Knowledge of CLL biology and the development of effective treatment regimens has accelerated tremendously over the last decade. The American Society of Hematology (ASH) annual meeting held in San Diego, CA in December 2004 showcased the extensive gains in knowledge of CLL during the last year. At this year’s meeting, there were probably three times as many reports on CLL research as there were ten years ago. The presentations were outstanding and the potential for new breakthroughs in CLL is apparent. I would like to take this opportunity to report on three major areas of discussion from the ASH meeting.
Genetic abnormalities
Genetic abnormalities that occur in CLL were discussed in great detail at ASH. Much of the discussion centered on the association between prognosis and mutation status of the immunoglobulin gene. A favorable mutation status appears associated not only with a long time until treatment but also a good response to treatment and longer remission duration. Mutation status has not been widely available to clinicians prompting many investigators to look at surrogate markers.
At ASH, there was extensive discussion regarding the predictive power of the enzyme ZAP70. ZAP70 may be expressed in CLL because of a deletion of a small gene in chromosome 11 as reported by Dr. Carlo Croce (Ohio State University, [180]). ZAP70 patients as a group are more likely to progress and have a good response to treatment; however, these patients tend to have shorter durations of remission.
Like ZAP70, the lipoprotein lipase (LPL) gene is expressed in CLL and has prognostic predictive power. [477] It is currently unclear how LPL functions to predict prognosis. However, we do know that LPL is associated with fat metabolism and a cluster of other genes associated with fat metabolism. The relationship, if any, of fat metabolism to CLL is not clear. We will continue to explore the influence of gene expression and implications in potential treatment interventions through gene regulation.
A number of chromosome abnormalities were also presented at ASH. Deletions in chromosome 17p (the likely source of abnormalities in the tumor suppressor gene p53) are associated with a poor prognosis. During initial stages of the disease, this abnormality is much less common but occurs more frequently as the disease evolves. Professor Daniel Catovsky (United Kingdom) reported at ASH that more than 20% of CLL cells have to contain this abnormality to predict the poor prognosis associated with the 17p deletion. [480]
The ataxia telangiectasia gene (ATM) is also associated with poor prognosis and is found on chromosome 11q. There are mutations in the ATM gene, which may lead to an adverse outcome. A new technique was reported at ASH which enhances the ability to analyze chromosomes. Although cumbersome, the technique stimulates CLL cells to divide. The division will allow researchers to uncover a number of important genetic abnormalities.
Both 17p and 11q chromosome abnormalities are detectable by FISH technology.
Conventional Therapeutics
New information on conventional therapeutics, particularly used in combination treatments, was presented at the ASH meeting. [475] Dr. Ian Flinn (John Hopkins) and his colleagues demonstrated in a randomized trial that the combination of fludarabine/cyclophosphamide (FC) is superior to fludarabine (F) alone. With the combination, higher complete and overall response rates were achieved as well as prolongation of remission and a lower incidence of high-grade adverse events. Dr. Tadeusz Robak (Poland) and colleagues conducted a study looking at the single agent cladribine, which in many ways is similar to fludarabine (as a single agent) compared to cladribine and cyclophosphamide or cladribine, cyclophosphamide, and mitoxantrone. [337] There were higher complete remission rates using the combination regimens. Despite a higher complete response rate, the three-drug regimen was associated with more episodes of infection.
The monoclonal antibody alemtuzumab was also discussed broadly. It is clear that this agent can be used to move patients from partial remissions to complete remissions including PCR negativity. Dr. Stephan Stilgenbauer (Germany) and his colleagues presented data confirming that subcutaneous alemtuzumab gives a similar response rate in fludarabine-refractory patients to the intravenous formulation. [478] Other studies explored the combination of alemtuzumab with more conventional regimens. Dr. William Wierda (MD Anderson) reported on a high response rate in very heavily previously treated patients with a regimen called CFAR in which alemtuzumab is added to fludarabine, cyclophosphamide, and rituximab (FCR). [340] This regimen shows a very rapid response rate and will be explored in subsequent trials.
An important element of alemtuzumab therapy is the suppression of normal T-cell function. It is important to note that the Xcyte program, where patient’s receive their own expanded and activated T-cells, is continuing to shows signs of antitumor activity and reestablishing the immune system in CLL patients. [2508] A new antibody, which is a super-agonistic antibody activating CD28, was reported by the company TeGenero AG from Germany. [2519] The antibody stimulates normal T-cell production and may be able to reconstitute T-cell immunodeficiency in patients with CLL. Finding ways to restore the patient’s immune system to normal is an important element of the overall treatment strategy in CLL.
Novel Agents
During the ASH meeting, the potential of new agents was highlighted. [341] The Ohio State group led by Drs. John Byrd and Michael Grever reported on flavopiridol, a drug that appears to be very potent as illustrated by its ability to cause tumor lysis although with substantial toxicity. The drug was active in patients with very adverse prognostic features but was associated with sometimes life threatening lysis of the tumor. Further investigation conducted in a meticulous fashion will be necessary to obtain more information on flavopiridol as it appears to be a very potent drug with novel mechanisms of action.
At ASH, studies were presented involving Genasense (oblimersen sodium). A randomized comparison was reported with the fludarabine/cyclophosphamide (FC) protocol versus FC combined with Genasense. [338] The trial showed improvement in the complete or near complete remission rate in previously treated patients with CLL. There was no significant impact on survival or time-to-treatment failure noted with this study. It is encouraging that this agent which blocks bcl2 (an important protein which keeps CLL cells alive) showed significant activity in combination approaches as the single agent activity of the drug was not very impressive.
The next ASH meeting will be held in New Orleans in December 2005. We look forward to continued research activity over the next year. ASH always provides an excellent opportunity to learn about the advances in CLL research. Another important meeting, the International Workshop on CLL (IWCLL) will be held in New York in September 2005. We look forward to sharing the progress discussed at IWCLL, ASH and other worthwhile meetings.
Dr. Michael Keating, professor of medicine at MD Anderson Cancer Center, serves as president and CEO of the CLL Global Research Foundation. He is an internationally renowned CLL clinical scientist dedicated to patient care and to development of potentially curative CLL therapies.
