Recently in Prague, Hoffmann-La Roche hosted an international symposium on the role of Rituximab (Rituxan in the U.S. and MabThera in other parts of the world) in lymphoproliferative disorders. While this drug is approved for the management of lymphoma, only one day was committed to lymphoma and a full half-day was committed to research in CLL. This signifies the intense interest in the use of Rituximab in CLL.
The CLL session was kicked off by Dr. Bruce Cheson from Georgetown University and formerly of the National Cancer Institute on the present status of CLL. Dr. Cheson highlighted the developments over the last number of years, in particular the improved understanding of the biology of the disease. The roles of the mutation status of the immunoglobulin gene, ZAP70, and other genes which have been found to be over expressed by gene profiling using microarray techniques and CD38 were addressed specifically. There is still some debate as to the optimal use of these new parameters.
Development of fluorescent in situ hybridization (FISH) techniques in identifying the common genetic changes in CLL were also highlighted and their prognostic significance discussed. It appears in particular that patients with abnormalities in chromosome 17p are less likely to respond to traditional measures and more likely to respond to treatment with alemtuzumab (Campath-1H).
The development of monoclonal antibodies both alemtuzumab and rituximab and their integration into chemoimmunotherapy induction programs such as fludarabine and rituximab ? cyclophosphamide (FR or FCR) was also highlighted.
The improvement in complete remission rate of frontline patients from < 5% with chlorambucil to 70% with the FCR program was emphasized. It is clear that we are now getting to the point where minimal residual disease measured either by flow cytometry or polymerase chain reaction (PCR) techniques are transforming the way we evaluate CLL, formerly considered to be incurable. Dr. Cheson highlighted the dramatic shift in our thinking, which has occurred in a period as short as 15 years.
Dr. Thomas Lin highlighted the results of the fludarabine + rituximab (FR) protocol developed by the Cancer and Leukemia Group B. He emphasized, that while the FR protocol was superior to fludarabine alone (F) in induction of remissions, there has been no improvement demonstrated in this arm of the study with respect to time-to-relapse of remission or overall survival. Further follow-up is indicated. This was the first study to illustrate the role of chemoimmunotherapy induction in consolidation therapy in CLL.
Dr. Thomas Kipps from the University of California in San Diego, the leader of the Clinical Research Consortium (CRC) on CLL highlighted the improved understanding we have of the role of the immune system in CLL and the relevance of markers such as ZAP70 in identifying patients more likely to develop progression of their disease. Dr. Kipps has pioneered the gene therapy approach to CLL and also has been a major contributor to the development of accelerated T-cells (Xcyte) in improving responsiveness to the immune cells reinfused and laceration of the more normal immune profile. Dr. Kipps emphasized the expanding role of immune manipulation techniques in the management of CLL.
Dr. Michael Hallek, the Chairman of the CLL Study Group, presented some of the outstanding clinical trials being conducted by German collaborators. He has identified that the fludarabine/cyclophosphamide (FC) regimen is superior to F alone from the point of view of complete response rate, overall response rate, and progression free survival and event free survival in patients less than 65 years of age. Similarly, he emphasized that fludarabine is superior to chlorambucil from the point of view of response rate and quality of life in patients over the age of 65. Further studies with this outstanding cooperative group will be addressing the role of treatments in earlier stage disease identified by prognostic markers and the role of transplantation in the management of CLL.
The session then concluded with a debate between Dr. Terry Hamblin of Southhampton and myself. The topic was “Is CLL Curable?” Prior to the debate, approximately 20% of the audience considered CLL potentially curable. Dr. Hamblin took the approach that we should consider learning to live with our CLL as many patients will have very long periods of good health in persistence of the CLL. He emphasized the role of mutation status in identifying the patients that are likely not to behave as if they have a disease. Patients with mutated immunoglobulin heavy chain genes have an outstanding prognosis and should be considered potentially to have a benign condition.
I agreed that many patients with CLL never progress, but once progression has occurred, their survival was measured in terms of five to six years. New developments in treatment, in particular application of chemoimmunotherapy protocols such as the FCR program, have led to a very high complete remission rate with many patients having no disease detectable when evaluated by flow cytometry and PCR. The relapse rate in patients that have residual cells by either of these techniques is higher whereas patients that are negative by these techniques will have an 80 – 90% likelihood of staying in remission for more than five years.
The development of consolidation therapies with alemtuzumab to improve the response in patients with minimal residual disease was exemplified in a combined MD Anderson/CRC protocol with improvement in response in the majority of patients with almost 40% of patients becoming PCR negative in the bone marrow. Non-ablative stem cell transplant patients (mini-transplants) have emerged as a very potent modality in treatment of relapsing or refractory patients with CLL. This technique has improved with the addition of rituximab to the preparative regimens and many patients are now in complete remission with no evidence of disease on PCR testing.
At the end of the debate, 40% of the clinicians present thought that CLL might be curable. The fact that one-third of the entire content was focused on CLL at such an important meeting was a tribute to the improvement in outcome that has emerged over time. The audience and presenters anticipated that there would be no slowing down of progress in response and survival. In fact, it should be accelerated as new drugs and newer application techniques becomes more readily available.
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.
