Over the past decade, major breakthroughs have been made in both the molecular understanding and the treatment of chronic lymphocytic leukemia (CLL). In this article, old and new concepts of CLL biology are explored and insights into the relevance of the newer prognostic factors are discussed. The therapeutic landscape has changed dramatically with the advent of purine analogs, monoclonal antibodies, and combination therapy. As opposed to older agents, these new therapies commonly yield complete remissions. This improvement has spurred a debate as to new goals in treating CLL patients.
Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western hemisphere. Both the Rai and Binet staging systems have been important clinical tools for predicting outcomes of this heterogeneous disease. In the past 10 years, an explosion of research using newer techniques has helped us to learn more about the molecular biology of CLL and the impact it has on prognosis. In tandem with this increased knowledge on the molecular level, the menu of treatment options has improved significantly.
CLL is commonly found when an absolute lymphocytosis is discovered in an entirely asymptomatic person. Other patients notice some degree of painless lymphadenopathy and consult a physician. A minority of patients present with typical B symptoms of lymphoma (weakness, night sweats, weight loss, or fever). Finally, some patients present with an infection or autoimmune phenomenon (such as hemolytic anemia) related to immune dysfunction.
The threshold for diagnosing CLL was originally 5,000 lymphocytes/µL. A recent update of the 1996 National Cancer Institute–Working Group requires the presence of 5,000 B lymphocytes/µL (past guidelines did not specify B lymphocytes). Examination of the peripheral blood smear should reveal many small morphologically mature lymphocytes with a narrow border of cytoplasm and a dense nucleus. Flow cytometry must demonstrate clonality, as determined by kappa or lambda light chain restriction, with CD19, CD20, CD23, and CD5 coexpression. Surface membrane immunoglobulin and CD20 are typically dim. Most other types of B-cell lymphoproliferative disorders are associated with high expression of surface membrane immunoglobulin and cells that do not express CD5. The exception is mantle cell lymphoma, which expresses CD5 but usually can be distinguished from CLL by lack of CD23 positivity and an overexpression of cyclin D1.
A bone marrow biopsy is not required for the diagnosis of CLL. However, if performed, it will show either hyper- or normocellularity, with a nodular or diffuse pattern of lymphocytic infiltration representing more than 30% of all nucleated cells. Prognostic tests such as molecular genetics, fluorescence in situ hybridization (FISH), mutational status of immunoglobulin heavy chain genes, and expression of ZAP-70 or CD38 are not required for the diagnosis of CLL.
Biology and Prognostic Markers
Rai and Binet Staging
Until recently, the prognosis of patients with CLL was based solely on clinical stage. Two staging systems, Rai and Binet, are used to describe extent of disease and portend prognosis.[3,4] In the series published by Rai and colleagues, median survival from time of diagnosis ranged from 150 months for stage 0 patients to only 19 months for those with stage III and IV disease. Binet and colleagues categorized patients as low risk (stage A), intermediate risk (stage B) and high risk (stage C), which correspond, respectively, to Rai stage 0, I or II, and III or IV.
The staging systems are most useful in predicting outcomes in patients with advanced disease (Rai stage III/IV or Binet stage C). Patients in the low- and intermediate-risk groups have a varied clinical course that may ultimately prove to be indolent or aggressive. New prognostic factors have allowed some degree of predictability of disease course in these patients with early-stage disease, and have also shed light on the biology of CLL growth.
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