Hematology 2002 193 Chronic Lymphocytic Leukemia Neil E. Kay, Terry J. Hamblin, Diane F. Jelinek, Gordon W. Dewald, John C. Byrd, Sherif Farag, Margaret Lucas, and Thomas Lin This update of early stage B-cell chronic lympho- cytic leukemia (B-CLL) embraces current informa- tion on the diagnosis, biology, and intervention required to more fully develop algorithms for management of this disease. Emphasis on early stage is based on the rapid advancement in our understanding of the disease parameters and our increasing ability to predict for a given early stage patient whether there is a need for more aggressive management. In Section I, Dr. Terry Hamblin addresses the nature of the disease, accurate diagnostic proce- dures, evidence for an early “preclinical” phase, the use of newer prognostic features to distinguish who will be likely to progress or not, and whether it is best to watch or treat early stage disease. In Section II, Dr. Neil Kay and colleagues address the biologic aspects of the disease and how they may relate to disease progression. Review of the newer insights into gene expression, recurring genetic defects, role of cytokines/ autocrine pathways, and the interaction of the CLL B cell with the microenvironment are emphasized. The relationship of these events to both trigger disease progression and as opportunities for future therapeutic intervention even in early stage disease is also considered. In Section III, Dr. John Byrd and colleagues review the historical and now current approaches to management of the previously untreated pro- gressive B-CLL patient. They discuss what decision tree could be used in the initial decision to treat a given patient. The use of single agents versus newer combination approaches such as chemoimmunotherapy are discussed here. In addition, the place of marrow transplant and some of the newer antibodies available for treatment of B- CLL are considered. Finally, a challenge to utilize our growing knowledge of the biology of B-CLL in the early stage B-CLL is proffered. I. THE NATURE AND NATURAL HISTORY OF EARLY-STAGE B-CLL Terry J. Hamblin, MD* Some people think that we are getting better at treating B-cell chronic lymphocytic leukemia (B-CLL) and pro- duce survival curves that seem to show an improved sur- vival for more recently diagnosed cases. At least part of that improvement is artificial, caused by earlier diagno- sis or even the recognition as B-CLL of conditions that would not previously have crossed the threshold of di- agnosis. As we diagnose B-CLL on lower and lower lym- phocyte counts, we need to be doubly sure that the diag- nosis is correct. It may be that a similar distinction needs to be made between B-CLL and “monoclonal lympho- cytosis of undetermined origin” as that between myeloma and monoclonal gammopathies of undetermined signifi- cance (MGUS). As the proportion of cases diagnosed in early stage increases it becomes vital for the practicing physician to know who is likely to require therapy. It may be that the “watchful waiting” paradigm for early stage B-CLL needs to be challenged. Diagnosis of True B-CLL As time has passed we have lowered the threshold for diagnosing B-CLL. At one time a lymphocyte count of 10,000/mm 3 was required 1 but today we are happy with 5000/mm 3 . 2 This reflects a greater certainty that we can distinguish B-CLL from other types of lymphocytosis, a certainty provided by the availability of immunologic markers. One consequence has been to include within the diagnosis more patients whose B-CLL is utterly benign. This lowered guard demands a sterner conformity to the correct profile of lymphocyte markers in order to define B-CLL and exclude other types of exfoliating lym- phoma in which a mild lymphocytosis is common (Table 1). The characteristic B-CLL pattern (CD5 and CD23 * Royal Bournemouth Hospital, Castle Lane East, Bournemouth BH7 7DW, Dorset, United Kingdom