Abstract: We screened a total of 1150 records. Seven RCTs involving 1763 patients were identified, but only five could be included in the two separate meta-analyses we performed. We judged the overall the quality of these trials as moderate to high. All trials were randomised and open-label studies. However, two trials were published as abstracts only, therefore we were unable to assess the potential risk of bias for these trials in detail. Three RCTs (N = 1421) assessed the efficacy of monoclonal anti-CD20 antibodies (i.e. rituximab) plus chemotherapy compared to chemotherapy alone. The meta-analyses showed a statistically significant OS (HR 0.78, 95% confidence interval (CI) 0.62 to 0.98, P = 0.03, the number needed to treat for an additional beneficial effect (NNTB) was 12) and PFS (HR 0.64, 95% CI 0.55 to 0.74, P < 0.00001) advantage for patients receiving rituximab. In the rituximab-arm occurred more AEs, World Health Organization (WHO) grade 3 or 4 (3 trials, N = 1398, RR 1.15, 95% CI 1.08 to 1.23, P < 0.0001; the number needed to harm for an additional harmful outcome (NNTH) was 9), but that did not lead to a statistically significant difference regarding TRM (3 trials, N = 1415, RR 1.19, 95% CI 0.70 to 2.01, P = 0.52). Two trials (N = 177) evaluated rituximab versus alemtuzumab. Neither study reported OS or PFS. There was no statistically significant difference between arms regarding complete response rate (CRR) (RR 1.21, 95% CI 0.94 to 1.58, P = 0.14) or TRM (RR 0.31, 95% CI 0.06 to 1.51, P = 0.15). However, the CLL2007FMP trial was stopped early owing to an increase in mortality in the alemtuzumab arm. More serious AEs occurred in this arm (43% with alemtuzumab versus 22% with rituximab; P = 0.006). Two trials assessed different dosages or time schedules of monoclonal anti-CD20 antibodies. One trial (N = 104) evaluated two different rituximab schedules (concurrent arm: fludarabine plus rituximab (Flu-R) plus rituximab consolidation versus sequential arm: fludarabine alone plus rituximab consolidation). The comparison of the concurrent versus sequential regimen of rituximab showed a statistically significant difference of the CRR with 33% in the concurrent-arm and 15% in the sequential-arm (P = 0.04), that did not lead to statistically significant differences regarding OS (HR 1.14, 95% CI 0.20 to 6.65, P = 0.30) or PFS (HR 0.96, 95% CI 0.43 to 2.15, P = 0.11). Furthermore results showed no differences in occurring AEs, except for neutropenia, which was more often observed in patients of the concurrent arm. The other trial (N = 61) investigated two different dosages (500 mg and 1000 mg) of ofatumumab in addition to FluC. The arm investigating ofatumumab did not assess OS and a median PFS had not been reached owing to the short median follow-up of eight months. It showed no statistically significant differences between arms regarding CRR (32% in the FCO500 arm versus 50% in the FCO1000 arm; P = 0.10) or AEs (anaemia, neutropenia, thrombocytopenia). This meta-analysis showed that patients receiving chemotherapy plus rituximab benefit in terms of OS as well as PFS compared to those with chemotherapy alone. Therefore, it supports the recommendation of rituximab in combination with FluC as an option for the first-line treatment as well as for the people with relapsed or refractory CLL. The available evidence regarding the other assessed comparisons was not sufficient to deduct final conclusions.

Plain-language summary: Three trials (N = 1421) were included in the meta-analysis assessing the efficacy of chemotherapy plus rituximab compared to chemotherapy without further therapy. The meta-analysis showed for patients receiving additional rituximab a statistically significant improvement of overall survival and a longer time without progression of the disease. Treatment with rituximab caused more adverse events, but this did not lead to a statistically significant difference regarding death caused by treatment. However, patients who were treated within these trials did not suffer from other severe health problems aside from CLL; therefore, it remains unclear whether patients with severe co-morbidities will benefit from this treatment option. In summary, this meta-analysis showed that patients receiving chemotherapy plus rituximab benefited in terms of survival compared to those with chemotherapy alone. Therefore, it supports the recommendation of rituximab in combination with fludarabine and cyclophosphamide as an option for the first-line treatment as well as for people with relapsed or refractory CLL. Further research should focus on the evaluation of benefits of adding rituximab to other chemotherapy regimens than fludarabine with cyclophosphamide in the therapy of previously untreated, relapsed or refractory patients. It should also assess whether patients with serious co-morbidities will benefit from the addition of rituximab to chemotherapy. The available evidence regarding assessed comparisons from four other trials was not sufficient to deduct final conclusions.Two trials evaluated polychemotherapy in combination with rituximab versus alemtuzumab respectively. One trial evaluated two different rituximab schedules: rituximab given concurrently with primary treatment plus rituximab therapy given subsequently to the primary treatment versus primary treatment alone with subsequent administration of rituximab. One trial investigated two different dosages (500 mg and 1000 mg) of ofatumumab in addition to fludarabine with cyclophosphamide. Randomised Controlled Trials (RCTs) are needed to determine the clinical effects of novel anti-CD20 antibodies, such as ofatumumab or GA101, compared to rituximab. We are aware of 16 ongoing studies, including three trials comparing ofatumumab with or without additional chemotherapy versus no treatment. The findings of these trials will be included in an update of this review and could lead to different conclusions and may allow a judgement on general efficacy and safety of monoclonal anti-CD20 antibody in the treatment of CLL.