Chronic Lymphocytic Leukemia (CLL) as a Platform for Functional Profiling

Among the most common forms of leukemia in adults is chronic lymphocytic leukemia. This neoplasm usually arises in a subset of lymphocytes known as B-cells. However, T-cell variants also occur. The disease presents clinically as an elevation of the circulating lymphocytes. This may be associated with enlarged lymph nodes, splenomegaly or liver enlargement.

The decision to treat patients is largely based upon clinical staging systems know as the Rai or Binet classifications. Low risk patients can often be observed without treatment, while more aggressive presentations (such as those associated with anemia and low platelet counts) require intervention. More recently, molecular determinants of aggressiveness have been applied in the prognosis of this disease. These include: CD38, VH gene mutation and Zap 70. Additional findings include ATM mutations, principally in the T-cell and pro-lymphocytic variants.

For more than 40 years, the treatment of choice for this disease was oral chlorambucil. Although effective, chlorambucil resulted in the development of resistance and was associated with rather significant myelosuppression over time. The introduction of fludarabine (FAMP) and 2-CDA revolutionized the management of this disease —providing high response rates with relatively tolerable toxicities.

The introduction of 2-CDA and fludarabine in the 1980s offered an opportunity for our laboratory to examine drug interactions in CLL patients. Combining the alkylating agents (of which, chlorambucil is a member) with 2-CDA revealed synergy (supra-additvity) in 100 percent of the CLL samples we studied (Nagourney, R; et al. British Journal of Cancer, 1993). Based on this observation, we began treating patients with CLL and related lymphoid malignancies with a combination of Cytoxan and 2-CDA, resulting in dramatic and durable remissions.

O’Brian, Keating and other investigators at the MD Anderson then undertook this work (using fludarabine), providing for the most effective therapy for CLL in today’s literature. Unfortunately, a percentage of patients who receive this combination develop deep myelo-suppression. Therefore, the administration of this combination requires careful monitoring by the physician.

One of the most interesting aspects of the high activity observed for fludarabine was the capacity of this “anti-metabolite” to induce cell death in short term cultures of CLL cells. It was well known that CLL cells were not highly proliferative, yet the anti-metabolite class of drugs was specifically designed to stop cell proliferation at the level of DNA synthesis. We realized that 2-CDA and Fludarabine had to be killing cells, not preventing their growth. This conundrum provided an opportunity for us to test a related anti-metabolite in this disease. We chose cytarabine (Ara-C), a drug not considered effective for CLL (e.g. low proliferative rate, no likelihood of DNA synthesis inhibition, no likelihood of cytotoxicity). To our delight, low doses or Ara-C proved highly effective in controlling even the most advanced cases of CLL as we then reported.

CLL became one of our favored models for the study of human tumor biology, enabling us to study drug responses at the molecular level. Many of the observations that we made in this hematologic malignancy granted us insights that we continue to apply in solid tumors today.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

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