CONCLUSIONS AND RELEVANCE: Dasatinib, nilotinib, and ponatinib increase vascular occlusive events. New-generation TKIs improve MMR but not the overall survival at 1 year in patients with CML.
IMPORTANCE: A phase 3 trial with ponatinib in patients with chronic myeloid leukemia (CML) was interrupted due to an important increase of vascular occlusive events. A similar risk was also suspected with nilotinib, another BCR-ABL tyrosine kinase inhibitor (TKI) used in patients with CML. OBJECTIVE: To assess the risk of vascular occlusive events in patients with CML treated by new generations of TKIs and provide an overall assessment of the clinical benefit. DATA SOURCES: Two independent reviewers selected studies from PubMed, Scopus, and the Cochrane library database from their inception to October 21, 2014. Abstracts published during the past 3 years at international congresses and a trial register were also searched. STUDY SELECTION: Two independent reviewers screened abstracts and titles against inclusion and exclusion criteria published previously in the PROSPERO 2014 protocol: CRD42014014147. Among the 249 abstracts identified, 10 studies fulfilled the established criteria. DATA EXTRACTION AND SYNTHESIS: Two investigators independently extracted data using a standard form. MAIN OUTCOMES AND MEASURES: Information extracted included study and patients characteristics, type of intervention and data on vascular occlusive events, overall survival, and major molecular response (MMR). The meta-analysis was performed using a fixed-effects model. Odds ratios (ORs) with 95% CIs were computed using the Peto method. RESULTS: Ten randomized clinical trials (3043 patients) were analyzed. Risk of vascular occlusive events was increased with dasatinib (OR, 3.86; 95% CI, 1.33-11.18), nilotinib (OR, 3.42; 95% CI, 2.07-5.63), and ponatinib (OR, 3.47; 95% CI, 1.23-9.78) compared with imatinib in patients with CML. No significant difference was found with bosutinib (OR, 2.77; 95% CI, 0.39-19.77). New-generation TKIs increased the rate of MMR at 1 year compared with imatinib (overall OR, 2.22; 95% CI, 1.87 to 2.63). No statistical difference in overall survival at 1 year was found (overall OR, 1.20; 95% CI, 0.63-2.29). Inaccessibility to individual data and time-to-event data and differences in evaluation criteria between studies could have introduced bias. CONCLUSIONS AND RELEVANCE: Dasatinib, nilotinib, and ponatinib increase vascular occlusive events. New-generation TKIs improve MMR but not the overall survival at 1 year in patients with CML.
Authors: Srila Gopal; Qing Lu; Joshua J Man; Wendy Baur; Sitara P Rao; Lev Litichevskiy; Malvina Papanastasiou; Amanda L Creech; Katherine C DeRuff; James Mullahoo; Adam Officer; Shawn B Egri; Desiree Davison; Jacob D Jaffe; Iris Z Jaffe Journal: Blood Adv Date: 2018-07-24
Authors: Koji Sasaki; Hagop M Kantarjian; Susan O'Brien; Farhad Ravandi; Marina Konopleva; Gautam Borthakur; Guillermo Garcia-Manero; William G Wierda; Naval Daver; Alessandra Ferrajoli; Koichi Takahashi; Preetesh Jain; Mary Beth Rios; Sherry A Pierce; Elias J Jabbour; Jorge E Cortes Journal: Int J Hematol Date: 2019-03-04 Impact factor: 2.490