CLL INTRODUCTION: Biology

CLL is characterized by an accumulation of small normal-looking B cell lymphocytes. Despite their mature appearance, these lymphocytes are immunologically and functionally incompetent. The lymphocytes accumulate in the bone marrow, blood, and other primary lymphoid organs including lymph nodes, liver, and spleen.

Accumulation of CLL lymphocytes is partly due to a defect of the CLL cells to undergo a normal program of cell death (also referred to as apoptosis). CLL cells produce a number of proteins inside the cells and on their surface that prevent these cells from responding to death signals.

Only recently has it been recognized that part of the biology of CLL cells is also characterized by a group of cells with increased proliferation not just by the inability of the lymphocytes to die when their time is due. From a clinical point of view, CLL is traditionally considered an indolent disorder characterized by a stable disease course or slow progression. Although compared to the course of acute leukemias or some of the aggressive Non-Hodgkin's lymphomas this may be correct, the biological characteristics and clinical behavior of CLL are far more variable than previously thought and in many patients CLL may follow a rather unpredictable disease course.

The first attempt to capture the clinical heterogeneity (variability) of CLL led to the hallmark clinical staging systems by Drs. Kanti Rai and Jacques-Louis Binet. Although these staging systems correlate with survival, they are far too inaccurate to define the biologic heterogeneity of CLL especially of early clinical stage patients. Patients with early stage CLL have an estimated median survival time of 10 to 15 years. However, some of the patients with active disease may succumb to CLL or its associated complications within only a few years.

New Prognostic Factors In CLL - Predicting Survival and Treatment Response

Over the last few years, the search for additional prognostic factors has yielded important new information regarding the clinical behavior of CLL. New techniques such as fluorescence-in-situ-hybridization [FISH] have enabled us to detect abnormalities of certain genes in CLL cells. In addition to providing prognostic information, these abnormalities also provide clues as to the involvement of certain genes and biochemical pathways that are associated with the development of CLL.

In about half of the CLL patients, the immunoglobulin genes that produce antibodies are mutated. CLL patients whose malignant lymphocytes contain rearranged (mutated) genes typically have a less aggressive course and require treatment later than CLL patients whose lymphocytes contain unmutated genes. Traditionally, the scientific community held the view that CLL lymphocytes did not have contact with antigens and did not go through certain mutation stages. Investigators from the US and Europe have recently found that this is not necessarily the case.

An important enzyme, ZAP70, is not normally present in B lymphocytes. However, in half of the CLL patients ZAP70 can be detected and is strongly associated with the unmutated type of CLL and other adverse prognostic factors. This test is new and false negative and false positive results will occur if the pathologist is not experienced with the test.

In summary, our knowledge of CLL biology has grown over the last few years. Where CLL was once thought to be due to a uniform defect in programmed cell death, we now understand CLL has a much more heterogeneous biology.