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Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid leukaemia: a systematic review and economic evaluation |
Rogers G, Hoyle M, Thompson Coon J, Moxham T, Liu Z, Pitt M, Stein K |
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CRD summary This review concluded that, despite the limited data, dasatinib and nilotinib appeared efficacious in achieving a complete cytogenetic response and haematological responses in both imatinib-resistant and imatinib-intolerant patients. These conclusions reflect the evidence presented and are likely to be reliable, although some limitations in the review process and methods should be borne in mind. Authors' objectives To assess the effectiveness of dasatinib and nilotinib for the treatment of imatinib-resistant or imatinib-intolerant chronic myeloid leukaemia. The clinical effectiveness of the report is appraised by this abstract. Searching Seven databases (including MEDLINE, EMBASE and DARE) were searched from inception up to January 2009 for studies in English. An updated search was performed in June 2009. Search terms were reported. The conference proceedings from American Society of Clinical Oncology and American Society of Haematology were searched from 2008 to 2009. The ClinicalTrial.gov and Meta Register of Controlled studies database were searched for ongoing trials. Reference lists of included studies were also screened for further relevant studies. Study selection Randomised controlled trials (RCTs) that compared dasatinib or nilotinib with relevant standard treatment in patients with imatinib-resistant or imatinib-intolerant chronic myeloid leukaemia were eligible for inclusion. For patients with imatinib-resistant chronic myeloid leukaemia, the eligible relevant comparator was high-dose imatinib (800mg per day). For patients with imatinib-intolerant chronic myeloid leukaemia, the eligible relevant comparator was interferon-alpha (except in blast crisis). Eligible trials had to report at least one of the primary outcomes of molecular and cytogenetic response rate, or haematological response rate. Secondary outcomes were time to response, duration of response, progression free survival, overall survival, adverse effects, and health-related quality of life. Data from Phase II trials and non-randomised studies were eligible only when there was insufficient evidence from good-quality RCTs. Conference abstracts in which there was sufficient detail to assess quality or update the results of included trials were also included. Most of the included studies were observational studies evaluating dasatinib. Of the three included RCTs, two trials compared different dose regimens of dasatinib in accelerated phase and chronic phase, and one trial compared dasatinib with high-dose imatinib. All the three RCTs were multicentre trials. Most included studies were of patients with chronic myeloid leukaemia in chronic phase. The dosage regimens varied across the studies (some details reported in the review). The median age of studied patient cohorts were within the mid to late 50s; most groups were fairly well balanced for gender. The duration of chronic myeloid leukaemia history prior to dasatinib/nilotinib therapy ranged from 50 to 70 months for chronic phase cohorts and 70 to 90 months for accelerated phase cohorts. Patients in blast crisis phase were associated with a fairly short previous chronic myeloid leukaemia history (ranging from 20 to 50 months). One reviewer examined all titles and abstracts, with a sample of these checked by a second. Two reviewers independently assessed full text of potentially relevant studies, with any disagreements resolved by discussion. Assessment of study quality The quality of RCTs was assessed using a range of specified criteria, including power calculation, specification of eligibility criteria, randomisation, allocation concealment, baseline comparability, blinding, withdrawals/drop-outs and intention-to-treatment analysis. The quality of observational studies was assessed using a range of specified criteria, including clear reporting inclusion and exclusion criteria, prospective collection of data, consecutive recruitment of patients, all patients receiving the same intervention, adequate description of any concurrent therapies, drop-outs, intention-to-treat analysis, and generalisability of results. Quality assessment was performed by one reviewer and checked by a second. Any disagreements were resolved by discussion or a third reviewer. Data extraction Data were extracted on proportions of patients who experienced an event for dichotomous outcomes. Where necessary, 95% confidence intervals of proportions for the dichotomous data were calculated using the Clopper-Pearson method. Data were extracted on the basis of intention-to-treat approach were appropriate. Data were extracted by one reviewer, and checked by a second reviewer. Any disagreements were resolved by discussion or a third reviewer. Methods of synthesis Random-effects DerSimonian and Laird model was used to calculate the pooled proportions with 95% confidence intervals. Statistical heterogeneity was assessed using Ι². For situations in which zero frequencies complicated the calculation of standard errors required to calculate weights in meta-analyses, correction factors (0.5 and 1.0) were added to the numerator and denominator of the calculations. Results of the review Fifteen studies (three RCTs and 12 observational studies) were included in the review. The sample size appeared to range from 17 to 387 patients. All the three RCTs had substantial methodological flaws; all had an open-label design, and failed to report methods of allocation concealment or provide a power calculation. The observational studies provided heterogeneous evidence with difficulties to compare and generalise. Due to a lack of robust comparative evidence between interventions, the authors provided the absolute treatment effect for each intervention. Dasatinib in chronic phase: About two-thirds of imatinib-intolerant patients and 30% to 40% of imatinib-resistant patients achieved a complete cytogenetic response. Around 75% of imatinib-intolerant patients and 50% of imatinib-resistant patients achieved a major cytogenetic response, which was maintained for at least two years in most patients. Around 90% of patients had a complete haematological response. About 75% of patients experienced progression-free survival for at least two years. Dasatinib in accelerated phase: About one-third of patients achieved a complete cytogenetic response and approximately 35% to 45% of patients achieved a major cytogenetic response. Around 80% to 90% of those who achieved a major cytogenetic response appeared to maintain the response for at least one year. Around 50% of patients had a complete haematological response. There was no evidence of differences in these outcomes between imatinib-resistant and imatinib-intolerant patients. The average progression-free survival in accelerated phase patients was just over two years. Dasatinib in blast crisis: About one-third of patients achieved a complete cytogenetic response. Around 45% of patients achieved a major cytogenetic response. About one-third of patients had a complete haematological response. Most patients experienced progression-free survival for at least three to six months. Nilotinib in chronic phase: About one-third of patients achieved a complete cytogenetic response. Nearly half of patients achieved a major cytogenetic response. Approximately 80% of patients had a complete haematological response. Most patients experienced progression-free survival for at least three years. Nilotinib in accelerated phase: Approximately one-sixth of patients achieved a complete cytogenetic response. Around 30% of patients achieved a major cytogenetic response. Proximately half of patients had a complete haematological response. The average progression-free survival was almost 1.5 years. Further details on the above outcomes were reported in the report. The results for other outcomes (including adverse events) were also reported. Cost information Based on the 2009 edition of the British National Formulary (BNF), the cost of dasatinib treatment (100mg per day) was £86.85 per day and the cost of nilotinib treatment (400mg twice daily) was £86.89 per day. Authors' conclusions Despite the limited data, dasatinib and nilotinib appeared efficacious in achieving a complete cytogenetic response and haematological responses in both imatinib-resistant and imatinib-intolerant patients. CRD commentary This review addressed a clear research question, supported by appropriate inclusion criteria. A range of relevant databases were searched for both published and unpublished studies, which minimised the potential for publication bias. Only studies in English were included in the review, which may have introduced the risk of language bias. Steps were made to minimise reviewer errors and biases during data extraction and quality assessment. However, only one reviewer assessed the titles and abstracts during study selection, with only a sample of these being checked by a second reviewer, so reviewer error and bias could not be completely ruled out during this stage. Appropriate criteria were used to assess study quality; all of the included studies were of low quality. The synthesis approach appeared to be generally appropriate, with statistical heterogeneity observed in some outcomes. As the authors noted, in the presence of zero frequencies in meta-analyses and the use of correction factors may have introduced higher event rates for single-arm studies as the correction was not balanced in a comparator arm. The authors also acknowledged that there was a high degree of clinical and methodological heterogeneity across studies. The authors' conclusions reflect the evidence presented and are likely to be reliable, although some limitations in the review process and methods should be borne in mind. Implications of the review for practice and research Practice: The authors did not state any implications for practice. Research: The authors stated that a three-arm, double-blind RCT of dasatinib, nilotinib and high-dose imatinib was required. Funding National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme. Bibliographic details Rogers G, Hoyle M, Thompson Coon J, Moxham T, Liu Z, Pitt M, Stein K. Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid leukaemia: a systematic review and economic evaluation. Health Technology Assessment 2012; 16(22): 1-410 Indexing Status Subject indexing assigned by NLM MeSH Benzamides; Blast Crisis /drug therapy; Clinical Trials as Topic; Cost-Benefit Analysis; Dasatinib; Decision Support Techniques; Disease Progression; Drug Resistance, Neoplasm; Health Care Costs /statistics & Humans; Imatinib Mesylate; Incidence; Leukemia, Myelogenous, Chronic, BCR-ABL Positive /drug therapy; Leukemia, Myeloid, Accelerated Phase /drug therapy; Leukemia, Myeloid, Chronic-Phase /drug therapy; Models, Economic; Piperazines /pharmacology /therapeutic use; Prognosis; Protein Kinase Inhibitors /economics /therapeutic use; Pyrimidines /economics /pharmacology /therapeutic use; Quality of Life; Thiazoles /economics /therapeutic use; numerical data AccessionNumber 12012032554 Date bibliographic record published 08/08/2012 Date abstract record published 20/05/2013 Record Status This is a systematic review that meets the criteria for inclusion on DARE. It is linked to: |
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