A randomised, phase IIB trial in previously untreated patients with Chronic Lymphocytic Leukaemia (CLL) to compare fludarabine, cyclophosphamide and rituximab (FCR) with FC, mitoxantrone and low dose rituximab (FCM-miniR
- Start date: 01.01.2009
- End date: 01.06.2015
- Value: £636,052
- Partners and collaborators: National Institute for Health Research (NIHR) HTA
- Primary investigator: Prof Peter Hillmen
Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia, affecting approximately 6.9 per 100,000 of the population. The incidence of CLL increases with age and twice as many men are affected as women. CLL results from the clonal proliferation of B-cells and is diagnosed by the pattern of expression of various cell surface antigens on the CLL cells. Patients most commonly present with lymphocytosis, lymphadenopathy, splenomegaly and systemic symptoms, such as fatigue, weight loss and malaise. The clinical course of CLL is highly variable, with a median survival from diagnosis in the region of 7 years. Patients with more advanced disease (Binet stages B, C and stage A progressive) have a significantly worse survival.
The first treatment that patients with CLL usually receive is a combination of the drugs fludarabine, cyclophosphamide and rituximab (Mabthera®, Roche Products Ltd) (FCR). However, research suggested that adding a fourth drug called mitoxantrone to FCR would improve response rates and that a lower dose of rituximab would work just as well as the standard dose.
The objective of the ARCTIC trial was to assess whether the combination of fludarabine, cyclophosphamide and mitoxantrone with a low dose of rituximab (FCM-miniR; 100 mg per cycle) was non-inferior to the conventional FCR therapy in patients with CLL requiring therapy for the first time. This included the complete remission (CR) rate as the primary end point, with important secondary end points including progression-free survival (PFS), overall survival (OS), overall response rate (ORR), eradication of minimal residual disease (MRD) following treatment, safety and toxicity, and cost-effectiveness. The objective was to use the results of ARCTIC, assuming they were positive, to help design a larger, definitive, Phase III trial.
Participants randomised to FCM-miniR had a significantly lower CR rate than those randomised to FCR (FCM-miniR 55% vs. FCR 76%), indicating that FCR is the more effective treatment. Key secondary end points also indicated that FCR had greater efficacy, with a higher proportion of participants achieving eradication of MRD (57% for FCR compared with 46% for FCM-miniR). The follow-up in the trial is still immature (median 37.3 months from randomisation) but, to date, the PFS and OS are good compared with previous studies and there is no significant difference between the two treatment arms, although there is a possible trend towards FCR patients having improved PFS and OS. The cost-effectiveness analysis indicates that, although FCM-miniR is expected to be cost-effective in the short term, it is unlikely to be cost-effective when taking into account long-term costs and health benefits.
There is strong evidence to suggest that FCM-miniR is not non-inferior to FCR in terms of CR at 3 months post treatment and that the addition of mitoxantrone adds toxicity to FCR. Although FCM-miniR was found to be cost-effective over the trial period, it is unlikely to be cost-effective in the long term. In view of this, FCM-miniR will not be taken forward into a larger, definitive, Phase III trial. The trial demonstrated that oral FCR yields extremely high response rates compared with historical series in which the chemotherapy was given intravenously and it remains the gold-standard therapy for CLL in patients considered fit for fludarabine-based therapy.
Publications and outputs
Howard DR, Munir T, McParland L, Rawstron AC, Milligan D, Schuh A, Hockaday A, Allsup DJ, Marshall S, Duncombe AS, O’Dwyer JL, Smith AF, Longo R, Varghese A, Hillmen P. Results of the randomized phase IIB ARCTIC trial of low dose Rituximab in previously untreated CLL. Leukemia (2017) 31: 2416-2425; doi:10.1038/leu.2017.96.
Smith A, Hall P, O’Dwyer J, Hulme C, Cohen D, Gregory W. Modelling cost-effectiveness and value of information in clinical trials to inform stop go decisions: results from the arctic study. Trials (2015), 16(Suppl 2); O27. http://doi.org/10.1186/1745-6215-16-S2-O27.