title: Dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia: a systematic review and economic evaluation.
abstract: BACKGROUND
  The present report was commissioned as a supplement to an existing technology assessment report produced by the Peninsula Technology Assessment Group (PenTAG), which evaluated the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in patients who are either resistant or intolerant to standard-dose imatinib.
  
  
  OBJECTIVE
  This report evaluates the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and high-dose imatinib within their licensed indications for the treatment of people with chronic myeloid leukaemia (CML) who are resistant to standard-dose imatinib.
  
  
  METHODS
  Bibliographic databases were searched from inception to January 2011, including The Cochrane Library, MEDLINE (Ovid), EMBASE (Ovid), and MEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were screened, key conferences were searched, and experts were contacted to identify additional published and unpublished references.
  
  
  METHODS
  This report includes systematic reviews of clinical effectiveness and cost-effectiveness studies, an independent appraisal of information submitted by drug manufacturers to the National Institute for Health and Clinical Excellence (NICE), an independent appraisal of the PenTAG economic evaluation, and new economic analyses adapting the PenTAG economic model. Standard systematic procedures involving two reviewers to maintain impartiality and transparency, and to minimise bias, were conducted.
  
  
  RESULTS
  Eleven studies met the inclusion criteria. Four of these studies included new data published since the PenTAG report; all of these were in chronic-phase CML. No relevant studies on the clinical effectiveness of nilotinib were found. The clinical effectiveness studies on dasatinib [one arm of a randomised controlled trial (RCT)] and high-dose imatinib (one arm of a RCT and three single-arm cohort studies) had major methodological limitations. These limitations precluded a comparison of the different arms within the RCT. Data from the studies are summarised in this report, but caution in interpretation is required. One economic evaluation was identified that compared dasatinib with high-dose imatinib in patients with chronic-phase CML who were CML resistant to standard-dose imatinib. Two industry submissions and the PenTAG economic evaluation were critiqued and differences in the assumptions and results were identified. The PenTAG economic model was adapted and new analyses conducted for the interventions dasatinib, nilotinib and high-dose imatinib and the comparators interferon alfa, standard-dose imatinib, stem cell transplantation and hydroxycarbamide. The results suggest that the three interventions, dasatinib, nilotinib and high-dose imatinib, have similar costs and cost-effectiveness compared with hydroxycarbamide, with a cost-effectiveness of around £30,000 per quality-adjusted life-year gained. However, it is not possible to derive firm conclusions about the relative cost-effectiveness of the three interventions owing to great uncertainty around data inputs. Uncertainty was explored using deterministic sensitivity analyses, threshold analyses and probabilistic sensitivity analyses.
  
  
  CONCLUSIONS
  The paucity of good-quality evidence should be considered when interpreting this report.
  
  
  CONCLUSIONS
  This review has identified very limited new information on clinical effectiveness of the interventions over that already shown in the PenTAG report. Limitations in the data exist; however, the results of single-arm studies suggest that the interventions can lead to improvements in haematological and cytogenetic responses in people with imatinib-resistant CML. The economic analyses do not highlight any one of the interventions as being the most cost-effective; however, the analysis results are highly uncertain owing to lack of agreement on appropriate assumptions. Recommendations for future research made by PenTAG, for a good-quality RCT comparing the three treatments remain.
authors.affiliation: Southampton Health Technology Assessments Centre (SHTAC), University of Southampton, Southampton, UK.
authors.forename: E
authors.initials: E
authors.lastname: Loveman
authors.forename: K
authors.initials: K
authors.lastname: Cooper
authors.forename: J
authors.initials: J
authors.lastname: Bryant
authors.forename: J L
authors.initials: JL
authors.lastname: Colquitt
authors.forename: G K
authors.initials: GK
authors.lastname: Frampton
authors.forename: A
authors.initials: A
authors.lastname: Clegg
mesh_terms: D000970:Antineoplastic Agents / Q000191:economics / Q000627:therapeutic use*; D001549:Benzamides; D016001:Confidence Intervals; D003362:Cost-Benefit Analysis; D000069439:Dasatinib; D018450:Disease Progression; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000191:economics; D018803:Models, Economic; D010879:Piperazines / Q000191:economics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000191:economics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000191:economics / Q000627:therapeutic use*; D019057:Quality-Adjusted Life Years; D013844:Thiazoles / Q000191:economics / Q000627:therapeutic use*; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; C498826:nilotinib; D000069439:Dasatinib