AFTER FLUDARABINE HAS FAILED, WHAT NEXT?
The majority of patients with chronic lymphocytic leukemia (CLL) who achieve remission following fludarabine treatment are known to suffer a relapse after a median of 20–30 months . CLL often becomes refractory to repeated courses of treatment with the same drug. For patients who become refractory or who demonstrate a primary resistance to fludarabine, the prognosis is generally poor. Resistance to the purine analogues is emerging as a major problem in the management of patients with CLL. In addition to fludarabine or any other purine analogues, many of these patients have also already been exposed to (and may be resistant to) alkylating agents. The most effective salvage regimens are considered to be combinations of purine analogues and cyclophosphamide . The use of alternative nucleoside analogues, such as cladribine or pentostatin, has been studied in the setting of fludarabine-refractory CLL. Response rates with these drugs have been reported to be modest (32%) with accompanying toxicities of grade 3–5 neutropaenia (75%), thrombocytopaenia (68%) and infections (43%) . Alternative therapies are needed for such patients, preferably using agents whose mechanisms of action do not overlap with those of prior chemotherapies. The use of monoclonal antibodies offers such an approach. Alemtuzumab is a humanised monoclonal antibody directed against CD52 that has been approved for the treatment of CLL that is refractory to fludarabine. This article will review the development and role of alemtuzumab for the treatment of relapsed/refractory CLL.
EARLY TRIALS OF CAMPATH-1H IN LYMPHOPROLIFERATIVE DISEASES
Alemtuzumab, also called Campath-1H, was initially investigated in three multi-centre Phase I trials in non-Hodgkin lymphoma (NHL) at doses ranging up to 240 mg per week. Prophylactic pre-medications were not allowed during these trials and infusion related toxicities (rigors, fever, hypotension, rash) were common. Following these early NHL trials, two multi-centre Phase II trials (Protocol 125-K32–005 and 125-K32–009) were conducted in Europe and the USA, respectively. These trials treated a total of 149 patients with a variety of lymphoproliferative diseases.
Osterborg and colleagues  published a report on a subset of 29 of the patients treated on study 125-K32–005, who had CLL and who had relapsed after an initial response to chemotherapy (n = 8) or who were refractory to chemotherapy (n = 21). Of interest is that only 3 of these 29 patients had previously been treated with fludarabine. This was due primarily to the fact that fludarabine was not available in Europe until 1994. All patients were treated with Campath-1H at a dose of 30 mg intravenously over 2 h three times per week (TIW) for a maximum of 12 weeks.
Osterborg and co-workers reported that 3 of 8 patients (38%) with relapsed and 9 of 21 (43%) with refractory disease were able to achieve a response using Campath-1H. It was also shown that CLL cells were rapidly eliminated from blood in ...