AUTHOR'S PROOF! UNCORRECTED PROOF 1 2 3 ORIGINAL ARTICLE 4 First-line treatments for chronic lymphocytic leukaemia: 5 interpreting efficacy data by network meta-analysis Q1 7 Andrea Messori & Valeria Fadda & Dario Maratea & 8 Sabrina Trippoli 9 10 11 Received: 12 September 2014 /Accepted: 27 January 2015 12 # Springer-Verlag Berlin Heidelberg 2015 13 Abstract When multiple treatments are available, network 14 meta-analysis can synthesize evidence and rank relative effec- 15 tiveness. We applied this approach to current treatments for 16 previously untreated chronic lymphocytic leukaemia. Data 17 search was conducted in PubMed and websites of regulatory 18 agencies (year 2000 through present time). Our analysis in- 19 cluded randomized controlled trials assessing treatments for 20 previously untreated chronic lymphocytic leukaemia. The 21 endpoint of the analysis was the rate of progression-free sur- 22 vival at 3 years. At least two reviewers abstracted study data 23 and outcomes. Agents examined for their relative effective- 24 ness included four monotherapies (chlorambucil, fludarabine, 25 bendamustine, alemtuzumab) and four combination treat- 26 ments (cyclophosphamide + fludarabine, cyclophosphamide 27 + cladribine, cyclophosphamide + fludarabine + rituximab, 28 cyclophosphamide + fludarabine + alemtuzumab). A Bayes- 29 ian network meta-analysis was conducted to comparatively 30 evaluate these treatments. Nine trials (3620 patients) were 31 included in the analysis. Odds ratio (with 95 % credible inter- 32 vals) was estimated for all direct and indirect comparisons. 33 Combinations treatments were found to be significantly more 34 effective than single-agent treatments. Ranking in effective- 35 ness was as follows: (1) cyclophosphamide + fludarabine + 36 rituximab, (2) alemtuzumab, (3) cyclophosphamide + 37 fludarabine + alemtuzumab, (4) cyclophosphamide + 38 fludarabine and (at same ranking) cyclophosphamide + 39 cladribine, (6) fludarabine, (7) bendamustine and (8) 40 chlorambucil. Bendamustine fared worse in our analysis than 41 in its pivotal trial. Overall, the estimated rankings appeared to 42 be robust according to probabilistic analysis. Numerous indi- 43 rect comparisons were assessed in the absence of RCTs. Some 44 progression-free rates were unavailable from the publications 45 and were estimated graphically from the survival curve. We 46 generated an updated synthesis of the effectiveness of these 47 treatments and we ranked them according to a Bayesian prob- 48 abilistic model. In our probabilistic analysis, cyclophospha- 49 mide + fludarabine + rituximab ranked first in the base case 50 while the worst-case scenario of this analysis placed this treat- 51 ment at a remarkable second place. 52 Keywords Meta-analysis . Chronic lymphocytic leukaemia . 53 Chlorambucil . Fludarabine . Bendamustine . Alemtuzumab . 54 Cyclophosphamide . Cladribine . Rituximab 55 Introduction 56 The literature on the effectiveness of treatments for previously 57 untreated chronic lymphocytic leukaemia (CLL) covers more 58 than 50 years and is therefore sufficiently settled [1]. Howev- 59 er, a relatively large number of new agents have been ap- 60 proved in recent times [2–11], and for this reason, an updated 61 comparative synthesis of effectiveness data can be of interest. 62 In the present study, we examined the data of comparative 63 effectiveness published after 2000 in randomized controlled 64 trials (RCTs) and we applied network meta-analysis to syn- 65 thesize this information. The main purpose of our study was to 66 comparatively evaluate the effectiveness of current treatments 67 and to rank them according to their effectiveness. In particular, 68 our assessment of outcomes was focused on progression-free 69 rates at 3 years in order to capture a sufficiently long time 70 interval. Furthermore, our analysis differed from others Electronic supplementary material The online version of this article (doi:10.1007/s00277-015-2310-6) contains supplementary material, which is available to authorized users. A. Messori (*) : V. Fadda : D. Maratea : S. Trippoli HTA Unit, ESTAV Toscana Centro, Regional Health Service, 50100 Firenze, Italy e-mail: andrea.messori.it@gmail.com Ann Hematol DOI 10.1007/s00277-015-2310-6 JrnlID 277_ArtID 2310_Proof# 1 - 10/02/2015