Comparative efficacy and safety of tyrosine kinase inhibitors for chronic myeloid leukaemia: A systematic review and network meta-analysis

Eur J Cancer. 2018 Nov;104:9-20. doi: 10.1016/j.ejca.2018.08.016. Epub 2018 Oct 5.

Abstract

Background: The pharmacotherapy of chronic myeloid leukaemia (CML) is mainly based on tyrosine kinase inhibitors (TKIs). The aim of this study was to compare the efficacy and safety of all TKIs in CML patients.

Methods: We conducted a systematic review with network meta-analysis (NMA) of randomised controlled trials (RCTs), including imatinib, nilotinib, dasatinib, bosutinib, radotinib and ponatinib. Searches were performed in PubMed, Scopus, Web of Science and SciELo (March 2018). The NMAs were built for six outcomes at 12 months: complete cytogenetic response (CCyR), major cytogenetic response (MCyR), deep molecular response, major molecular response (MMR), complete haematologic response and incidence of serious adverse events. We conducted rank order and surface under the cumulative ranking curve (SUCRA) analyses.

Results: Thirteen RCTs were included (n = 5079 patients). Statistical differences were observed for some comparisons in all outcomes. Imatinib 400 mg was considered the safest drug (SUCRA values of 10.3%) but presented low efficacy. Overall, nilotinib 600 mg was superior to the other TKI in efficacy (SUCRA values of 61.1% for CCyR, 81.0% for MMR, 90.0% for MCyR); however, no data on its safety profile at 12 months were reported.

Interpretation: Our results suggest that nilotinib should be upgraded to first-line therapy for CML, although further cost-effectiveness analyses, including the new TKI (i.e., ponatinib, radotinib), are needed.

Keywords: Chronic myeloid leukaemia; Efficacy; Network meta-analysis; Safety; Tyrosine kinase inhibitors.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / economics
  • Antineoplastic Agents / therapeutic use*
  • Cost-Benefit Analysis
  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Humans
  • Imatinib Mesylate / administration & dosage
  • Imatinib Mesylate / economics
  • Imatinib Mesylate / therapeutic use
  • Imidazoles / administration & dosage
  • Imidazoles / adverse effects
  • Imidazoles / therapeutic use
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / blood
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Markov Chains
  • Molecular Targeted Therapy*
  • Monte Carlo Method
  • Multicenter Studies as Topic / statistics & numerical data
  • Neoplasm Proteins / antagonists & inhibitors*
  • Network Meta-Analysis
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / economics
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyridazines / administration & dosage
  • Pyridazines / adverse effects
  • Pyridazines / therapeutic use
  • Pyrimidines / administration & dosage
  • Pyrimidines / adverse effects
  • Pyrimidines / economics
  • Pyrimidines / therapeutic use
  • Randomized Controlled Trials as Topic / statistics & numerical data
  • Treatment Outcome

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Antineoplastic Agents
  • Imidazoles
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Pyridazines
  • Pyrimidines
  • ponatinib
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl