Chronic lymphocytic leukemia

Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL


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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  1. 1

    Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 2016; 127: 208–215.

  2. 2

    Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376: 1164–1174.

  3. 3

    Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do K-A et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008; 112: 975–980.

  4. 4

    McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16: 2825–2833.

  5. 5

    Keating M, O'Brien S . High-dose rituximab therapy in chronic lymphocytic leukemia. Semin Oncol 2000; 27 (6 Suppl 12): 86–90.

  6. 6

    O’Brien SM, Kantarjian H, Thomas DA, Giles FJ, Freireich EJ, Cortes J et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001; 19: 2165–2170.

  7. 7

    Byrd JC, Murphy T, Howard RS, Lucas MS, Goodrich A, Park K et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 2001; 19: 2153–2164.

  8. 8

    Williams ME, Densmore JJ, Pawluczkowycz AW, Beum PV, Kennedy AD, Lindorfer MA et al. Thrice-weekly low-dose rituximab decreases CD20 loss via shaving and promotes enhanced targeting in chronic lymphocytic leukemia. J Immunol 2006; 177: 7435–7443.

  9. 9

    Almasri NM, Duque RE, Iturraspe J, Everett E, Braylan RC . Reduced expression of CD20 antigen as a characteristic marker for chronic lymphocytic leukemia. Am J Hematol 1992; 40: 259–263.

  10. 10

    Aue G, Lindorfer MA, Beum PV, Pawluczkowycz AW, Vire B, Hughes T et al. Fractionated subcutaneous rituximab is well-tolerated and preserves CD20 expression on tumor cells in patients with chronic lymphocytic leukemia. Haematologica 2010; 95: 329–332.

  11. 11

    Zent CS, Taylor RP, Lindorfer MA, Beum PV, LaPlant B, Wu W et al. Chemoimmunotherapy for relapsed/refractory and progressive 17p13-deleted chronic lymphocytic leukemia (CLL) combining pentostatin, alemtuzumab, and low-dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells. Am J Hematol 2014; 89: 757–765.

  12. 12

    Bosch F, Ferrer A, Villamor N, González M, Briones J, González-Barca E et al. Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication. Clin Cancer Res 2008; 14: 155–161.

  13. 13

    Bosch F, Abrisqueta P, Villamor N, Terol MJ, González-Barca E, Ferra C et al. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol 2009; 27: 4578–4584.

  14. 14

    Hillmen P, Cohen DR, Cocks K, Pettitt A, Sayala HA, Rawstron AC et al. A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia. Br J Haematol 2011; 152: 570–578.

  15. 15

    Munir T, Howard DR, McParland L, Pocock C, Rawstron AC, Hockaday A et al. Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL. Leukemia 2017; (in press).

  16. 16

    Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on chronic lymphocytic leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood 2008; 111: 5446–5456.

  17. 17

    Dearden CE, Richards S, Else M, Catovsky D, Hillmen P . A comparison of the efficacy and safety of oral and intravenous fludarabine in chronic lymphocytic leukemia in the LRF CLL4 trial. Cancer 2011; 117: 2452–2460.

  18. 18

    Rawstron AC, Fazi C, Agathangelidis A, Villamor N, Letestu R, Nomdedeu J et al. A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study. Leukemia 2016; 30: 929–936.

  19. 19

    Rawstron AC, Bottcher S, Letestu R, Villamor N, Fazi C, Kartsios H et al. Improving efficiency and sensitivity: European Research Initiative in CLL (ERIC) update on the international harmonised approach for flow cytometric residual disease monitoring in CLL. Leukemia 2013; 27: 142–149.

  20. 20

    Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, 2003. Available at:

  21. 21

    Hallek M, Fingerle-Rowson G, Fink A-M, Busch R, Mayer J, Hensel M et al. Immunochemotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus fludarabine and cyclophosphamide (FC) improves response rates and progression-free survival (PFS) of previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL). ASH Annual Meeting Abstracts 2008; 112 (11): 325.

  22. 22

    Kay R. Equivalence and Non-Inferiority Trials. Parexel, PSI sponsored course notes: UK, 2000..

  23. 23

    O'Brien PC, Fleming TR . A multiple testing procedure for clinical trials. Biometrics 1979; 35: 549–556.

  24. 24

    Dolan P . Modeling valuations for EuroQol health states. Med Care 1997; 35: 1095–1108.

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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.

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Correspondence to P Hillmen.

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Competing interests

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.

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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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