Report from the 9th International Conference on Malignant Lymphoma (ICML) – Lugano, Switzerland (June 2005)
Chronic lymphocytic leukemia (CLL) was one of the major features of the 9th ICML conference. An entire session was dedicated to CLL illustrating the emergence of this formerly orphan disease as a major player in the lymphoma area. Our Scientific Advisory Board member Federico Caligaris-Cappio and colleagues made a major presentation on the interaction between the supporting (stromal) cells and the CLL cells. This gives rise to the possibility of interfering with stromal nourishment of CLL cells as a new method of treatment. The group from Ulm, Germany presented information that there is not a clear correlation between all of the poor prognosis cytogenetic categories such as 11q- and 17p- and ZAP70. Patients who have a particular mutated V3-21 gene have high ZAP70 expression, which would not be anticipated. It is obvious that the interaction between the prognostic factors such as FISH cytogenetics, ZAP70, mutation status CD38 expression is still evolving. The discussion at recent meetings is that it appears that different treatments may be more effective in different cytogenetic categories.
Dr. Hallek of the German CLL Study Group reported on their series of studies. It is clear that fludarabine is superior to chlorambucil in patients over the age of 65 and the combination of fludarabine and cyclophosphamide (FC) is superior to single agent fludarabine. Future studies will investigate in a randomized fashion the role of monoclonal antibodies such as rituximab in the treatment of the disease. A major new initiative has been the concept of “slow-go” and “go-go” for patients particularly those of advanced age. Many patients who are over the age of 65 and have significant other illnesses will be allocated to the “slow-go” strategy with a treatment program that is less likely to cause significant morbidity or complications.
The group from Barcelona headed by Dr. Montserrat presented information on a combination of three chemotherapy drugs, fludarabine, cyclophosphamide, and mitoxantrone (FCM) in previously untreated CLL. Dr. Francesco Bosch reported an overall response rate of 91%. Half of the patients were able to achieve a complete remission with half of those patients having no evidence of disease on flow cytometry or PCR analysis. This confirms their previous report on previously treated patients, which showed a very high response rate. It appears that the three-drug combination may be the optimal regimen and future studies by their group and MD Anderson Cancer Center (MDACC) will add rituximab to this regimen.
Dr. Stilgenbauer from the German CLL Study Group reported on a subcutaneous alemtuzumab (Campath-1H) response in fludarabine-refractory patients. The results that they obtained from subcutaneous administration were almost identical to those that were obtained in a similar patient population with the intravenous route of administration. In addition it appears that patients who have a severe abnormality such as unmutated VH gene, 11q-, or 17p- appear to respond. The morbidity was significant because of this advanced patient population but there was much less in the way of fever, chills, and time occupied of the administration of treatment with the subcutaneous route compared to the intravenous route.
Dr. Dreger of the German CLL Study Group presented data on long-term disease control by non-ablative transplants. It is clear that a number of patients, even those with unfavorable characteristics can achieve a long-term remission with a non-ablative stem cell transplantation. Two thirds of the patients were still alive with no evidence of disease at one year. Relapse following that time is very uncommon.
The MDACC results presented at the meeting continue to indicate FCR as the “gold standard” for management of CLL. The complete response rate is now 73% and two-thirds of patients on study are still free of recurrence of disease at five years. At this stage, the PCR test appears to be superior to flow cytometry using two-parameter flow at predicting patients who are likely to be disease-free on a long-term basis. The FCR results in 300 patients are clearly superior to those reported from chemotherapy alone regimens. Further comparisons of fludarabine and Rituxan (FR) with FCR or other such comparisons will be of interest in the future.
Dr. Tsimberidou of MDACC presented an analysis of Richter’s transformation (large cell lymphoma) developing after the diagnosis of CLL. This complication is associated with a very serious prognosis with an average survival of one year or less. It does appear that if the patients are able to obtain a remission with chemotherapy and then have a non-ablative stem cell allogeneic transplant, the prospects for long-term control exist.
Restructuring of CLL Initial Treatment Program at MDACC
Analysis of the FCR regimen has demonstrated that while there is a very high complete remission rate (47%) of patients over the age of 70 treated with FCR, this is not translated into an improvement of survival because of a higher likelihood of patients dying while in remission of infection or developing other malignancies. Since relatively few patients are referred to the MDACC over the age of 70, a combination program has been initiated which is not suppressive of bone marrow and perhaps will enhance the immune reactivity. Low grade lymphoma studies have demonstrated that Rituxan + Leukine (GMCSF) is associated with an improved complete remission rate compared to previous studies. The MDACC CLL investigators have taken this initiative to patients over the age 70. This will be the initial therapy for all patients over 70.
There is clear evidence that elevation of the beta-2-microglobulin (β2M) above twice normal is associated with a number of adverse outcomes such as failure to respond, early relapse, autoimmune complications, marrow failure and second malignancies including Richter’s transformation. With this in mind and with the promising results that have been obtained with the FCM regimen developed in Barcelona, patients < 70 years of age with β2M less than twice normal will receive FCM + rituximab. Patients < 70 years of age with a higher β2M (greater than twice normal) will have Campath (alemtuzumab) added to the FCR regimen (CFAR). The CFAR regimen in relapsed and refractory patients is associated with a promising response rate. Patients are achieving remission more quickly than with FCR. The goal of all of the studies on patients < 70 years of age will be to achieve a state where there is no evidence of disease (minimal residual disease negative for flow cytometry and PCR).
The goal of therapy in patients with CLL who are older is to get a safe effective treatment. New strategies to eradicate the disease without decreasing the immune system and making them candidates for vaccine and gene therapy strategies are important.
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.