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BACKGROUND AND OBJECTIVE: Cellular and molecular features including tumor cell proliferation, immunophenotype, adhesion molecule expression and release, and karyotypic abnormalities have been linked with survival in B-cell chronic lymphocytic leukemia (CLL) patients. Although information provided from these studies makes it possible to better appreciate the biological heterogeneity of the disease, it is not clear whether they may substitute clinical features in the prognostic assessment of CLL patients. The objective of this article is to analyze the performance of new prognostic variables, keeping in mind that clinicians should give priority to less expensive biological assays. INFORMATION SOURCES: In the present review, we examined personal papers in this field, and articles or abstracts published in journals covered by the Science Citation Index and Medline. STATE OF ART: Clinico-prognostic staging systems do not provide criteria accurate enough to identify patients with progressive disease. Although several in vitro methods have been utilized to evaluate tumor cell proliferation and to correlate this parameter with long-term survival, it is difficult to translate the results of kinetic studies into prognosis. Interestingly, prognostic implications of kinetic parameters are exemplified by clinical studies based on lymphocyte doubling time (LDT). Attempts to correlate immunophenotype with prognosis have yielded inconclusive results. This is probably due to the absence of strict immunological criteria. The membrane instability of CD23, rapidly cleaved into a soluble form, provides a highly specific and reliable serum marker. Expression of myelomonocytic antigens (i.e., CD11b, CD13) appears to be restricted to patients with CD5- CLL. Both cellular expression and release in the serum of some adhesion molecules (i.e., CD54, CD44 standard) have been linked with prognosis. The increased use of fluorescence in situ hybridization (FISH) techniques, which make it possible to identify karyotypic abnormalities even in cases with inadequate mytoses, has contributed to a better definition of incidence and clinical relevance of karyotypic abnormalities in CLL. Trisomy 12 is significantly associated with atypical morphological and/or immunological features, high proliferative activity and poor prognosis; the prognostic effect of 11q deletions is consistent in patients under 55 years of age. Usually, in absence of the rearrangement of the bcl-2 locus, B-CLL cells express bcl-2 gene product, whose intracellular levels do not correlate with clinical stages but do correlate with survival, thereby suggesting a possible independent prognostic value. Finally, p53 tumor suppressor gene has been associated with resistance to therapy with fludarabine. PERSPECTIVES: Even though prognostic assessment of CLL patients is generally based on clinical staging systems new biological parameters which reflect the clinical heterogeneity of the disease are under evaluation. Whether in the future clinicians will substitute biological variables for clinical features is matter of debate. The prognostic value of biological parameters is hampered, in some instances, by the small number of patients presenting these features (i.e., 11q deletions in 20%, p53 mutations in 15%). More likely, biological parameters might be incorporated into clinico-prognostic models thus leading to the formulation of a clinical-biological system for CLL.