Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States. This prevalence is due to two factors. First, the incidence of CLL rises with advancing age with the median age in the sixties. As noted previously, the population over the age of 60 continues to grow. Second, patients with CLL can experience a long survival, with median survival approaching 6 years. Thus, the prevalence of the disease is quite high.

CLL is generally a neoplasm of activated B lymphocytes. The leukemic cell morphologically resembles mature small lymphocytes normally seen in the peripheral blood. A sustained blood lymphocyte count that is greater than 10 × 10³/mL has been required to diagnose CLL. Additionally, 30% of nucleated cells in the bone marrow should be lymphocytes, and the peripheral blood lymphocytes should be positive for B-cell markers. In some clinical situations, CLL can be diagnosed with fewer total lymphocytes if surface markers confirms a monoclonal population of typical lymphocytes.

The exact cell of origin in CLL is unknown. Although 95% of patients have a B-cell phenotype, T-cell CLL can rarely occur. The typical B-cell CLL does stain positive with antibody to CD5, which is normally a T-cell antigen, and this has been taken to imply that the malignant cell is arrested at an intermediate stage of B-cell differentiation. Other diseases, such as hairy cell leukemia, to be considered later, are thought to result from the malignant transformation of a lymphocyte at a different stage of development.

Lymphoproliferative Disorders

• Chronic Lymphocytic Leukemia  
• Hairy Cell Leukemia  
• Plasma Cell Dyscrasias  
• Monoclonal Gammopathy of Uncertain Significance  
• Multiple Myeloma  
• Waldenstrom’s Macroglobulinemia  
• Amyloidosis

The etiology of CLL is also unknown. Retroviruses and ionizing radiation, which lead to other forms of leukemia, apparently do not increase the risk for CLL. Interestingly, the incidence of CLL is far less in Japan than in Western populations. In addition, there is an increased risk of a variety of autoimmune disorders in relatives of patients with CLL, implying a genetic predisposition to the development of lymphocytic disorders.

The lymphocytes in CLL usually express a specific surface immunoglobulin, although at low intensity. Normal control of antibody production in patients with CLL is disrupted. There is a marked reduction in normal antibody production manifested as a diffuse hypogammaglobulinemia, resulting in a high incidence of infections. On the other hand, there is a paradoxical increase in autoimmune complications, including hemolytic anemias. This dysregulation is an exaggeration of the phenomena seen in normal aging.

The diagnosis and staging of CLL has produced two excellent classification systems, one by Binet and one by Rai. Recently, these two staging systems have been combined and are represented in

Table 38.2, along with the expected median survivals. There are a few points worth making regarding the stage of CLL at the time of diagnosis.

Approximately 25% of patients present with only a lymphocytosis in the peripheral blood and the marrow but no evidence of lymphadenopathy, organomegaly, or other cytopenias. These patients have an exceedingly good prognosis and in general should not undergo any therapy unless their disease progresses. The development of multiple enlarged lymph nodes, hepatomegaly, or splenomegaly mark progression to stage B disease. The development of either anemia or thrombocytopenia on the basis of marrow compromise portends a significantly worse prognosis.

The treatment of CLL has, in general, been aimed at controlling the disease rather than curing it. Therapy is withheld until significant cytopenias or symptomatic lymphadenopathy or organomegaly develops. In general, treatment is initiated with an alkylating agent. Most frequently chlorambucil is used, in either low daily doses or pulses from 2 to 4 weeks. Fludarabine is an active agent for the treatment of CLL. It produces a higher rate of complete remissions and a longer duration of response than chlorambucil. This agent has response rates of 50% to 80% in both previously untreated as well as treated patients. Overall survival is not improved, and because fludarabine is associated with increased toxicity, especially for older patients with renal impairment, many clinicians use it only after failure of chlorambucil. Other alkylating agents such as cyclophosphamide are also effective. Prednisone is usually given with the alkylating agent and sometimes alone for patients with manifestations of autoimmune phenomena.

Unfortunately, the course of CLL is progressive despite initiation of therapy. Several attempts have been made to predict the course of patients with CLL more accurately than the current staging system. At least two criteria appear to suggest rapid progression of disease. The rate of increase of blood lymphocytes has long been recognized to be a useful indicator of prognosis. Most authors recommend a period of observation before initiating cytotoxic therapy in an effort to evaluate the pace of the disease. A doubling of lymphocytes in the peripheral blood in less than 1 year is associated with a worse prognosis. Investigators have also reported that the pattern of bone marrow infiltration with lymphocytes is prognostic. Patients with a diffuse lymphocytic infiltration have more rapid progression of their disease than patients with nodular involvement of the bone marrow.

Future Direction
Recently, there has been renewed interest in immunotherapy of CLL. Recombinant monoclonal antibodies have demonstrated activity against this disease. Campath 1-H is approved for patients with CLL who have failed fludarabine. This modified antibody recognizes the CD-52 antigen on the surface of CLL lymphocytes and can initiate antibody-dependent cell-mediated cytotoxicity (ADCC), as well as activate the complement cascade causing death of CLL cells. There is a considerable infusion-related reaction with the drug, and patients can be immunosupressed because of the resultant lymphopenia resulting in reactivation of latent CMV. Nonetheless, this new avenue of attack may prove quite beneficial to elderly patients.

Supportive therapy is very important for patients with CLL because of the many associated clinical phenomena. Autoimmune phenomena, such as anemia or thrombocytopenia, can be treated with a steroid alone without cytotoxic therapy. Pure red cell aplasia, which occasionally occurs, may respond to either cyclosporin or antithymocyte globulin (ATG). Recurrent infections with encapsulated organisms frequently result from the hypogammaglobulinemia that occurs in these patients. The mainstay of therapy is prompt initiation of appropriate antibiotics. However, intermittent intravenous gamma globulin can be effective in reducing the frequency of infections, especially in those patients with very low levels of serum immunoglobulin G (IgG).