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Dasatinib and Nilotinib for Imatinib-Resistant or -Intolerant Chronic Myeloid Leukaemia: A Systematic Review and Economic Evaluation
Health Technology Assessment, No. 16.22
G Rogers, M Hoyle, J Thompson Coon, T Moxham, Z Liu, M Pitt, and K Stein.
Author Information and AffiliationsSouthampton (UK): NIHR Journals Library; 2012 Apr.
Abstract
Background:
Chronic myeloid leukaemia (CML) is a form of cancer affecting the blood, characterised by excessive proliferation of white blood cells in the bone marrow and circulating blood. In the UK, an estimated 560 new cases of CML are diagnosed each year.
Objectives:
The purpose of this study was to assess the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in the treatment of people with imatinib-resistant (ImR) and imatinib-intolerant (ImI) CML. A systematic review of the clinical effectiveness literature, a review of manufacturer submissions and a critique and exploration of manufacturer submissions for accelerated phase and blast crisis CML were carried out and a decision-analytic model was developed to estimate the cost-effectiveness of dasatinib and nilotinib in chronic phase CML.
Systematic review methods:
Key databases were searched for relevant studies from their inception to June 2009 [MEDLINE (including MEDLINE In-Process & Other Non-Indexed Citations), EMBASE, (ISI Web of Science) Conference Proceedings Citation Index and four others]. One reviewer assessed titles and abstracts of studies identified by the search strategy, with a sample checked by a second reviewer. The full text of relevant papers was obtained and screened against the full inclusion criteria independently by two reviewers. Data from included studies were extracted by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through narrative review.
Economic evaluation methods:
Cost-effectiveness analyses reported in manufacturer submissions to the National Institute of Health and Clinical Excellence were critically appraised and summarised narratively. In addition, the models for accelerated phase and blast crisis underwent a more detailed critique and exploration. Two separate decision-analytic models were developed for chronic phase CML, one simulating a cohort of individuals who have shown or developed resistance to normal dose imatinib and one representing individuals who have been unable to continue imatinib treatment owing to adverse events. One-way, multiway and probabilistic sensitivity analyses were performed to explore structural and parameter uncertainty.
Results:
Fifteen studies were included in the systematic review. Chronic phase: effectiveness data were limited but dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic response and haematological response in both ImR and ImI populations. In terms of cost-effectiveness, it was extremely difficult to reach any conclusions regarding either agent in the ImR population. All three models (Novartis, PenTAG and Bristol-Myers Squibb) were seriously flawed in one way or another, as a consequence of the paucity of data appropriate to construct robust decision-analytic models. Accelerated and blast crisis: all available data originated from observational single-arm studies and there were considerable and potentially important differences in baseline characteristics which seriously undermined any process for making meaningful comparisons between treatments. Owing to a lack of available clinical data, de novo models of accelerated phase and blast crisis have not been developed. The economic evaluations carried out by the manufacturers of nilotinib and dasatinib were seriously undermined by the absence of evidence on high-dose imatinib in these populations.
Limitations:
The study has been necessarily constrained by the paucity of available clinical data, the differences in definitions used in the studies and the subsequent impossibility of undertaking a meaningful cost-effectiveness analyses to inform all policy questions.
Conclusions:
Dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic and haematological responses in both ImR and ImI populations. It was difficult to reach any cost-effectiveness conclusions as a consequence of the paucity of the data. Future research should include a three-way, double-blind, randomised clinical trial of dasatinib, nilotinib and high-dose imatinib.
Funding:
The National Institute of Health Research Health Technology Assessment Programme.
Contents
- NIHR Health Technology Assessment programme
- Glossary
- List of abbreviations
- Executive summary
- 1. Background
- Description of underlying health problem
- Epidemiology of chronic myeloid leukaemia
- Disease monitoring
- Treatment
- Quality of life
- Current service provision
- Description of new interventions
- Current use of new interventions in the NHS
- Definition of the decision problem
- Overall aims and objectives of the assessment
- 2. Assessment of clinical effectiveness
- 3. Cost-effectiveness: introduction
- 4. Cost-effectiveness: systematic review
- 5. Cost-effectiveness: chronic myeloid leukaemia in chronic phase
- 6. Cost-effectiveness: chronic myeloid leukaemia in accelerated phase
- 7. Cost-effectiveness: chronic myeloid leukaemia in blast crisis
- 8. Discussion
- Acknowledgements
- References
- Appendix 1 Review protocol
- Appendix 2 Search strategies
- Appendix 3 Systematic review of clinical effectiveness: data extraction forms
- Appendix 4 Appraisal of economic evaluations in industry submissions: checklists
- Appendix 5 Surrogate outcomes in chronic myeloid leukaemia
- Appendix 6 Estimation of overall survival by treatment in the PenTAG model
- Appendix 7 Estimation of treatment duration in the PenTAG model
- Appendix 8 Cost-effectiveness in imatinib-resistant chronic myeloid leukaemia in chronic phase (including interferon)
- Appendix 9 Modelled versus empirical overall survival: alternative calibration for imatinib intolerant people
- Appendix 10 Ongoing studies
- Health Technology Assessment programme
Note: This monograph is based on the Technology Assessment Report produced for NICE. The full report contained a considerable number of data that were deemed commercial-in-confidence. The full report was used by the Appraisal Committee at NICE in their deliberations. The full report with each piece of commercial-in-confidence data removed and replaced by the statement ‘commercial-in-confidence information (or data) removed’ is available on the NICE website: www.nice.org.uk.
The present monograph presents as full a version of the report as is possible while retaining readability, but some sections, sentences, tables and figures have been removed. Readers should bear in mind that the discussion, conclusions and implications for practice and research are based on all the data considered in the original full NICE report.
Suggested citation:
Rogers G, Hoyle M, Thompson Coon J, Moxham T, Liu Z, Pitt M, et al. Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid leukaemia: a systematic review and economic evaluation. Health Technol Assess 2012;16(22).
Declared competing interests of authors: none
The research reported in this issue of the journal was commissioned and funded by the HTA programme on behalf of NICE as project number 08/31/01. The protocol was agreed in January 2009. The assessment report began editorial review in August 2009 and was accepted for publication in October 2010. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors' report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.
The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.
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