Dartigeas C, et al. - Researchers planned this study to determine the efficacy and safety of rituximab maintenance treatment vs observation for elderly patients in remission after front-line abbreviated induction by fludarabine, cyclophosphamide, and rituximab (FCR). Observations revealed that in selected elderly patients, 2-year maintenance rituximab improved progression-free survival and demonstrated an acceptable safety profile. They identified immunotherapy maintenance strategy as a relevant option in front-line treatment of chronic lymphocytic leukaemia, even in the age of targeted therapy.

Methods

• Researchers performed this randomised, open-label, multicentre phase 3 trial at 89 centres in France
• They enrolled treatment-naive and fit patients aged 65 years or older with chronic lymphocytic leukaemia without del(17p).
• For this study, eligible patients were those who had an Eastern Cooperative Oncology Group performance status of 0–1 and adequate renal and hepatic function.
• For randomisation, patients in response to complete induction treatment with four monthly courses of full-dose FCR with two interim rituximab doses on day 14 of cycles 1 and 2 (oral fludarabine [40 mg/m² per day] and oral cyclophosphamide [250 mg/m² per day] for the first 3 days of each cycle, rituximab at 375 mg/m² intravenously on day 0 of cycle 1 and subsequently at 500 mg/m² on day 14 of cycle 1, days 1 and 14 of cycle 2, and day 1 of cycles 3 and 4) were eligible.
• To continue the trial, recovery from FCR toxicity and patient willingness were mandatory.
• With a central computer-generated randomisation list using randomly permuted blocks of variable sizes, random assignment (1:1) of patients to either receive intravenous rituximab (500 mg/m²) every 8 weeks for up to 2 years or undergo observation was performed.
• By IGHV mutational status, the presence or absence of del(11q), and response level to induction treatment, stratification of randomisation was done.
• Progression-free survival was assessed as the primary endpoint, with the objective to determine the superiority of rituximab maintenance relative to observation.
• They performed the final analysis in the intention-to-treat population.
• In all patients who received at least one dose of study drug in the rituximab group and in all patients in the observation group, safety was analysed.
• This trial is closed to accrual whilst continuing patient follow-up.

Results

• Researchers enrolled 542 patients from Dec 14, 2007 to Feb 18, 2014.
• Of these, 525 started FCR induction.
• From June 10, 2008 to Aug 14, 2014, they randomly assigned 409 (78%) patients to rituximab maintenance (n=202) or observation (n=207).
• The allocated treatment was not administered to 4 (2%) patients in the rituximab group (progressive disease [n=1], adverse events [n=3]).
• Median progression-free survival in the rituximab group (59·3 months, 95% CI 49·6–not estimable) was improved after a median follow-up of 47·7 months (IQR 30·4–65·8), compared with the observation group (49·0 months, 39·9–60·5; hazard ratio 0·55, 95% CI 0·40–0·75; p=0·0002).
• With rituximab maintenance, neutropenia and grade 3–4 infections were more frequent (105 [53%] of 198 patients vs 74 [36%] of 207 patients and 38 [19%] vs 21 [10%], respectively) during the study.
• Lower respiratory tract infection was identified as the most common grade 3–4 infection (24 [12%] vs eight [4%]).
• Both groups were similar in terms of incidence of second cancers, except basal cell carcinoma (29 [15%] vs 23 [11%]).
• In this study, 23 (11%) patients in the rituximab group and 16 (8%) in the observation group died in relation to adverse events.