We searched CENTRAL and MEDLINE (from January 1985 to November 2011), and EMBASE (from 1990 to 2009) as well as conference proceedings for randomised controlled trials (RCTs). Two review authors (KB, NS) independently screened search results.
SELECTION CRITERIA: We used hazard ratios (HR) as an effect measure for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) for response rates, treatment-related mortality (TRM) and adverse events. Two review authors independently extracted data and assessed the quality of trials.
MAIN RESULTS: Our search strategies led to 1542 potentially relevant references. Of these, we included five RCTs involving 845 patients. Overall, we judged the quality of the five trials as moderate. All trials were reported as 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. Because of the small number of studies in each analysis (two), the quantification of heterogeneity was not reliable.Two trials (N = 356) assessed the efficacy of
alemtuzumab compared with no further
therapy. One trial (N = 335), reported a statistically significant OS advantage for all patients receiving
alemtuzumab (HR 0.65 (95% confidence interval (CI) 0.45 to 0.94; P = 0.021). However, no improvement was seen for the subgroup of patients in Rai stage I or II (HR 1.07; 95% CI 0.62 to 1.84; P = 0.82). In both trials, the complete response rate (CRR) (RR 2.61; 95% CI 1.26 to 5.42; P = 0.01) and PFS (HR 0.58; 95% CI 0.44 to 0.76; P < 0.0001) were statistically significantly increased under
therapy with
alemtuzumab. The potential heterogeneity seen in the forest plot could be due to the different study designs: One trial evaluated
alemtuzumab additional to
fludarabine as relapse
therapy; the other trial examined
alemtuzumab compared with no further
therapy for consolidation after first remission.There was no statistically significant difference for TRM between both arms (RR 0.57; 95% CI 0.17 to 1.90; P = 0.36). A statistically significant higher rate of CMV reactivation (RR 10.52; 95% CI 1.42 to 77.68; P = 0.02) and
infections (RR 1.32; 95% CI 1.01 to 1.74; P = 0.04) occurred in patients receiving
alemtuzumab. Seven severe
infections (64%) in the
alemtuzumab arm in the GCLLSG CLL4B study led to premature closure.Two trials (N = 177), evaluated
alemtuzumab versus
rituximab. Neither study reported OS or PFS. We could not detect a statistically significant difference for CRR (RR 0.85; 95% CI 0.67 to 1.08; P = 0.18) or TRM (RR 3.20; 95% CI 0.66 to 15.50; P = 0.15) between both arms. However, the CLL2007FMP trial was stopped early due to an increase in mortality in the
alemtuzumab arm. More serious adverse events occurred in this arm (43% versus 22% (
rituximab), P = 0.006).One trial (N = 297), assessed the efficacy of
alemtuzumab compared with
chemotherapy (
chlorambucil). For this trial, no HR is reported for OS. Median survival has not yet been reached, 84% of patients were alive in each arm at the data cut-off or at the last follow-up date (24.6 months). The TRM between arms shows no statistical significant difference (0.6% versus 2.0%; P = 0.34).
Alemtuzumab statistically significantly improves PFS (HR 0.58; 95% CI 0.43 to 0.77; P = 0.0001), time to next treatment (23.3 compared with 14.7 months; P = 0.0001), ORR (83.2% versus 55.4%; P < 0.0001), CRR (24.2% versus 2.0%; P < 0.0001), and
minimal residual disease rate (7.4% versus 0%; P = 0.0008) compared with
chlorambucil. Statistically, significantly more asymptomatic (51.7% versus 7.4%) and symptomatic cytomegalovirus (CMV)
infections (15.4% versus 0%) occurred in the patients treated with
alemtuzumab.
AUTHORS' CONCLUSIONS: In summary, the currently available evidence suggests an OS, CRR and PFS benefit for
alemtuzumab compared with no further
therapy, but an increased risk for
infections in general, CMV
infections and CMV reactivations. The role of
alemtuzumab versus
rituximab still remains unclear, further trials with longer follow-up and overall survival as primary endpoint are needed to evaluate the effects of both agents compared with each other.
Alemtuzumab compared with
chlorambucil seems to be favourable in terms of PFS, but a longer follow-up period and trials with overall survival as primary endpoint are needed to determine whether this effect will translate into a survival advantage.