New directions in the diagnosis and treatment of chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia of adults in Western countries. It is a systemic haematological malignancy that originates from B cells (B-CLL) in 95% of patients, while only a minority are derived through malignant transformation of T cells (T-CLL). Although B-CLL is classified as a non-Hodgkin's lymphoma, several issues make this leukaemia a unique entity among malignant lymphoma. Inhibition of the programmed cell death (apoptosis) and upregulation of the anti-apoptotic protein Bcl-2 are key elements of the pathophysiology of B-CLL cells and define clinical prognosis. Furthermore, B-CLL cells are arrested in G0/G1 phase of the cell cycle. Dysfunctional apoptosis and cell cycle are the main reasons for the clinical enigma, that CLL can not yet be cured with conventional chemotherapy. However, the molecular pathways that are responsible for this characteristic feature of the B-CLL cells still need further definition. Recently, considerable progress has been made in defining the molecular basis for the pathogenesis of CLL and in finding new therapeutic options. Recent studies indicate that B-CLL cells may be delineated from two main groups of normal B cells, i.e. pre- and postgerminal B cells, and can be distinguished through lack of or existence of mutations of the V heavy chain gene. This differential mutational status of the Ig V gene has significant impact on patient survival. Modern cytogenetic methods such as fluorescence in situ hybridisation (FISH) have opened a new era in the molecular analysis of CLL cells. Determining the chromosomal aberration of the leukaemic cells has become a standard scientific programme for each clinical trial. The cytogenetic profile may soon help to define a clinical risk profile and guide the various treatment strategies. Further progress has been made in the therapy of CLL. Purine analogues such as fludarabine were able to induce significant improvement in remission rates; however, they did not lead to improved survival. Chimera of murine or rat monoclonal antibodies and human antibodies were designed to treat CLL. Antibodies such as rituximab and alemtuzumab (Campath-1H), directed against CD20 and CD52, respectively, appear as attractive alternatives to conventional chemotherapy because of their lack of significant myelotoxicity. Studies using myeloablative chemotherapy followed by autologous or allogeneic stem cell transplantation were initiated with the hope of finding a cure for CLL. In contrast to autologous stem cell transplantation, allogeneic transplants appear to display a plateau of relapse rates. In conclusion, for many years CLL was considered as a chronic haematological malignancy that required only few diagnostic tools and for whom no hope of cure could be offered. The current review focuses on recent improvements in diagnosis and treatment of CLL that have opened a new era in the management of patients with this systemic malignancy.