John C. Byrd, MD
Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164-1174.
Therapy for chronic lymphocytic leukemia (CLL) over the past five decades has included different types of chemotherapy treatment including alkylator agents (chlorambucil and cyclophosphamide) and nucleoside analogs (fludarabine, cladribine, and pentostatin). While these non-targeted chemotherapy-based approaches have effectively palliated symptoms of CLL, no impact on improving overall survival of CLL patients has been appreciated. The early introduction of the anti-CD20 chimeric antibody rituximab with chemotherapy-based approaches in phase I/II studies in the late ’90s yielded dramatic disease reduction resulting in a high proportion of complete remissions that over time remained durable. These very encouraging data derived from the combination chemotherapy (fludarabine or fludarabine and cyclophosphamide) and rituximab (i.e., chemoimmunotherapy) raised significant excitement in the field of CLL for this approach. Derived from this excitement were well-designed phase III studies by several different study groups to examine formally the importance of rituximab therapy for improving CLL therapy outcome. In a recent Lancet publication, Hallek and colleagues from the German CLL Study Group report the first such phase III study (CLL8) comparing rituximab, fludarabine, and cyclophosphamide to fludarabine and cyclophosphamide alone in a large number of symptomatic, previously untreated CLL patients. The results of this study are very exciting, as they demonstrate in a large definitive study population that addition of rituximab to fludarabine and cyclophosphamide dramatically improves response rate, progression-free survival, and overall survival. The extra side effects seen with rituximab were quite minimal except for asymptomatic neutropenia, a finding not seen in other chemoimmunotherapy trials. As part of this trial, the German CLL group also examined specific genetic groups where the greatest benefit of chemoimmunotherapy was observed in patients having del(13q14), del(11q22.3), and trisomy 12. In contrast, patients without a detectable interphase cytogenetic abnormality or those with del(17p13.1) gain little benefit from this treatment. Collectively, this study validates the value of rituximab as an essential component of CLL therapy and also that specific genetic groups derive the most benefit from this treatment.
The importance of this paper is that it is transforming to the field of CLL. The finding of a targeted agent rituximab prolonging survival in CLL has not been appreciated with any other chemotherapy examined prior to this time. Moving forward, it provides strong justification to improve on the properties that make the anti-CD20 rituximab antibody effective against CLL and also for the development of alternative agents that might target pathways influenced by rituximab. It also opens the question about whether applying such therapy earlier in the course of the disease in patients with high-risk but asymptomatic disease might also improve CLL survival further. This question is now being studied by the German CLL Study Group, and we will anxiously await the answer of this second study.
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