The role of the monoclonal antibody alemtuzumab for treatment of people with chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is a cancer and accounts for 25% of all leukaemias. The disease is the most common cancer of the lymphatic system 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. Others are symptomatic at diagnosis or early thereafter and can experience infectious and autoimmune complications, leading to a reduced lifespan. Standard treatment includes chemotherapy with one or more agents. Nowadays monoclonal antibodies are added, especially alemtuzumab and rituximab. However, the impact of these agents remains unclear, as there were hints for increased overall survival, but also risk for severe infections in non-randomised trials. In this systematic review we summarised and analysed the evidence from randomised controlled trials (RCTs) on efficacy and safety of alemtuzumab in the treatment of CLL. We searched several important medical databases such as CENTRAL, MEDLINE and EMBASE and found five RCTs fulfilling our pre-defined inclusion criteria. We included trials that compared alemtuzumab with no further therapy or with anti-cancer therapy in newly-diagnosed or relapsed patients with CLL. In total, 845 patients were treated within the five trials.

Two trials assessed whether alemtuzumab is favourable compared with no further therapy. One trial reported data on overall survival, showing a significant advantage for those patients receiving additional alemtuzumab. The time without progression was statistically significantly improved in both trials with alemtuzumab, but more patients had an infection, especially a virus infection (cytomegalovirus infection). Because of severe infections, one trial was closed prematurely.

Two trials evaluated alemtuzumab versus rituximab. Neither study reported data on survival or survival without a relapse of the disease. We found no statistically significant differences for response to therapy or for deaths during study treatment. One trial was stopped early due to an increase in mortality in the alemtuzumab arm.

In the fifth trial alemtuzumab was compared with chemotherapy (chlorambucil). In this trial no difference in survival could be detected until the last publication of the study. Alemtuzumab statistically significantly improves the survival without a relapse, the time to anti-cancer treatment for relapse, and the response rate. Again, more infections occurred in the patients treated with alemtuzumab, especially infections with the cytomegalovirus that could lead to lung and retina infections.

In summary, the currently available evidence suggests an survival advantage for alemtuzumab compared with no further therapy, but an increased risk for infections in general and for cytomegalovirus.

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.

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Background: 

Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in Western countries. Standard treatment  includes mono- or poly-chemotherapies. Nowadays, monoclonal antibodies are added, especially alemtuzumab and rituximab. However, the impact of these agents remains unclear, as there are hints of an increased risk of severe infections.

Objectives: 

To assess alemtuzumab compared with no further therapy, or with other anti-leukaemic therapy in patients with CLL.

Search strategy: 

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 included RCTs comparing alemtuzumab with no further therapy or comparing alemtuzumab with anti-leukaemic therapy such as chemotherapy or monoclonal antibodies in patients with histologically-confirmed B-cell CLL. Both pretreated and chemotherapy-naive patients were included.

Data collection and analysis: 

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.

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