title: Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia.
abstract: BACKGROUND
  Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in western countries. Standard treatments include mono- or polychemotherapies, usually combined with monoclonal antibodies such as rituximab or alemtuzumab. However, the impact of these agents remains unclear, as there are hints for increased risk of severe infections.
  
  
  OBJECTIVE
  The objectives of this review are to provide an evidence-based answer regarding the clinical benefits and harms of monoclonal anti-CD20 antibodies (such as rituximab, ofatumumab, GA101) compared to no further therapy or to other anti-leukaemic therapies in patients with CLL, irrespective of disease status.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 12, 2011), MEDLINE (from January 1990 to 4 January 2012), and EMBASE (from 1990 to 20 March 2009) as well as conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association and European Society of Medical Oncology) for randomised controlled trials (RCTs).
  
  
  METHODS
  We included RCTs examining monoclonal anti-CD20 antibodies compared to no further therapy or to anti-leukaemic therapy such as chemotherapy or monoclonal antibodies in patients with newly diagnosed or relapsed CLL.
  
  
  METHODS
  We used hazard ratios (HR) as effect measures for overall survival (OS), progression-free survival (PFS) and time to next treatment, and risk ratios (RR) for response rates, treatment-related mortality (TRM) and adverse events (AEs). Two review authors independently extracted data and assessed quality of trials.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cochrane Haematological Malignancies Group, Department I of Internal Medicine, University Hospital of Cologne, Cologne,Germany. kathrin.bauer@uk-koeln.de
authors.forename: Kathrin
authors.initials: K
authors.lastname: Bauer
authors.forename: Michaela
authors.initials: M
authors.lastname: Rancea
authors.forename: Verena
authors.initials: V
authors.lastname: Roloff
authors.forename: Thomas
authors.initials: T
authors.lastname: Elter
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
authors.forename: Nicole
authors.initials: N
authors.lastname: Skoetz
mesh_terms: D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D000069283:Rituximab; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000074323:Alemtuzumab; D000069283:Rituximab; D014740:Vidarabine; C527517:ofatumumab; C024352:fludarabine