Chronic Lymphocytic Leukemia

The early histories of treating CML and CLL have much in common owing to the limited therapy available and the inability to distinguish the diseases with any degree of accuracy. In the 1940s and 1950s, Osgood77-79 tested the hypothesis that whole-body external irradiation or administration of radioactive phosphorus could be used in a titratable manner to control the leukocyte count at a level below 30 X 109/L. He claimed that this strategy was effective in patients with slowly progressing disease and that it could increase the chance of survival to 20 years. However, his results were not confirmed in later randomized trials comparing irradiation with chlorambucil and other alkylating agents.80,81

Progress in the clinical management of patients with CLL has relied on improved understanding of the different types of disease and improved prognosis. In the past, diseases diagnosed as CLL would have included a mixture of T- and B-cell leukemias, hairy-cell leukemia, and a variety of other conditions associated with lymphocytosis. In contrast, the cells can now be identified accurately by cellular morphology, immunophenotype, and other features,82 so that subtypes of disease can be grouped together and clinical trials can be designed. In the future, expression profiling may allow further subgrouping of CLL, as it has done for non-Hodgkin's lymphoma.

It has been recognized for many years that cases of CLL have variable clinical courses.33 This wide range in survival times for patients with CLL, from a few years to more than a decade, made therapeutic decisions difficult, particularly because some patients remained well even if they were not treated. This led to the development of staging systems, based on prognostic indicators and other criteria, to facilitate the choice of therapy for individual patients. The long list of prognostic indicators in CLL now includes age, sex, lymphocyte doubling time, cell morphology, bone marrow involvement, immunophenotype, and cytogenetic abnormalities.82

Long-term low-dose treatment with chlorambucil has been a mainstay of CLL therapy and regulates the size of the malignant B-cell clone without major fluctuations in the blood count. The slowly progressing nature of the disease and its occurrence in the elderly has meant that experimental approaches to improve disease control and attempt to achieve a cure are attempted only in the rare cases of patients less than 50 years old or those with progressive disease who become cytopenic.

Progress has been due to several large studies83-85 and to the introduction of more specific drugs. It is now clear that treatment of stage 0 nonprogressing disease is not indicated and can be harmful. Patients who are resistant to chlorambucil may benefit from the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) drug regimen, and fludara-bine and 2'-deoxycoformycin seem to have better selectivity of action than other drugs.86,87 Fludarabine has become acceptable as first-line therapy for symptomatic untreated CLL patients following the results of phase III trials.88 Monoclonal antibodies such as Campath 1-H (anti-CD52) and rituximab (a chimeric IDEC-CD2B8 monoclonal antibody, which binds to CD20 expressed on B lymphocytes) have also been used to treat CLL.88-90 Bone marrow transplantation can be curative,91 but most patients are above the upper age limit for this procedure. However, research is now being carried out into nonmyeloabla-tive conditioning regimens for transplantation, although evidence of efficacy remains confined to small series or case reports.

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