Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic
lymphocytic leukaemia.
Author(s): Bauer K, Rancea M, Roloff V, Elter T, Hallek M, Engert A, Skoetz N.
Affiliation(s): Cochrane Haematological Malignancies Group, Department I of Internal Medicine,
University Hospital of Cologne, Cologne,Germany. kathrin.bauer@uk-koeln.de
Publication date & source: 2012, Cochrane Database Syst Rev. , 11:CD008079
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.
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.
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