The clinical staging systems independently developed by Rai et al. (3) and Binet et al. (4) in the early 1980s, which are 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 compare trials based on the risk of disease. Rai's stages were further classified as low (Rai stage 0), intermediate (Rai stages I and II), and high (Rai stages III and IV) risk. The International Workshop on CLL (IWCLL) proposed an integration of the two staging systems, but this did not gain wide acceptance (14). Median survival for Binet stage A is 15 yr, declining to 5 and 3 yr for Binet stages B and C, respectively (Fig. 2A) (15). Median survival for Rai stage 0 is 16 yr, 8 yr for Rai stages I and II, and 3 yr for Rai stages III and IV (Fig. 2B) (15).
Although they are easy to apply and reproducible, staging systems are not devoid of limitations. For example, the mechanisms accounting for cytopenias (i.e, bone marrow infiltration, hypersplenism, autoimmune basis) are not taken into consideration. As a result, patients are classified in an advanced stage independently of the origin of the anemia or thrombocytopenia, although there is some indication that the mechanism of the cytopenia is also a factor in prognosis (16). Most important, perhaps, is the prognostic heterogeneity within each of the clinical stages. Thus, staging systems do not allow identification of individuals in an 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 that patients in an early stage who are likely to progress could benefit from treatment immediately after diagnosis, before progression occurs. Conversely, in some patients presenting in an advanced stage the disease runs an indolent course and for long periods they may not require therapy; the staging systems do not identify these patients either.
Other classification methods have been proposed in the last two decades. The GIMEMA study group, in a large retrospective analysis of prognostic factors, identified four parameters associated with poor prognosis: lymphocytosis (> 60 x 109/L), anemia (Hb < 10 g/dL), number of enlarged lymph nodes (> 2 cm), or palpable hepatoesplenomegaly (> 3 cm) (17). On the other hand, Jaksic and Vitale (18) defined the total tumor mass score, a quantitative staging system based on the clinical assessment of disease involvement within all major compartments.
Although the great majority of CLL patients are diagnosed in an indolent phase, of them 30-40% progress to a more advanced clinical stage and finally die of their leukemia (15). Several efforts have been made to identify subpopulations of CLL patients in an early stage who have a high risk of progressing to a more advanced stages. Han et al. (19) coined the term "benign monoclonal lymphocytosis" to describe the clinical course of a small but interesting series of 20 patients whose disease did not show progressive changes during the follow-up time. Oscier et al. (20) analyzed their series of Rai stage 0 patients to identify factors predictive of disease progression. Parameters that correlated with an increased risk of disease progression included the initial lymphocyte count, surface immunoglobulin phenotype, and some complex karyotype abnormalities.
Montserrat et al. (21) further extended these observations and proposed the term smoldering CLL for a subset of stage A patients whose life expectancy was not different from that of an age-and sex-matched control population. Patients with smoldering CLL, which accounts for 30% of all patients with CLL, had a hemoglobin level greater than 13 g/dL, lymphocyte count less than 30 x 109/L, a nondiffuse pattern of BM involvement, and a lymphocyte doubling time (LDT) of less than 12 mo. The French Cooperative Group on CLL analyzed a large, prospective series of stage A CLL, randomized for early vs delayed therapy. This provided a definition of smoldering CLL differing from that of Montserrat et al. through exclusion of LDT and bone marrow (BM) pattern (22,23). Finally, Molica et al. (24) demonstrated that whatever criteria were used, all the proposals succeeded in defining a subset of patients with a low rate of progression (about 15% at 5 yr) and long life expectancy (>80% at 10 years).
Recent studies have investigated whether novel prognostic factors may be helpful in the identification of a subset of early-stage CLL patients with high risk of progression. Three serum parameters ^-microglobulin, serum thymidine kinase, and sCD23) may add prognostic information to the subclassification of patients in stage A (25-27). Moreover, CD38 lymphocyte expression and the presence of somatic mutations of the immunoglobulin gene in early CLL stages have recently been correlated with a high risk of progression (28,29).
How these results translate into the timing of therapy is still a complex issue. A meta-analysis studied 2048 patients with early disease in which immediate therapy with chlorambucil or chlorambucil plus prednisone/prednisolone was compared with deferred therapy using the same agents. The 10-yr survival was not different (44% vs 47%) (30), thus supporting a conservative treatment strategy for patients with early CLL. Nonetheless, this approach should be reconsidered when results of trials based on new treatments become available.
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