Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid
leukaemia: a systematic review and economic evaluation.
Author(s): Rogers G, Hoyle M, Thompson Coon J, Moxham T, Liu Z, Pitt M, Stein K.
Affiliation(s): Peninsula Technology Assessment Group (PenTAG), Peninsula Medical School,
Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.
Publication date & source: 2012, Health Technol Assess. , 16(22):1-410
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.
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