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Chemoimmunotherapy of chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) has long been regarded as an incurable disease of the elderly, worthy only of symptom palliation. Past generations of chemotherapy resulted in improved response rates, but did not change the natural history of the disease. Prolonged remissions and improvements in survival are, however, now possible owing to therapeutic advances including the use of purine analogs as frontline treatment and the emergence of monoclonal antibody-containing chemoimmunotherapy combinations. Moreover, consolidation strategies using non-cross resistant agents have improved the success rates of patients with residual disease at the end of induction treatment. Together, these new developments promise to deliver the tools necessary to render a state of minimal residual disease negativity in the majority of patients commencing treatment for CLL. This Review will outline the history and results of chemoimmunotherapy regimens that contain purine analogs and rituximab—the most successful combinations developed to date. We will also discuss how new developments in induction and consolidation strategies are leading the path towards cure.

Key Points

  • Fludarabine and cyclophosphamide (FC) has been selected as the most effective chemotherapy regimen in chronic lymphocytic leukemia (CLL) based on a number of randomized trial comparisons

  • The addition of rituximab to FC (FCR) doubles the proportion of patients entering complete remission, and significantly prolongs remission duration and overall survival

  • The pursuit of the best possible therapy response, including eradication of minimal residual disease as detected by high-resolution assays, is an important therapeutic goal in CLL

  • The future direction for improving the outcome of FCR and similar chemoimmunotherapy regimens lies in the inclusion of new active agents, either in combination or as sequential (consolidation) treatment.

  • A better understanding of the mechanism behind unexpected toxic effects, and exploration of how chemoimmunotherapy can best be tailored for safe administration in vulnerable patients is also necessary

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Figure 1: Selected chemoimmunotherapy regimens.
Figure 2: Survival for patients receiving frontline treatment for chronic lymphocytic leukemia in sequential phase II studies at the University of Texas MD Anderson Cancer Center.

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Acknowledgements

The authors would like to thank Ms Susan Lerner in assistance with preparation of figures.

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C. S. Tam and M. J. Keating contributed equally to the literature review and writing of this manuscript.

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Correspondence to Michael J. Keating.

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Tam, C., Keating, M. Chemoimmunotherapy of chronic lymphocytic leukemia. Nat Rev Clin Oncol 7, 521–532 (2010). https://doi.org/10.1038/nrclinonc.2010.101

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