Classical and new prognostic factors in chronic lymphocytic leukemia: where to now?

Abstract

Chronic lymphocytic leukemia (CLL) has a variable clinical course. Although the median survival of patients with this form of leukemia is around ten years, in individual patients the prognosis is extremely variable, ranging from a very short to a normal lifespan. The clinical staging systems independently developed by Rai et al. and Binet et al. in the early 1980s, based on easily obtainable biological and clinical parameters, are extremely useful for assessing prognosis in patients with CLL. These staging systems not only facilitate the treatment of patients according to individual prognosis, but also make it possible to conduct and to compare trials based on the risk of the disease. Although easy to apply and reproducible, staging systems are not devoid of limitations. For example, the mechanisms accounting for cytopenias (ie, bone marrow in®ltration, hypersplenism, autoimmune basis) are not taken into consideration. As a result, patients are classi®ed as being in advanced stage, independently of the origin of the anemia or thrombocytopenia. Yet there is some indication that the mechanism of the cytopenia is also a factor in prognosis. Most important, perhaps, is the prognostic heterogeneity within each of the clinical stages. Thus, staging systems do not allow identi®cation of individuals in early stage (40 ± 60% of all patients) who are likely to progress and those in whom the disease will remain stable for many years. This is important since it is possible ± but not yet proven ± that patients in early stage who are likely to progress, could bene®t from being treated immediately after diagnosis, before progression occurs. Conversely, some patients presenting in advanced stage run an indolent course and may not require therapy for long periods of time; staging systems do not identify these patients either. Since the introduction of the clinical staging systems there has been a continuous e€ort to identify new prognostic factors in CLL, as evidenced by the many articles on that issue. Thus, in a MEDLINE search, 119 articles dealing with `Prognostic factors in CLL' can be identi®ed. The reader interested in a comprehensive review of prognostic parameters in CLL is referred to some of the many reviews recently published on this subject. With such a plethora of information, how does one separate the wheat (ie, the relevant prognostic factors) from the cha€? In this regard, it is important to keep in mind the conditions that prognostic factors should ful®ll, the most important of which are shown in Table 1. Besides clinical stages, classical parameters with proven independent prognostic value include: the number of lymphocytes in peripheral blood; the degree of bone marrow in®ltration; the proportion of atypical lymphoid cells in peripheral blood; and the lymphocyte doubling time (Table 2). These parameters are simple, reproducible and add prognostic power to clinical stages. Nevertheless, it should be noted that these prognostic factors were identi®ed at a time when CLL treatment was based on alkylating agents. In most of the trials in which the newer and more e€ective