Chronic lymphocytic leukaemia (CLL) is the commonest of the adult leukaemias in the western world. The clinical course is highly variable with some patients surviving decades without requiring therapy while others have more aggressive disease requiring immediate treatment and associated with a shortened survival. Conventional treatment has relied on alkylating agents such as chlorambucil and, more recently, purine analogues such as a fludarabine. As single agents these therapies achieve good overall response (OR) rates of up to 80%, but complete remission (CR) rates of <10% for chlorambucil and 15–20% for single-agent fludarabine. Combinations of these drugs, such as fludarabine together with cyclophosphamide, have shown an increase in CR rates up to 40% with a prolongation of progression-free survival (PFS). However, none of the randomised studies has shown any survival advantage. This latter observation is largely due to the ability to successfully re-treat relapsed patients. However, patients who become refractory to alkylator- and fludarabine-based treatments have traditionally had a poor response (<20%) to salvage therapy and a greatly shortened survival (median 10 months).1 Over the past decade this bleak situation for patients has been improved by the introduction of novel agents, including monoclonal antibodies. Alemtuzumab is a fully humanised monoclonal antibody directed against the CD52 antigen, which is widely expressed on B and T lymphocytes. It is licensed for the treatment of fludarabine refractory CLL and has been shown to induce remissions in 33–53% of patients in this setting.2,3 The standard dosing schedule is 30mg given three times a week intravenously for 12 weeks.

Alemtuzumab Monotherapy

The first report of the use of alemtuzumab as front-line therapy was in 1996 by Osterborg et al.4 Nine patients received the standard treatment, although in four patients the antibody was administered subcutaneously, and therapy was continued in all patients up to 18 weeks. The OR rate was 89% with three patients achieving CR. This group expanded the patient cohort and reported a further 41 patients treated with subcutaneous alemtuzumab as first-line therapy for a total of 18 weeks.5 The OR rate was maintained at 81% in 38 evaluable patients. Nineteen per cent of patients achieved CR and 68% a partial remission (PR). At the time of publication in 2002 the time to treatment failure had not been reached at 18+ months. These results are comparable to those observed for single-agent fludarabine6 and superior to those for single-agent rituximab7 (see Table 1). Interestingly, complete responders required 18 weeks of therapy to achieve their best response, with significant improvement in bone marrow clearance between the 12- and 18-week evaluation points. Furthermore, patients with low-volume lymphadenopathy also achieved complete remissions in contrast to the observation in relapsed refractory patients that lymphadenopathy predicted a poor response to single-agent antibody treatment. Ten per cent of patients developed cytomegalovirus (CMV) reactivation that responded rapidly to treatment with intravenous ganciclovir. There was no increase in bacterial sepsis. Although transient injection site reactions were observed with the subcutaneous administration in the majority of patients, many of the initial reactions associated with intravenous administration such as rigours, nausea and hypertension were not seen. One in five patients had a transient grade 4 neutropaenia, but other side effects were rare.

At the American Society of Hematology (ASH) meeting in December 2006 the results of an international prospective, randomised, controlled trial (CAM307) comparing chlorambucil with intravenous alemtuzumab as front-line therapy for CLL were reported.8 Two hundred and ninety-seven patients were randomised to receive either alemtuzumab at the standard dose of 30mg three times per week for up to 12 weeks or chlorambucil 40mg/m2 once every 28 days up to 12 cycles. Response rates assessed by an independent panel showed OR of 83% for alemtuzumab compared with 55% for chlorambucil with CR rates of 24% and 2%, respectively (see Table 1). This translated into improved PFS for the patients who received alemtuzumab, with a 43% lower risk of progression or death. Notably, in patients who had the cytogenetic deletion of 17p (p53), there was a three-fold increase in OR with alemtuzumab (64%) compared with chlorambucil (26%). Statistically significant superior responses were also seen for patients with deletion 13q and deletion 11q treated with alemtuzumab compared with chlorambucil. Infections, including CMV, were reported in 76% of patients receiving alemtuzumab compared with 50% of chlorambucil patients while on study. Grade 3 and 4 lymphopaenia and neutropaenia were more common with alemtuzumab, but anaemia and thrombocytopenia were similar in the two treatment groups. Episodes of bacterial sepsis and febrile neutropaenia were comparable and the increase in infection in the alemtuzumab arm was almost entirely attributable to CMV reactivation. Although CMV reactivation occurred in half the patients, it was only symptomatic in 16%. This toxicity was therefore manageable by screening and pre-emptive treatment. Grade 3 or 4 infusion-related events were seen in 13% of patients receiving alemtuzumab and these were largely confined to the first few weeks of therapy. In contrast, adverse events increased over time in the chlorambucil arm where the median duration of treatment was twice as long. The toxicity profile of alemtuzumab in previously untreated patients appears to be much more acceptable with no increased treatment-related mortality compared with chlorambucil in the CAM307 randomised study. The Lundin study showed that efficacy for 18 weeks of subcutaneous alemtuzumab was equivalent to 12 weeks of intravenous therapy. Since subcutaneous administration results in fewer infusion-related side effects, this may be the preferable route.