Emergence of BCR-ABL kinase domain mutations associated with newly diagnosed chronic myeloid leukemia: a meta-analysis of clinical trials of tyrosine kinase inhibitors

J Manag Care Spec Pharm. 2015 Feb;21(2):114-22. doi: 10.18553/jmcp.2015.21.2.114.

Abstract

Background: Tyrosine kinase inhibitors (TKIs) are a mainstay of treatment for patients suffering from chronic myeloid leukemia (CML). Testing for various mutations in the BCR-ABL gene may help predict lack of response to specific TKIs where resistance has developed.

Objective: To estimate the emergence of BCR-ABL kinase domain mutations associated with newly diagnosed CML patients exposed to first-line TKI treatment.

Methods: Published studies were identified using a structured search of online databases. Original research studies were included if they reported the incidence of specific BCR-ABL kinase domain point mutations after first-line TKI treatment failure or baseline mutations for second-line TKI treatment following first-line treatment failure. Meta-analysis of mutation rates across studies was based on DerSimonian and Laird's random-effects model.

Results: Of 1,323 citations, 12 studies met the inclusion criteria, involving a total of 1,698 patients. Overall mutation rates (95% CI) were imatinib 9.7% (6.2%-13.3%); dasatanib 1.7% (0.0%-4.3%); and nilotinib 3.3% (0.0%-7.7%). The most common specific mutations were T315I, E255K, and M351T. T315I mutations constituted 58% (7 of 12) of dasatinib-related mutations and 13% (15 of 117) of imatinib-related mutations.

Conclusions: Lack of response to TKIs associated with mutation in the BCR-ABL gene was significantly higher in imatinib-treated patients, and all mutations arose after treatment. T315I was a common treatment-emergent mutation. Further research is needed to assess the prognostic value of testing for mutations and the economic implications of treatment-emergent mutations.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Clinical Trials as Topic
  • Female
  • Fusion Proteins, bcr-abl / genetics*
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Male
  • Middle Aged
  • Mutation*
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*

Substances

  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl