Chronic Lymphocytic Leukemia:
Old Disease, New Biology

By S. Vincent Rajkumar, MD.

Gone are the days when chronic lymphocytic leu-kemia (CLL) was a simple disease with two straightforward choices for treatment: observation or chlorambucil. Recent advances have totally transformed the classification, prognosis, and treatment of this disease. In today’s Educational Session, Biology and Treatment of Chronic Lymphocytic Leukemia (10:15 a.m. -12:00 p.m.), attendees have the opportunity to review the latest developments in CLL, including current approach to therapy. Dr. Nicholas Chiorazzi discusses basic concepts in lymphocyte biology and the classification of CLL. Two major subtypes of B-cell CLL have been identified. Subgroup I is defined by expression of unmutated B-cell receptors.

Patients in this subgroup usually have an adverse prognosis, require therapy early and often present with advanced stage with rapid lymphocyte doubling. In contrast, Subgroup II is characterized by expression of mutated B-cell receptors (>2% difference from germline V genes). Patients in Subgroup II usually have a good prognosis and present with early stage disease that does not require therapy. Dr. Chiorazzi also discusses the various genetic events that occur in B-CLL. These are primarily DNA deletions, with events at 13q14, 11q22-q23, 17p13, and 6q21 being the most common.

Finally, he discusses the clinical implications of these findings and presents a model for the pathogenesis of the disease. The current status of immunotherapy in CLL will be presented by Dr. Thomas Kipps. He will also discuss transgenic mouse and other animal models in CLL, and ways to use these models to further understand the biology of the disease. Particularly, he will present data on the role of zeta associated protein (ZAP-70), a cytoplasmic protein tyrosine kinase normally expressed only in natural killer cells.

ZAP-70 is expressed in the unmutated subgroup of B-CLL (subgroup I). Expression of ZAP-70 in these cells increases the signaling capacity of the B-cell receptor complex resulting in a growth stimulus to these malignant cells. Clearly these findings have significant prognostic and therapeutic implications in this disease. Finally, Dr. Kipps discusses the use of rituximab, alemtuzumab, cellular vaccines, and activated T-cell therapy in CLL.

The session is concluded by Dr. Michael Keating who will critically review the various therapeutic options available for patients with CLL. He challenges current paradigms for the treatment of CLL and argues that we may be reaching the point of having adequate “tools” to eventually cure this disease.

He presents the latest data on the use of purine nucleoside analogs, monoclonal antibodies, and chemotherapy alone and in combination. He also reviews the role of stem cell transplantation including nonmyeloablative allogeneic transplants.

It will be clear from this session how advances in biology of CLL are being translated into advances in patient care. The session will also be available tomorrow 9.45 a.m. –11.30 a.m. Other advances in lymphocyte biology are being discussed elsewhere at the meeting. A Scientific Committee session today entitled Lymphocyte Biology: Natural Killer Cells Revisited- New Biology and Clinical Approaches for Therapy of Cancer (10:15 a.m.–12.00 p.m.), will discuss the biology of NK cells, how these cells play a role in tumor immunosurveillance, and how malignant cells are able to outsmart these host tumor defense systems. This session is offered again later today at 4.15 p.m. – 6.00 p.m.