Prediction of disease progression and survival (prognosis): After the diagnosis of CLL, some patients do well for years, while others progress and need treatment soon after diagnosis. Our studies of patients with CLL have allowed us to use some clinical tests to predict early in the course of disease which patients will do poorly and require treatment early.

Our recent studies have disclosed a new pathway involving apolipoprotein E that is especially useful in predicting the disease prognosis in women with CLL. This discovery has led to our experiments using novel apolipoprotein E peptides as CLL treatment agents. In other work, we are working to improve this prognosis process by using gene chip technology studying the RNA from our patients with CLL.

Prediction of drug sensitivity or resistance: When physicians recommend that CLL patient needs to be treated with chemotherapy, drugs are chosen based on the efficacy of the drug among CLL patients as a group. However, some patients may fail to respond to the chosen drug.

We are taking the RNA from our patients with CLL and using gene chip technology to study gene expression pathways so as to allow selection of drug treatments that are targeted to the specific biology pathways that are unique to the individual patient with CLL. This would allow the selection of drugs that will have the highest likelihood of being effective.

Improving immune responses to CLL: Humans can respond to CLL by activating immune cells that can eliminate the leukemia cells by natural means. We are studying CLL patients’ T cells (cells that can kill or regulate the growth of CLL cells) in hopes of improving this natural defense against leukemia. This is a unique approach and may explain some of the diversity seen among patients and even among family members with CLL.

Development of better drugs to treat CLL: We have several drugs used for treatment of CLL. However, they have toxicities, and they do not cure the disease. Thus, we are working to develop better drugs for CLL. We are working on inhibitors of (a) PI-3-kinase/Akt (perifosine), (b) phosphatases, (c) phosphodiesterase 4, (d) nitric oxide synthase, (e) and tumor necrosis factor. We are also developing drugs in the apolipoprotein receptor pathways as new and better CLL treatments. Based on results of our laboratory research, we are preparing to start a phase II trial of the PI-3-kinase/Akt inhibitor perifosine in CLL patients this year.

Genetic basis of CLL: CLL is the most frequent leukemia or lymphoma associated with an hereditary pattern. Occurrence of familial CLL indicates that genetic abnormalities likely contribute to the cause of CLL.

We are working (a) to identify genes causing CLL, (b) to identify early forms of CLL in apparently normal family members (“pre-CLL” conditions, also known as monoclonal B cell lymphocytosis [MBL]), and (c) to determine if these genetic factors noted in families with CLL also apply to sporadic cases of CLL.

Identification of a gene(s) will help us diagnose CLL cases early, identify targets for new treatments, and possibly prevent the development of full blown disease. In our studies, we are collaborating with other leading CLL research centers (Mayo Clinic, National Cancer Institute, University of Minnesota, University of Utah, MD Anderson Cancer Center, and University of California at San Diego) in the “Genetics of CLL Consortium.”

In our Duke University work, we have studied 170 subjects from 23 CLL families. We found 35 cases of overt CLL in these families, and 14 cases of MBL (“pre-CLL”). We are studying these patients in great detail, examining the biology of the disorder and determining the likelihood that subjects with MBL will develop typical CLL.

A mouse model of CLL: As we worked to understand CLL better and strived to develop new drugs for CLL treatment, we wanted to be able to do some of the studies in an experimental animal model to avoid undue problems and toxicities for our patients. Thus, we have begun using a mouse model of CLL -- the Eµ-TCL-1 mouse model. These mice develop a disease very similar to human CLL. Our studies are probing novel genes and pathways that may be important in CLL. We are also testing certain drugs noted above in this leukemia model.

For More Information

If you are a CLL patient or care for CLL patients and would like more information about how to participate in this research, please contact us at centerforcll@duke.edu.