The initial use of chemotherapy for CLL has evolved over the past 15 years from alkylator-based monotherapy to fludarabine and then to fludarabine/cyclophosphamide (FC) based upon well-designed randomized phase III studies demonstrating improved overall response (OR), complete remission (CR), and progression-free survival (PFS) with successive treatment regimens. Several phase II studies adding rituximab to the fludarabine regimens demonstrated further promising incremental increases in CR rates and durations of PFS as compared to historical trials. At the 2008 ASH meeting, two large randomized phase III trials demonstrated that FC plus rituximab (FCR) was better than FC alone with respect to OR, CR, and PFS. All of the large phase III combination studies of FC or FCR to date have administered the therapeutic agents together based upon multiple preclinical studies suggesting synergy between each agent. While this approach is based upon pre-clinical work, disadvantages to concurrent therapy include the inability to deliver dose intensity of each agent and also the potential of enhanced toxicity, such as secondary acute myeloid leukemia.
Lamanna, et al., from the Memorial Sloan-Kettering Lymphoma Program, have now reported promising data with sequential use of standard-dose fludarabine, high-dose cyclophosphamide, and consolidation rituximab (F→C→R) for previously untreated CLL where they demonstrate similar response, CR, and PFS as observed with the FCR-based regimens. This regimen was well tolerated despite a high proportion of advanced Rai stage patients, as compared to most other trials reported for CLL. This group rightfully calls attention to their previous study of sequential fludarabine followed by cyclophosphamide (F→C) and a randomized phase II study comparing sequential versus concurrent rituximab with fludarabine that all demonstrated no obvious disadvantage to sequential treatment with respect to PFS but improved tolerability for patients. It is only through a randomized phase III trial that this will be adequately evaluated, and this study suggests that performing such a trial should be considered in the future.
The phase II trial reported by Lamanna, et al. brings forth other important points that are worthy for consideration in the practice of caring for CLL patients. Specifically, they demonstrated that patients attaining a CR with absence of minimal residual disease (MRD) in the bone marrow had an extended PFS and overall survival (OS). This finding provides impetus to consider a bone marrow biopsy/aspirate with appropriate diagnostics for detecting MRD in all CLL patients receiving combination therapy. Given the short PFS and OS of patients not attaining a CR in this and other previously reported studies, it emphasizes that additional therapies should be considered as part of future clinical trials. It is in this context that sequential treatment to the point of absence of detectable MRD might provide an interesting study question and potentially limit unnecessary exposure to multiple agents among early-treatment responders.
Finally, the long-term results of this study support other phase II studies that have suggested that the addition of rituximab to CLL therapy may improve OS, as compared to historical controls. The recently reported randomized phase III trial by the German CLL study group should address this question in the future.
Lamanna, Weiss, and colleagues are to be commended for their systematic pursuit of the sequence-treatment concept over the past decade that has added another relevant question for future clinical trials in CLL.
Dr. Byrd receives support for the cost of clinical trials with agents that are currently being developed by Genentech and Biogen IDEC.