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INTRODUCTION

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Alemtuzumab (Campath-1H) is a humanised unconjugated monoclonal antibody directed against the CD52 antigen, which is located on lymphocytes at various stages of differentiation, monocytes, macrophages and eosinophils [1–3]. Hematopoietic stem cells, erythrocytes and platelets do not express CD52. The highest levels are expressed on cells from T-cell prolymphocytic leukaemia (T-PLL), followed by B-CLL, with the lower levels on normal` B cells [4]. High expression of CD52 is also present on cells from most B-cell lymphomas, including high-grade non-Hodgkin’s lymphoma (NHL) and mantle cell lymphoma (MCL) [3, 5], hairy cell leukaemia [6] and Waldenstrom’s macroglobulinaemia [7–10]. In contrast, lower or no expression is seen in multiple myeloma and plasma cell dyscrasias [10–14], and acute lymphoblastic leukaemia (ALL) [15–17]. Postulated mechanisms of action of alemtuzumab include complement-dependent cytolysis, antibody-dependent cellular cytotoxicity (ADCC) and direct induction of apoptosis [18–21].

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CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)

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Alemtuzumab has appreciable activity in fludarabine (F)-refractory CLL, including in those patients with p53 mutations and/or deletions [22–31]. However, responses were less likely to be observed in patients with advanced disease (Rai stage IV), significant adenopathy or poor performance status [23–25]. Therefore, in patients with advanced disease and/or significant adenopathy alemtuzumab may have greater efficacy when administered in combination with other cytoreductive agents or as consolidation therapy, in an attempt to eradicate residual disease.

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PREVIOUSLY TREATED PATIENTS

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Alemtuzumab-containing induction regimens
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Exposure of primary CLL cells to alemtuzumab in combination with rituximab or purine analogues (such as F and cladribine) resulted in a significantly higher degree of apoptosis than produced by either agent given alone [21]. This improved efficacy may be due to up-regulation of pro-apoptotic Bax expression or down-regulation of the anti-apoptotic proteins FLIP and bcl-2. Therefore, in an attempt to improve upon response rates and to prevent the development of resistance, alemtuzumab has been combined with purine analogues and/or monoclonal antibodies.

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Fludarabine and alemtuzumab (FCam)
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The combination of alemtuzumab (30 mg three times a week continuous; 12 doses every 4 weeks) with F (FCam) has shown to be efficacious in patients with refractory CLL [32] (Table 16.1). All 6 patients treated with this combination were refractory to single-agent alemtuzumab and 5 of 6 patients were refractory to single-agent F. The overall response (OR) rate was 83% (complete response (CR) 16%; partial response (PR) 67%) with 2 of 5 patients having no detectable marrow disease by high-sensitivity flow cytometry (MRD Flow). Two patients underwent stem cell harvest followed by autologous stem cell transplantation. Toxicity was acceptable with 1 patient requiring hospitalisation for pneumonia during neutropaenia and 2 patients requiring granulocyte colony-stimulating factor (G-CSF) for neutropaenia. There were no cases of cytomegalovirus (CMV) reactivation.

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