Cochrane Database of Systematic Reviews
`
`Rituximab, ofatumumab and other monoclonal anti-CD20
`antibodies for chronic lymphocytic leukaemia (Review)
`
`Bauer K, Rancea M, Roloff V, Elter T, Hallek M, Engert A, Skoetz N
`
`Bauer K, Rancea M, Roloff V, Elter T, Hallek M, Engert A, Skoetz N.
`
`Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia.
`
`Cochrane Database of Systematic Reviews 2012, Issue 11. Art. No.: CD008079.
`
`DOI: 10.1002/14651858.CD008079.pub2.
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`www.cochranelibrary.com
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`

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`T A B L E O F C O N T E N T S
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`HEADER .
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`ABSTRACT .
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`PLAIN LANGUAGE SUMMARY
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`SUMMARY OF FINDINGS FOR THE MAIN COMPARISON .
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`BACKGROUND .
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`OBJECTIVES
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`METHODS .
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`RESULTS .
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`Figure 1.
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`Figure 2.
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`Figure 3.
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`Figure 4.
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`ADDITIONAL SUMMARY OF FINDINGS
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`AUTHORS’ CONCLUSIONS
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`ACKNOWLEDGEMENTS
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`REFERENCES .
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`CHARACTERISTICS OF STUDIES
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`DATA AND ANALYSES .
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`Analysis 1.1. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 1 OS - overall analysis.
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`Analysis 1.2. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 2 OS - subgrouped by different anti-CD20 antibody treatment
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`regimens.
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`Analysis 1.3. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 3 OS - subgrouped by different treatment regimens.
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`Analysis 1.4. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 4 PFS - overall analysis.
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`Analysis 1.5. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 5 PFS - subgrouped by age. .
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`Analysis 1.6. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
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`Analysis 1.7. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 7 PFS - subgrouped by prognostic factor.
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`Analysis 1.8. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 8 PFS - subgrouped by different anti-CD20 antibody treatment
`regimens.
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`Analysis 1.9. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 9 PFS - subgrouped by different treatment regimens.
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`Analysis 1.10. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 10 Time to next treatment - overall analysis.
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`Analysis 1.11. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 11 Time to next treatment - subgrouped by different anti-CD20 antibody
`treatment regimens.
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`Analysis 1.12. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
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`Analysis 1.13. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 13 ORR - subgrouped by age.
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`Analysis 1.14. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 14 ORR - subgrouped by stage.
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`1
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`21
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`Analysis 1.15. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 15 ORR - subgrouped by prognostic factor.
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`Analysis 1.16. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 16 ORR - subgrouped by different anti-CD20 antibody treatment
`regimens.
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`Analysis 1.17. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 17 ORR - subgrouped by different treatment regimens.
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`Analysis 1.18. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 18 CRR - overall analysis.
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`Analysis 1.19. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 19 CRR - subgrouped by different anti-CD20 antibody treatment
`regimens.
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`Analysis 1.20. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 20 CRR - subgrouped by different treatment regimens.
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`Analysis 1.21. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 21 MRD negativity - overall analysis.
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`Analysis 1.22. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 22 MRD negativity - subgrouped by different treatment regimens.
`Analysis 1.23. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 23 Treatment-related mortality - overall analysis.
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`Analysis 1.24. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 24 Treatment-related mortality - subgrouped by different anti-CD20
`antibody treatment regimens.
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`Analysis 1.25. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 25 Treatment-related mortality - subgrouped by different treatment
`regimens.
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`Analysis 1.26. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 26 SAEs - overall analysis.
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`Analysis 1.27. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 27 SAEs - subgrouped by different treatment regimens.
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`Analysis 1.28. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 28 Grade 3/4 AEs - overall analysis.
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`Analysis 1.29. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 29 Grade 3/4 AEs - subgrouped by different anti-CD20 antibody
`treatment regimens.
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`Analysis 1.30. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 30 Grade 3/4 AEs - subgrouped by different treatment regimens.
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`Analysis 1.31. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 31 Anaemia grade 3/4 - overall analysis.
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`Analysis 1.32. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 32 Anaemia grade 3/4 - subgrouped by different anti-CD20 antibody
`treatment regimens.
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`Analysis 1.33. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 33 Neutropenia grade 3/4 - overall analysis.
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`Analysis 1.34. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 34 Neutropenia grade 3/4 - subgrouped by different anti-CD20 antibody
`treatment regimens.
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`Analysis 1.35. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 35 Neutropenia grade 3/4 - subgrouped by different treatment
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`regimens.
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`Analysis 1.36. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 36 Thrombocytopenia grade 3/4 - overall analysis.
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`85
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`86
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`87
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`88
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`89
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`90
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`91
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`Analysis 1.37. Comparison 1 Anti-leukaemic therapy plus anti-CD20 versus anti-leukaemic therapy alone (anti-leukaemic
`therapy identical in both groups), Outcome 37 Thrombocytopenia grade 3/4 - subgrouped by different anti-CD20
`antibody treatment regimens.
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`Analysis 2.1. Comparison 2 Anti-leukaemic therapy with anti-CD20 antibody versus anti-leukaemic therapy without anti-
`CD20 antibody (anti-leukaemic therapy not identical in both groups), Outcome 1 ORR - overall analysis.
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`Analysis 2.2. Comparison 2 Anti-leukaemic therapy with anti-CD20 antibody versus anti-leukaemic therapy without anti-
`CD20 antibody (anti-leukaemic therapy not identical in both groups), Outcome 2 ORR - subgrouped by different
`anti-CD20 antibody treatment regimens.
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`Analysis 2.3. Comparison 2 Anti-leukaemic therapy with anti-CD20 antibody versus anti-leukaemic therapy without anti-
`CD20 antibody (anti-leukaemic therapy not identical in both groups), Outcome 3 CRR - overall analysis.
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`Analysis 2.4. Comparison 2 Anti-leukaemic therapy with anti-CD20 antibody versus anti-leukaemic therapy without anti-
`CD20 antibody (anti-leukaemic therapy not identical in both groups), Outcome 4 CRR - subgrouped by different
`anti-CD20 antibody treatment regimens.
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`Analysis 2.5. Comparison 2 Anti-leukaemic therapy with anti-CD20 antibody versus anti-leukaemic therapy without anti-
`CD20 antibody (anti-leukaemic therapy not identical in both groups), Outcome 5 Treatment-related mortality.
`Analysis 2.6. Comparison 2 Anti-leukaemic therapy with anti-CD20 antibody versus anti-leukaemic therapy without anti-
`CD20 antibody (anti-leukaemic therapy not identical in both groups), Outcome 6 Treatment-related mortality -
`subgrouped by different anti-CD20 antibody treatment regimens.
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`ADDITIONAL TABLES .
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`APPENDICES
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`CONTRIBUTIONS OF AUTHORS
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`DECLARATIONS OF INTEREST .
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`SOURCES OF SUPPORT .
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`INDEX TERMS
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`

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`[Intervention Review]
`
`Rituximab, ofatumumab and other monoclonal anti-CD20
`antibodies for chronic lymphocytic leukaemia
`
`Kathrin Bauer1, Michaela Rancea1, Verena Roloff2, Thomas Elter3, Michael Hallek3, Andreas Engert1, Nicole Skoetz1
`
`1Cochrane Haematological Malignancies Group, Department I of Internal Medicine, University Hospital of Cologne, Cologne,
`Germany. 2MRC Biostatistics Unit, Cambridge, UK. 3Department I of Internal Medicine, Center of Integrated Oncology Köln Bonn,
`University Hospital of Cologne, Cologne, Germany
`
`Contact address: Kathrin Bauer, Cochrane Haematological Malignancies Group, Department I of Internal Medicine, University
`Hospital of Cologne, Kerpener Str. 62, Cologne, 50924, Germany. kathrin.bauer@uk-koeln.de.
`
`Editorial group: Cochrane Haematological Malignancies Group.
`Publication status and date: New, published in Issue 11, 2012.
`
`Citation: Bauer K, Rancea M, Roloff V, Elter T, Hallek M, Engert A, Skoetz N. Rituximab, ofatumumab and other monoclonal anti-
`CD20 antibodies for chronic lymphocytic leukaemia. Cochrane Database of Systematic Reviews 2012, Issue 11. Art. No.: CD008079.
`DOI: 10.1002/14651858.CD008079.pub2.
`
`Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`Background
`
`A B S T R A C T
`
`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.
`
`Objectives
`
`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.
`
`Search 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).
`
`Selection criteria
`
`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.
`
`Data collection and analysis
`
`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.
`
`

`

`Main 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).
`
`Authors’ 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.
`
`P L A I N L A N G U A G E S U M M A R Y
`
`The role of the monoclonal anti-CD20 antibodies for treatment of patients with chronic lymphocytic leukaemia
`
`Chronic lymphocytic leukaemia (CLL) is a malignant disease and accounts for 25% of all leukaemias. The disease is the most common
`lymphoid malignancy in western countries, and is characterised by a highly variable clinical course and prognosis. Some patients may
`have minimal or no symptoms for many years with a normal life expectancy, without requiring treatment. Other people are symptomatic
`at diagnosis or soon thereafter and can experience infectious and autoimmune complications, leading to a reduced lifespan. Standard
`treatment includes chemotherapy with one or more agents. Presently monoclonal antibodies are added, especially alemtuzumab and
`rituximab. However, the impact of these agents remains unclear, as there have been hints for increased overall survival, but also for
`an increased risk of severe infections in non-randomised trials. In this systematic review we summarised and analysed the evidence
`from randomised controlled trials on efficacy and safety of monoclonal anti-CD20 antibodies (such as rituximab and ofatumumab) in
`the treatment of CLL. We searched medical databases, such as EMBASE, MEDLINE and CENTRAL, and found seven randomised
`controlled trials fulfilling our inclusion criteria. Included trials compared anti-CD20 antibodies, particularly rituximab, to no further
`therapy or compared to anti-cancer therapy in CLL, irrespective of whether the patients were newly diagnosed or relapsed patients.
`Only five of the seven identified trials could be included in one of the two performed meta-analyses.
`
`

`

`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.
`
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`S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
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`

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`B A C K G R O U N D
`
`Description of the condition
`
`Chronic lymphocytic leukaemia (CLL) accounts for 25% of all
`leukaemias and is the most common lymphoid malignancy in
`western countries (Chiorazzi 2005). The disease is characterised
`by a highly variable clinical course and prognosis. Some patients
`may have no or minimal symptoms for many years with a nor-
`mal life expectancy, without requiring treatment. Other people
`are symptomatic at diagnosis or soon thereafter. They experience
`infectious or autoimmune complications and may die of drug-
`resistant disease long before reaching the normal life expectancy.
`The extent of the disease is reflected by enlargement of lymph
`nodes, liver and spleen; raised lymphocyte count in blood and the
`degree of impairment of normal haematopoiesis. These variables
`can be used to define the different stages of the disease. The two
`most widely used staging systems, proposed by Rai et al. and Bi-
`net and co-workers, discriminate between early (Rai 0; Binet A),
`intermediate (Rai I, II; Binet B) and advanced (Rai III/IV; Binet
`C) disease with substantial differences in clinical course and long-
`term survival. However, these clinical staging systems are often
`of limited prognostic value at the time of diagnosis, when most
`patients are in the early stages of the disease (Binet 1981; Hallek
`2008; Rai 1975). Other prognostic factors have been identified
`that distinguish better between more and less active forms of the
`disease. In particular, patients with a 17p-deletion have an aggres-
`sive form of the disease with a median survival time of less than
`one year (Dohner 2000).
`Most patients with CLL are treated when they have an advanced
`stage of the disease with haematopoietic insufficiency or symp-
`toms. Standard treatment options include monotherapy with chlo-
`rambucil (Clb), bendamustine, or purine analogues (fludarabine,
`pentostatine); polychemotherapies with cyclophosphamide, dox-
`orubicin, vincristine, and prednisolone (CHOP); cyclophospha-
`mide, vincristine, and prednisolone (COP); or fludarabine with
`cyclophosphamide (FluC). During the last few years, antibody
`monotherapy and the addition of monoclonal antibodies to che-
`motherapy have moved into the focus of interest.
`While fludarabine leads to higher response rates and longer pro-
`gression-free survival (PFS) compared to other monotherapies,
`CHOP and COP do not improve overall survival (OS), as shown
`in a Cochrane Review (Steurer 2006). The same is true for the
`combination of FluC when compared to fludarabine alone in ran-
`domised trials (Eichhorst 2006; Flinn 2007). So far, there are no
`randomised data showing an impact on OS for any of the var-
`ious treatment options. However, patients with CLL are at in-
`creased risk of infection and infectious complications, including
`death. This may be related to the disease itself, the consequences
`of therapy, or both. Indeed, infections are more pronounced with
`treatments leading to longer PFS (e.g. fludarabine alone or FluC)
`(Hallek 2008).
`
`Monoclonal antibodies against surface proteins expressed in CLL
`cells may allow a more targeted therapy of CLL. Examples are alem-
`tuzumab (directed against CD52), rituximab (anti-CD20), ofatu-
`mumab (anti-CD20) and lumiliximab (anti-CD23). Both alem-
`tuzumab and rituximab have shown improved PFS compared to
`treatment without the antibodies (Hallek 2010; Hillmen 2007b).
`In a retrospective analysis comparing FluC with FluC-rituximab
`(FluC-R), Wierda et al. showed a possible benefit for OS (Wierda
`2006).
`This review is part of a series of reviews examining the role of
`monoclonal antibodies in CLL (Skoetz 2012).
`
`Description of the intervention
`
`ritux-
`three monoclonal anti-CD20 antibodies,
`Currently,
`imab, ofatumumab and GA101 (synonym: obinutuzumab,
`RO5072759), are being investigated in clinical trials.
`The most evaluated anti-CD20 antibody, rituximab, showed ef-
`ficacy in patients with CLL, both as a single agent (Huhn 2001)
`and in combination with chemotherapies (Schulz 2002). The early
`studies demonstrated that rituximab alone in relapsed CLL had
`only a moderate activity (seven of 28 patients showed a partial re-
`mission) (Huhn 2001). The effects of rituximab have been shown
`to be improved when it is given combined with chemotherapy (27
`of 31 fludarabine- and anthracycline-naive patients achieved com-
`plete remission or partial remission) (Schulz 2002). This led to
`further studies evaluating rituximab in combination with a variety
`of chemotherapeutic regimens (CALBG 9712; CLL2007FMP;
`GCLLSG CLL 8; Iannitto 2011; Kay 2010). The clinical effect
`of rituximab treatment is limited by the often occurring resistance
`or reduced response to re-treatment with rituximab. Therefore,
`novel anti-CD20 antibodies are in development, including ofatu-
`mumab and GA101 (Czuczman 2010).
`
`How the intervention might work
`
`The CD20 antigen is present on more than 90% of B-cell lym-
`phoma cells and is neither shed nor internalised after antibody
`binding (Tedder 1994). These characteristics make it an effective
`target for immunotherapeutic removal of malignant B cells by
`monoclonal anti-CD20 antibodies. Preclinical studies of mono-
`clonal anti-CD20 antibodies have shown that several mechanisms
`are involved in providing therapeutic efficacy, including comple-
`ment-dependent cytotoxicity, antibody-dependent cellular cyto-
`toxicity, and the induction of cell growth arrest and apoptosis (Li
`2008; Li 2009; Teeling 2004; Teeling 2006).
`Rituximab is less active in CLL than in follicular lymphoma unless
`very high doses are used, because CLL cells have a lower density of
`CD20 than most other B-cell malignancies (Huhn 2001; Jacobs
`2005). In non-randomised comparisons the combination of ritux-
`imab with chemotherapy showed promising results (Byrd 2003b;
`
`

`

`Schulz 2002). Similar observations were made for the combina-
`tion of rituximab with FluC (FluC-R) (Byrd 2005; Keating 2005;
`Wierda 2005), bendamustine (Robinson 2008), or mitoxantrone
`(FluCM) (Bosch 2008). In a historical comparison of FluC-R ver-
`sus FluC, FluCM, or fludarabine monotherapy, in both first-line
`and relapse therapy, survival benefits for rituximab combinations
`have been reported (Tam 2008; Wierda 2006). However, increased
`adverse haematological effects caused by rituximab, particularly in
`terms of neutropenia and leukocytopenia have also been observed
`(Hallek 2010; Robak 2008a).
`Ofatumumab,
`the
`second-generation anti-CD20 antibody,
`showed higher in vitro efficacy on CLL cells than rituximab
`(Teeling 2004). A Phase I/II clinical trial has been completed in
`patients with relapsed or refractory CLL, showing promising clin-
`ical efficacy in this difficult-to-treat patient population (Coiffier
`2008).
`
`Why it is important to do this review
`
`Based on the published trials, targeting CD20 with monoclonal
`antibodies in addition to chemotherapy may be an effective treat-
`ment and well-tolerated option for CLL patients (Coiffier 2008;
`Hallek 2010; Robak 2008a).
`So far, there is no systematic review assessing the efficacy and safety
`of monoclonal anti-CD20 antibodies in the treatment of CLL.
`This Cochrane review will identify and summarise the available
`evidence regarding the impact of these monoclonal anti-CD20
`antibodies on the treatment of patients with CLL. It will also
`examine differences of treatment effectiveness caused by different
`types of monoclonal anti-CD20 antibodies.
`
`Types of participants
`
`We included trials on patients with histologically confirmed B-
`cell CLL. Both pre-treated and chemotherapy-naive patients were
`included. If trial populations would have been mixed (i.e. patient
`groups with different haematological malignancies), data from the
`CLL subgroups would have been used. If subgroup data for CLL
`patients would not have been provided (after contacting the au-
`thors of the trial), the trial would have been excluded if less than
`80% of patients had CLL.
`
`Types of interventions
`
`We included all randomised trials of anti-CD20 antibody given
`alone or in combination with chemotherapy as primary treatment
`or maintenance treatment in untreated as well as refractory or
`relapsed patients.
`We considered different treatment approaches f