Future prospects for fludarabine-containing regimens in the treatment of hematological cancers

Developments in the understanding of disease biology and in therapeutic approaches during the last decade have failed to alter the natural history of many human hematological malignancies, including chronic lymphocytic leukemia (CLL). Despite better appreciation of the molecular foundations and phenotypic characteristics of these cancers, improvements to disease classification and prognosis, and the discovery of more effective cytotoxic and biological agents, these disorders remain largely incurable. The development of a new class of cytotoxic agents in the 1980 s, namely the purine analogs, heralded a period of renewed optimism in the treatment of indolent lymphoid leukemias and lymphomas. More recently, monoclonal antibodies that selectively target cell-surface proteins, and agents that target cell-cycle or apoptotic pathways, have been developed and their use alone or in combination promise to have a major impact on the treatment of these conditions. Of these, the anti-CD52 antibody alemtuzumab and the anti-CD20 antibody rituximab have demonstrated the most potential for the treatment of CLL. Further, because of their different mode of action in comparison to conventional cytotoxic agents, combination regimens involving fludarabine and these antibodies are showing particular promise in early trials. The encouraging findings with these combination therapies are moving the intent of therapy from palliation towards cure. This paper reviews the therapeutic application of present and future fludarabine-containing approaches. The strategies that are discussed include fludarabine given with alemtuzumab, rituximab, or other monoclonal antibodies, and the potential benefits of combining fludarabine with more experimental agents such as antisense oligonucleotides, immunotoxins, or radioimmunoconjugates. The successful application of fludarabine plus alemtuzumab, or fludarabine in combination with other cytotoxic agents, as preparative regimens for stem cell transplantation techniques is also covered.