Yesterday
As 2006 comes to an end, it is appropriate to consider the questions which persisted at the start of 2006, whether we have answers at the present time and our predictions for future developments in CLL. Because of the outstanding developments in identification of novel prognostic factors such as ZAP-70, CD38 expression on CLL cells, mutation status of the immunoglobulin gene (IgVh), FISH abnormalities, and beta-2-microglobulin levels, we now have an improved ability to prognosticate.
Great efforts have been put in place over the last year to evaluate the impact of these prognostic factors. Based on patient characteristics, we can now identify indolent versus more aggressive disease. New questions are arising as to whether the treatment guidelines outlined by the National Cancer Institute Working Group in 1996 should be modified. Should we be treating patients earlier based on these prognostic factors or not? If we initiate therapy early what treatments are most appropriate? Should we modify our treatment strategies based on characteristics such as age, abnormal FISH findings, or loss of chromosome material on chromosome 11 or 17 (11q-, 17p-)?
During 2006, great emphasis was placed on studies exploring the usefulness of eradication of minimal residual disease (MRD) after initial therapy. Should rituximab be used for MRD as it is in lymphoma or is alemtuzumab (Campath-1H) a superior approach for CLL patients? Is fludarabine and rituximab (FR) equivalent to FR + cyclophosphamide (FCR)? Are mini-allogeneic transplants emerging as a major opportunity for potential cure of the disease and are they getting safer? Which of the new agents are likely to enter the clinic and have a positive impact on outcome of patients with CLL?
Today
Prognostic Factors
Not all of the prognostic factor questions have been answered. The ZAP-70 laboratory results are plagued by lack of consistency. At MD Anderson Cancer Center (MDACC), we have compared the results obtained by the CLL Research Consortium (CRC) lab supervised by Drs. Thomas Kipps and Laura Rassenti with those from three separate laboratories with no concordance of the results. This is unfortunate as drugs are being developed specifically to address patients with high ZAP-70 levels and the data from the CRC suggests that ZAP-70 is a very important predictor of the patient’s likelihood of developing progressive disease and requiring therapy.
CD38 is an activation protein on the surface of CLL cells. A high CD38 level indicates that these cells are more likely to proliferate or grow. Research protocols are currently investigating whether more proliferative patients can be identified by the uptake of heavy water (deuterium-2-oxide).
Mutation status is another promising prognostic factor. Mutation status offers a reproducible and consistent finding throughout the clinical course of each patient. The use of various genes within the mutation status is emerging as a prognostic factor. For example, patients whose CLL cells use gene 3-21 have a worse prognosis than other gene usage patterns.
Fluorescent in situ hybridization (FISH) techniques can identify patients with changes in chromosomes 11, 12, 13, and 17 in most cases. It is now apparent that partial loss of chromosome 17 (17p-) is often associated with abnormalities in the p53 oncogene and poor prognosis. In addition, partial loss of chromosome 11 (11q-) is associated with bulky lymph nodes and a prognosis which is worse than all other changes except 17q-. These analyses are useful in predicting response to therapy. The fludarabine and cyclophosphamide (FC) combination is superior to F in patients with 11q- and alemtuzumab (Campath-1H) is showing activity in patients with 17p- whereas fludarabine-based regimens are usually less effective.
Nomograms developed by Dr. William Wierda allow us, at the time of initial diagnosis to predict the probability of progression and survival. The beta-2-microglobulin level has been confirmed as a major prognostic factor along with age. Because newer prognostic factors are just emerging, they were not available for inclusion in the current nomogram.
Apart from 17p- patients (only 3 – 5% of patients at initial diagnosis), it is still uncertain whether patients should be treated earlier. For a variety of malignancies, early treatment produces favorable response. However for CLL, a survival advantage is not necessarily apparent with earlier treatment and the impairment of the immune system associated with many treatments needs to be considered.
Treatment Questions
Is cyclophosphamide necessary in the chemo-immunotherapy regimens based on fludarabine and rituximab? Recently, an analysis of Cancer and Leukemia Group B (CALGB) studies demonstrated that patients with a mutated immunoglobulin gene had longer remission durations than patients that were unmutated. This outcome for either group of patients is inferior to the overall published data on the FCR program. Should FCR be given to all patients? While the complete remission rate is high in patients over the age of 70, there has been no evidence of improved survival in older patients. The small number of patients with 17p- do not appear to respond as well and protocols specific for these patients are now being developed. The group from the Mayo Clinic is recommending the pentostatin, cyclophosphamide, rituximab (PCR) regimen as safe and effective for patients over the age of 70 years whereas the MDACC is using the monoclonal antibody, rituximab, in combination with an immune stimulator (GM-CSF, Leukine). Patients over the age of 70 represent the majority of CLL patients and are in urgent need of specific clinical trials.
Another emerging therapy question is how to eradicate MRD. If MRD eradication is to be attempted with alemtuzumab, should administration be via intravenously or subcutaneously? There are suggestions that while the subcutaneous route has high response rates, the remissions are not as durable as previously reported with the I.V. route.
Encouraging results are emerging with the mini-transplants from siblings or unrelated donors. The unrelated donor outcome appears to be almost as good as the related donor results because of greater success in identifying closely matched donors. This provides the basis for immune approaches to CLL and the rebirth of gene therapy which was initially conducted in San Diego by Drs. Kipps and Wierda and colleagues. Originally, a mouse gene was used. This program, now using a human construct, is ongoing at MDACC headed by Dr. Wierda and will be expanded greatly in 2007.
New Agents
Intriguing new agents are emerging. HuMax-CD20, a fully human antibody against CD20 (the target of Rituxan, Zevalin, Bexxar), has already shown activity in clinical trials and is now being explored actively in relapsed patients and those with disease non-responsive to fludarabine and Campath-1H. Flavopiridol, largely developed at Ohio State University, has shown a high response rate. However, there is a high rate of tumor lysis associated with its administration. Studies with lenalidomide (Revlimid) suggest a response rate of 30 – 50% in patients treated at Roswell Park and also at MDACC. Other monoclonal antibodies such as HCD 122, formerly Chiron 1212 which acts against CD40, are in clinical trial.
Tomorrow
It is clear that the chemo-immunotherapy protocols of FR and FCR have had a major impact in improving the clinical eradication of most leukemic cells in majority of patients. Converting this improved response rate to a cure will require the continued exploration of attempts to eradicate minimal residual disease with antibodies, lenalidomide, etc. Mini-allogeneic transplants will certainly be offered earlier because of the improved safety and a possibility of cure. Adding rituximab to the preparative regimens appears to be a significant advance and will continue to be explored. Combination antibody approaches are very promising, producing higher response rates than would be expected if it was just the additive effects of the two drugs. This suggests that there may be some synergistic activity. Combination antibodies are now being included in chemo-immunotherapy programs.
We are continuing to improve our understanding of the biology of CLL which should lead to the exploration of targeted approaches to therapy. After identifying the loss of very small genes such as the micro-RNA genes, mir15 and 16, Drs. Carlo Croce and George Calin are looking at the synthesis of agents that might be administered intravenously to control leukemic cells. Immune restoration of the damage to the immune system from the disease and treatment will also be undertaken in the future with the eventual goal being to not only eradicate the disease but also restore the patient to normal immune health.
Conclusion
The future for CLL is bright. Never in the history of CLL has there been so much progress in such a short period of time as has occurred over the last 2 – 3 years. Real prospects for curative strategies are in place. Long term follow-up of these studies will require persistence of investigators and recruitment of investigators young enough to follow the studies through to maturity.
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.
