Update on Chronic Lymphocytic Leukemia: Overview of New Agents and Comparative Analysis

Treatment options for lymphoproliferative disorders, including chronic lymphocytic leukemia (CLL), increasingly are based upon molecular targets, taking advantage of the immense research output over the past several years elaborating genetic abnormalities, downstream signaling, cell-surface immunobiochemistry, and microenvironmental stimuli. The latter targets have been particularly useful for the treatment of multiple myeloma, transforming a previously uniformly, fatal disease to one of a more chronic and potentially curable disorder. Subsequently, new treatment approaches are less likely to be based on the more classic types of cytocidal therapy, which, although successful and essential for the more aggressive disorders that are immediately life-threatening, tend to be less so, with respect to quality of life, risk versus benefit ratio and overall curability for the indolent diseases. Because the majority of newer agents are not available to the clinicians practicing in the community, a number of treatment options developed over the past two decades are capable of significantly improving the quality of life of patients with advanced CLL. The initial clinical approach to the patient should be based on performance status, age, comorbidities, and increasingly on prognostic factors elucidated over the past three decades. Initially, both simple laboratory studies and easily measurable clinical manifestations were used to guide the clinician (lymphocyte count, anemia, thrombocytopenia, enlarging lymph nodes, splenomegaly, hepatomegaly), and clinical staging systems were developed. At present a cadre of biologic factors, including cytogenetic alterations, gene expression profiles with subsequent immunoglobulin abnormalities, and expression of CD38 and Zap-70, are now available and are standard decision-making criteria to treat a patient with CLL. An initial period of observation allows the clinician along with the patient to gather all the information necessary to make an informed treatment decision. Frequently, a "watch and wait" approach, which for CLL does not appear to harm the patient, is the most appropriate decision. Complications of CLL, such as autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura, will lead to treatment at least temporarily in those patients who might otherwise have not needed therapy. Frontline therapy will range from easily administrable single-agents to combination chemoimmunotherapy regimens. Experimental protocols, utilizing "post state of the art" treatments, are available in the form of research protocols at major treatment centers. At the present time, it is premature to recommend bone marrow ablative therapy as initial treatment unless the prognosis appears grave and the patient can withstand the rigors of this approach.