Advances in the treatment of
chronic lymphocytic leukemia (CLL) have improved initial overall response (OR) rates, complete response (CR) rates and progression free survival (PFS). Despite these advances, CLL remains incurable with standard
therapies. Thus, there remains a need for more effective
therapies in both the upfront and relapsed setting, particularly for patients with high-risk
cytogenetic abnormalities such as del(11q22) and del(17p13). The 2008 American Society of Hematology (ASH) Annual Meeting featured several presentations which highlighted the ongoing clinical advances in CLL. The benefit of adding
rituximab to
purine analog
therapy in the upfront setting was demonstrated by a large randomized study which showed that the addition of
rituximab to
fludarabine and
cyclophosphamide (FCR) significantly improved OR, CR and PFS. The improvement in PFS directly resulted from an improved ability to eliminate
minimal residual disease (MRD) in the peripheral blood, highlighting the importance of MRD eradication. However, a multi-center study suggested that the high CR rates to chemoimmunotherapy regimens such as FCR obtained in academic centers may not be reproducible when the same regimens are given in the community setting. The immunomodulatory drug
lenalidomide is active in relapsed high-risk CLL, but two studies of
lenalidomide in previously untreated CLL patients failed to achieve a CR and were associated with significant
tumor lysis,
tumor flare and hematologic toxicity. In the relapsed setting, a combination study of the bifunctional
alkylator bendamustine and
rituximab (BR) demonstrated a high OR rate in patients with del(11q22) and del(17p13), indicating that further studies to define's
bendamustine activity are warranted in high-risk CLL. Similarly, the CDK inhibitor
flavopiridol demonstrated significant clinical activity and durable remissions in heavily treated, refractory CLL patients with high-risk cytogenetic features and bulky
lymphadenopathy. The monoclonal anti-CD20 antibody
ofatumumab appeared to be superior to
rituximab in relapsed CLL patients with bulky nodal disease or high-risk cytogenetic features. Ongoing studies of these agents and other novel therapeutic agents in clinical development hold forth the promise that treatment options for CLL patients will continue to expand and improve.