Comparative Efficacy of First Line Treatment of Chronic Myeloid Leukaemia (CML): A Systematic Review and Meta-Analysis.

Abstract

AbstractAbstract 3436 Introduction:Historically, interferon-alpha, hydroxyurea or chemotherapy were used as first line therapy for individuals newly diagnosed with CML. Current practice, however, recommends that tyrosine-kinase inhibitors (TKIs) be used in this patient group, with imatinib (1st generation TKI) being the current standard of care. Recent publications provide data from randomized clinical trials on 2nd generation TKIs (dasatinib and nilotinib) in the first-line setting. In the absence of randomized head to head evidence for all three TKI's, a Bayesian mixed treatment comparison meta-analysis provides a means of indirectly estimating the treatment effect of one intervention relative to another. Methods:A systematic review identified RCTs that reported or summarized efficacy data for any of the treatments of interest in treatment-naive CML patients. In order to maximise the evidence network, RCT's of non-TKI's were also included in the review. Where reported, data was extracted for molecular, hematological and cytogenic response at three montly intervals. In addition, safety and progression free and overall survival data was extracted for all reported timepoints. Extracted data was analyzed in a Bayesian mixed treatment comparison using a fixed-effects model. The outputs from all analyses were expressed as odds ratios with Imatinib 400mg SID used as the baseline intervention in all analyses. Results:Overall, 44 articles arising from 19 distinct clinical trials were included in the review. The results for complete cytogenetic response (CCyR) at twelve months (expressed as both response probabilities and odds ratios) are presented in table 1.Table 1:CCyR at 12 months for TKI use (mean, 95% CrI) in first line CML treatmentInterventionProbability of responseOdds Ratio (95% CrI)Imatinib 400mg daily65% (Reference)N/A (reference)Imatinib 800mg daily70% (58%, 80%)1.32 (0.73, 2.22)Dasatinib 100mg daily79% (71%, 85%)2.05 (1.31, 3.09)Nilotinib 600mg daily80% (73%, 86%)2.23 (1.50, 3.22)Nilotinib 800mg daily78% (71%, 84%)1.95 (1.32, 2.80)High dose imatinib performed no better than standard dose imatinib. However, response with both 2nd generation TKIs was significantly better than with standard dose imatinib with the effect size being doubled on all endpoints. Head to head results for nilotinib and dasatinib showed no statistically significant differences (p=0.05) between the two products on all endpoints (see table 2).Table 2:Head to head CCyR results at 12 months (Odds ratios, 95% CrI) for dasatinib and nilotinibInterventionOdds RatioDasatinib 100mg daily vs. Nilotinib 600mg daily0.96 (0.52, 1.86)Dasatinib 100mg daily vs. Nilotinib 800mg daily1.10 (0.60, 1.86)Nilotinib 600mg daily vs. Nilotinib 800mg daily1.17 (0.76, 1.72) Conclusions:Compared to Imatinib, the use of 2nd generation TKI's for the treatment of newly diagnosed CML results in a significant improvement in complete cytogenic response. However, the current evidence base is not rich enough to distinguish between the two 2nd generation TKIs either in terms of response or progression free survival. The analyses presented will be strengthened by the inclusion of additional RCT data that may become available in the future. Disclosures:Mealing:Oxford Outcomes: Employment. Barcena:Oxford Outcomes: Employment. Hawkins:Oxford Outcomes: Employment. Clark:Oxford Outcomes: Employment. Davis:Bristol Myers-Squibb: Employment.