The XII International Workshop on CLL (iwCLL) was hosted in London, September 14-16, 2007, by Professor Daniel Catovsky, a legendary figure in the field of CLL. The meeting was an opportunity to hear the latest in CLL research. At this meeting we also recognized the seminal contribution of Prof. David Galton, who died in 2006 and was a major mentor for many of the early investigators in CLL.
The iwCLL has evolved from a small gathering of 12 – 30 people in the first few meetings to a total registration of several hundred for the meeting in London. This evolution reflects the increasing interest in the treatment and research of the disease due to the major advances which have improved our understanding of CLL.
PRE-IWCLL
Before the formal meeting, two smaller groups of investigators met to discuss seminal topics. The first was a meeting of the familial CLL investigators group. Four years ago in Stressa, this group began meeting at iwCLL to develop close working relationships between investigators in Europe and the United States looking at the familial nature of CLL. Incidentally, our donors provided financial support for the meeting in Stressa. The group is investigating the epidemiology and familial genetics of CLL using new technologies of genetics and epidemiologic clustering. It is clear that there are families with a strong expression of CLL and related lymphoid malignancies.
It is important to clarify which genes are involved in order to improve our understanding of the disease and to provide practical advice to family members who may be potentially impacted by these findings. Richard Houlston, a CLL Global grant recipient from the Institute of Cancer Research, provided an update on the inherited susceptibility to CLL and the identification of predisposed genes.
The other meeting which was held is the Young CLL Investigators Meeting which was organized and hosted by Drs. William Wierda (MD Anderson) and Paolo Ghia (Instituto Scientifico San Raffaele), two recipients of funding from the CLL Global. Twenty young investigators from both U.S. and Europe reported on basic, translational, clinical research, and prognostic markers. Many of the presenters are associated with the leading figures in CLL while others are independently emerging as innovative scientists.
Basic Research
Many of the presentations at the main meeting and preceding meetings addressed the genetics of CLL and the role of the B-cell receptor in the causation and progression of CLL. Other reports highlighted the emergence of lipid metabolism (e.g. the lipoprotein lipase gene) as a potential new drug target in CLL. Highlights of basic and translational research on the genetics of CLL were presented by Carlo Croce (Ohio State University), George Calin (MD Anderson), and Riccardo Dalla-Favera (Columbia Unviersity). These investigators have developed mouse models which are representative of the human disease and they illustrate involvement of genes in the initiation and transformation of CLL. The discovery of micro-RNAs by Croce and Calin was recognized by the Rai/Binet Medal which was presented to Professor Croce.
The meeting also highlighted new technologies such as the use of single nucleotide polymorphisms (SNP) arrays and new stimulators of cell division to enable conventional cytogenetics in CLL. Previously, researchers in the acute leukemias and lymphoma were far ahead of CLL in genetic and cytogenetic research. However, the burgeoning knowledge and interest in the genetics and cytogenetics of CLL is now allowing us to catch up.
Professor David Oscier, also funded by the CLL Global, presented updated information on the ZAP 70, FISH mutation status, and other parameters in identifying response to treatment and survival in the major United Kingdom study CLL4. It is clear that all of these parameters have some impact. Of interest, the classical features of age and beta-2-microglobulin emerged as major parameters for survival.
Many investigators are also exploring the relationship between the CLL cells and the immune system. Drs. Nick Chiorazzi (Feinstein Institute for Medical Research) and Ghia, both recipients of CLL Global funding, presented on the topic. There is tremendous impact on the survival of CLL cells resulting from their interaction with so called stromal cells. These are the “supporting cells” in the bone marrow, lymph nodes, spleen which send positive survival signals to CLL cells. An example of these cells are the nurse-like cells which are becoming more clearly defined as major supporting cells for CLL. Histologic research by Piers Patten (King’s College, London) highlighted the need for us to understand the pathology behind the interaction between these supporting cells and the CLL cells.
Prognostic Factors
The evaluation of important prognostic factors such as ZAP 70, mutation status, and genetic abnormalities identified by FISH (fluorescent in situ hybridization) were discussed in detail and at the present time there is no clear evidence as to how we should integrate all of these features into clinical trials.
Treatment
The iwCLL was characterized by relatively few reports on the big clinical trials which have been set up by cooperative groups. However great interest was displayed in the work from Ohio State University by John Byrd, Thomas Lin, and Michael Grever and the development of flavopiridol, a potent new agent in CLL. The information provided at this meeting suggests that earlier initiation of treatment will lead to better outcomes and that this drug may play a role in eradication of minimal residual disease (MRD).
Andy Rawstron (Leeds Teaching Hospital, UK) discussed MRD in detail. It is clear that alemtuzumab (Campath) is a very potent drug in clearing the blood and bone marrow of residual CLL cells. We have improved our ability to measure CLL cells in the blood and bone marrow. However, measurement of residual disease in the lymph nodes is not as well defined. Investigators also presented on the role of CT scans in evaluating total tumor burden and also their prognostic impact in evaluating residual disease. A number of new antibodies are being developed and our understanding of the role of alemtuzumab in CLL is increasing. Hopefully some of the new antibodies against CD20 will prove even more effective than rituximab in CLL.
Another area that was examined was the impact of CLL therapy in older patients. It is clear that many patients over the age of 65 with CLL have other diseases which we call “co-morbidity”. A number of co-morbidity indices have been developed which identify patients at risk of developing complications from traditional therapy. Much of this work has been led by the German CLL Study Group and was reported by Dr. Barbara Eichhorst (University Hospital, Cologne). It is also clear that many patients with CLL will tolerate conventional therapy but others need a “kinder/gentler” approach to maintain their quality of life.
Dr. William Plunkett (M.D Anderson), head of the CLL Global Scientific Advisory Board cataloged the tremendous opportunities which are still available in the nucleoside analog family of drugs. Fludarabine, chlorodeoxyadenosine (2-CDA), and pentostatin have all been major drugs in the development of new therapeutic modalities in CLL. Extension of this family is very actively being pursued and drugs are coming into or are already in the clinic. The next iwCLL meeting should certainly provide evidence of new approaches using this group of drugs.
As we have highlighted in past CLL Global publications, gene therapy is finally a reality. The early pioneering work by Drs. Thomas Kipps (University of California, San Diego) and William Wierda (while at UCSD) used a mouse gene (CD154) combined with a patients’ own cells to create a vaccine. Now a human construct of the CD40 ligand (ISF35) is being used and Dr. Wierda presented on the results of the phase I study. ISF35 is used to switch on the membrane of the CLL cells and make them a bright signal to the immune system in patients. This study will be going into phase II before the end of this year and already shows promise of significant activity.
The last morning of iwCLL was dedicated to the evaluation of transplantation in CLL. Previously, this topic was hardly ever discussed, but the development of non-ablative stem cell transplants (NST, mini-transplant) has awakened this field. It is clear that full transplants in patients that are young enough to take them and mini-transplants in younger and older patients have the potential to cure 40% – 50% of patients with CLL.
The use of these mini-transplants is increasing in a dramatic fashion. There is clear evidence that mini-transplants are safer and more effective when performed in the earlier phases of CLL treatment. In the future, when chronic graft versus host disease can be controlled, this modality will truly have the opportunity to make significant differences in survival of many patients.
While there is still some interest in autologous transplantation from a point of view of extending progression-free survival, there is no evidence that autologous transplantation is a major factor in curing the disease . On the other hand, allogeneic transplants from matched siblings, family members, unrelated donors and more frequently from cord blood transplants, demonstrate great promise for curing the disease. The MRD measurements that were discussed by Rawstron are obviously of importance in monitoring the effectiveness of transplants. This data was discussed by Drs. Carol Moreno and Emili Montserrat (University of Barcelona). The results from the Fred Hutchinson Cancer Research Center in Seattle were presented by Professor Rainer Storb (a pioneer in allogeneic transplants) confirming the earlier studies in smaller populations.
All in all, this was a very full and exciting meeting. There were so many outstanding abstracts submitted as posters that the organizers decided to include more short presentations from emerging young investigators in future iwCLL meetings rather than the more traditional approach of having established leaders provide overviews. It is likely that the meeting will continue to grow in size and sophistication.
All of these factors highlight the fact that CLL investigators can no longer be accused of being “optimists” but rather “optimistic realists”. The reality is that our understanding of CLL has increased dramatically. It is clear that treatment of patients is leading to much longer disease-free intervals and improvements in survival. The improvements in survival will be validated when comparative studies become available.
CLL Global’s investigators clearly appreciate our funding. There were approximately a dozen references to our support in various presentations and posters. The prominence of CLL Global’s grantees at this meeting was gratifying and points to our organization’s impact on accelerating CLL research.
