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Advances in CLL Therapy Offer Prolonged Survival; Toxicities Continue to Plague Elderly Patients
The identification of prognostic factors and advances in first-line chemoimmunotherapy has allowed for extended progression-free and overall survival in select patients with Chronic Lymphocytic Leukemia (CLL). However, challenges remain in treating elderly patients due to high toxicities associated with effective therapies. An update on the treatment of CLL incorporating recommendations from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) was the focus of a recent presentation given at the National Comprehensive Cancer Network® (NCCN®) 6th Annual Congress: Hematologic Malignancies™.
FORT WASHINGTON, PA — First-line chemoimmunotherapy options for patients with Chronic Lymphocytic Leukemia (CLL) offer prolonged survival, yet there remains a void for effective therapies that can be tolerated by elderly patients with the disease, according to Susan O`Brien, MD, of the University of Texas MD Anderson Cancer Center. Dr. O`Brien emphasized the importance of assessing the condition of the patient as well as exploring the clinical utility of cytogenetic abnormalities when selecting therapy. Several promising agents in clinical trials were also discussed during a presentation by Dr. O`Brien at the NCCN 6th Annual Congress: Hematologic Malignancies™.
One of the most common cytogenetic abnormalities in patients with CLL is del (11q). Deletion of 11q is associated with extensive lymphadenopathy, disease progression, and shorter median survival. However, the alkylating agent-based chemoimmunotherapy regimen of fludarabine (Fludara®, Genzyme/Sanofi ) / cyclophosphamide (Cytoxan®, Bristol-Myers Squibb) / rituximab (Rituxan®, Genentech BioOncology and Biogen Idec) also known as FCR, has shown to significantly improve clinical outcomes.
Dr. O`Brien spoke to the results of a recent clinical trial demonstrating why FCR has become the standard of care for healthy, fit patients with CLL del (11q) as noted in the NCCN Guidelines™ for Non-Hodgkin`s Lymphomas.
The study demonstrated that FCR is superior compared to other regimens in improving progression-free survival and overall survival in patients with CLL, said Dr. O`Brien. More importantly, it demonstrates that the choice of initial treatment for CLL may alter the clinical course of the disease.
A second common cytogenetic abnormality in patients with CLL is del (17p). Deletion of 17p is associated with low response rates with all treatments. Dr. O`Brien noted that since there is no standard treatment, the NCCN Guidelines recommend enrollment into a clinical trial.
The 17p deletion is the mother of all poor prognostic factors for CLL, said Dr. O`Brien.
Although a clinical trial is preferred, the NCCN Guidelines include a list of potential first-line therapy regimens for patients with del (17p). In addition, patients who have achieved partial or complete response to first-line therapy should be considered for allogeneic stem cell transplant.
Treating elderly patients or younger patients with significant co-morbidities continues to be a challenge for physicians.
There is no real standard of care for elderly patients with CLL as the more effective regimens are associated with higher hematologic toxicities, said Dr. O`Brien. The effect of age and co-morbidities on side effects of treatment is quite significant.
The FCR regimen can cause severe cytopenia during and after therapy and is not tolerated well by older patients. In addition, elderly patients often don`t meet the creatinine clearance requirements to receive a therapy such as FCR.
Since CLL is primarily a disease of the elderly, the treatment strategy needs to remain highly individualized, added Dr. O`Brien.
For those patients with poor prognostic factors, Dr. O`Brien described several promising agents in clinical trials.
The lack of myelosuppression, one of the largest issues in treating patients with CLL with the FCR regimen or almost any of the regimens, is particularly exciting with these novel agents, said Dr. O`Brien.
Dr. O`Brien touched upon PCI-32765, a small molecule inhibitor of Bruton`s Tyrosine Kinase (BTK) that has shown to be highly active in inhibiting CLL cell migration and adhesion. In addition to being effective, she noted that it appears to be extremely well tolerated in patients.
A second agent being investigated is CAL-101, an orally bioavailable small molecule that inhibits PI3K Delta. A Phase I study testing CAL-101 with bendamustine (Treanda®, Cephalon Oncology) and/or rituximab resulted in tumor shrinkage in all evaluable patients with CLL, including those with del (17p). The drug was well tolerated and marked reductions in peripheral lymphadenopathy were observed.
Research needs to focus on treatment options for the populations that are not suitable to receive FCR and other standard chemoimmunotherapy options, said Dr. O`Brien. With continued advances, the goal of therapy will no longer be to simply palliate symptoms, but to achieve long term remission and improve survival while preserving a good quality of life.