ARCTIC was a multicenter, randomized-controlled, open, phase IIB non-inferiority trial in previously untreated chronic lymphocytic leukemia (CLL). Conventional frontline therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). The trial hypothesized that including mitoxantrone with low-dose rituximab (FCM-miniR) would be non-inferior to FCR. A total of 200 patients were recruited to assess the primary end point of complete remission (CR) rates according to IWCLL criteria. Secondary end points were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity, safety and cost-effectiveness. The trial closed following a pre-planned interim analysis. At final analysis, CR rates were 76 FCR vs 55% FCM-miniR (adjusted odds ratio: 0.37; 95% confidence interval: 0.19–0.73). MRD-negativity rates were 54 FCR vs 44% FCM-miniR. More participants experienced serious adverse reactions with FCM-miniR (49%) compared to FCR (41%). There are no significant differences between the treatment groups for PFS and OS. FCM-miniR is not expected to be cost-effective over a lifetime horizon. In summary, FCM-miniR is less well tolerated than FCR with an inferior response and MRD-negativity rate and increased toxicity, and will not be taken forward into a confirmatory trial. The trial demonstrated that oral FCR yields high response rates compared to historical series with intravenous chemotherapy.
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ARCTIC is funded by the Health Technology Assessment (HTA) programme and is included in the National Institute for Health Research (NIHR) Clinical Research Network Portfolio. The views and opinions expressed there in are those of the authors and do not necessarily reflect those of HTA, NIHR or the NHS. We would like to thank all patients and hospital staff who contributed to this study. In addition, we acknowledge the invaluable support provided by the independent DMC and TSC.
Professor Hillmen received research funding and speakers' fees from Roche Products Limited. Dr Rawstron reports personal fees from Roche Products Limited. Dr Munir reports personal fees from Roche Products Limited. The remaining authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Leukemia website
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Howard, D., Munir, T., McParland, L. et al. Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL. Leukemia 31, 2416–2425 (2017) doi:10.1038/leu.2017.96
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