Therapies for Chronic Lymphocytic Leukemia
Leukemia Insights - Fall 2009
Advances continue in identifying new, active drugs for patients with CLL and understanding the biology of this disease. The utility of prognostic factors in managing patients with CLL continues to be of interest; prospective studies are ongoing to assess association of prognostic factors with time from diagnosis to first treatment, remission duration, time to becoming refractory, and overall survival. Specific chromosome abnormalities identified by FISH, including 11q deletion and 17p deletion, are associated with high-risk disease and are now being targeted with new treatment strategies. These chromosome abnormalities are associated with short remission duration and resistance to standard treatments; therefore identifying active agents for patients with these abnormalities will be an advance.
Two large phase III clinical trials conducted in Europe, one in frontline and one in salvage therapy, demonstrated the FCR regimen (fludarabine-cyclophosphamide-rituximab) as the superior frontline and salvage regimen compared with FC. The FCR regimen, originally developed at M. D. Anderson, has become the standard frontline treatment and standard salvage regimen for previously treated patients who had not received extensive prior treatment. We continue to work to develop the FCR regimen into a more effective regimen by studying dose modification and the addition of new agents that have a different mechanism of action.
The most notable new agent recently studied at M. D. Anderson, in collaboration with other US and European investigators, has been ofatumumab, a fully human monoclonal antibody that binds to CD20. Ofatumumab binds to a different epitope of CD20 than rituximab and is more efficient at mediating complement-dependent lysis of malignant B cells. Ofatumumab was shown to be active in treating patients who were refractory to both fludarabine and alemtuzumab and patients who were refractory to fludarabine and had bulky (>5cm) lymph nodes. The pivotal trial results were reviewed favorably by ODAC and it is likely the FDA will approve ofatumumab by the end of this year. M. D. Anderson investigators have a number of studies planned with ofatumumab, including in combination with chemotherapy, as single-agent for residual disease, and as single-agent for early treatment of high-risk patients.
When patients with CLL are evaluated at M. D. Anderson, they undergo prognostic factor evaluation including IgVH mutation status, ZAP-70 and CD38 assessment, cytogenetics by metaphase karyotyping, and FISH analysis. We provide this information, along with all diagnostic information, to our referring physicians. These tests are done to prospectively assess the clinical relevance of these prognostic factors in predicting outcome in CLL and we are working on developing treatments specifically for patients with high-risk features such as 11q deletion and 17p deletion.
Treatment for Older Patients
Patients older than 65 years have lower tolerance for more myelosuppressive regimens such as FCR. This is reflected in lower complete and overall response rates and shorter survival for these older patients. Clearly, effective treatment that is well-tolerated is needed for this group of patients who actually represent the majority of patients managed by community physicians. To develop new treatments for these patients, we are focusing on the activity and mechanism of action of the immune-modulating agent lenalidomide and monoclonal antibodies for patients older than 65.
The FCR regimen, developed at M. D. Anderson, is the most active combination for patients in both the frontline and salvage settings. We work to improve on that with novel combinations of chemotherapeutic agents with immunomodulating drugs. Strategies include combining FCR with GM-CSF (sargramostim), which is an immune-enhancing agent that upregulates expression of CD20 on
CLL B-cells and enhances in vivo antibody-dependent cell-mediated cytotoxicity (ADCC) activity. ABT-263 is an oral small molecule inhibitor of anti-apoptotic Bcl-2 family members. We are completing a phase I clinical trial of single-agent ABT-263 and are opening a clinical trial with combined ABT-263 with FCR. For previously treated patients, clinical trials with the FCR backbone include the addition of bevacizumab (anti-VEGF mAb). Ofatumumab, the new, fully human monoclonal antibody (mAb) against CD20, is being evaluated in combination with fludarabine and cyclophosphamide in previously untreated patients.
New Drug Development
Our research focuses on identifying new and effective drugs that work by different mechanisms of action than traditional purine analogs and alkylating agents. These agents include new nucleoside analogs that work by distinct mechanisms (DNA- and RNA-directed agents), monoclonal antibody against novel antigens, a small-molecule Bcl-2 family member inhibitor, protein kinase inhibitors, a hypomethylating agent, and a cyclin-dependent kinase inhibitor. Because these agents are not approved by the FDA, treatment and follow-up must be done at M. D. Anderson. Plerixafor (Mozobil) is an antagonist of the alpha-chemokine receptor CXCR4 and an agonist of CXCR7 and is FDA-approved for stem cell mobilization. Interactions between CLL cells and the
microenvironment are responsible for leukemia cell survival and protection from chemotherapy-induced apoptosis. We are evaluating plerixafor in combination with rituximab for previously treated patients with CLL.
Strategies to eliminate minimal residual disease are also under development including: lenalidomide and the bi-specific (anti-CD3 + anti-CD19) mAb. Completing these studies in a timely manner will allow us to move quickly on positive leads. We appreciate referrals and will make every effort, once a patient is enrolled on a study, to continue as much of the care as possible through the referring oncologist. We also will keep you apprised of the patient’s progress.
If you have questions about CLL-focused research, please contact Drs. William Wierda, Susan O’Brien, Michael Keating or Alessandra Ferrajoli. Or feel free to contact any other physician.