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Thrice-Weekly Low-Dose Rituximab Decreases CD20 Loss via Shaving and Promotes Enhanced Targeting in Chronic Lymphocytic Leukemia¹

Michael E. Williams^*, John J. Densmore^*, Andrew W. Pawluczkowycz, Paul V. Beum, Adam D. Kennedy, Margaret A. Lindorfer, Susan H. Hamil^*, Jane C. Eggleton^* and Ronald P. Taylor^2,

^* Hematology/Oncology Division and Hematologic Malignancy Program, and Department of Biochemistry and Molecular Genetics, University of Virginia Health System, Charlottesville, VA 22908

Treatment of chronic lymphocytic leukemia (CLL) patients with standard dose infusion of rituximab (RTX), 375 mg/m², induces clearance of malignant cells from peripheral blood after infusion of 30 mg of RTX. After completion of the full RTX infusion, substantial recrudescence of CLL cells occurs, and these cells have lost >90% of CD20. To gain insight into mechanism(s) of CD20 loss, we investigated the hypothesis that thrice-weekly low-dose RTX (20 or 60 mg/m²) treatment for CLL over 4 wk would preserve CD20 and enhance leukemic cell clearance. During initial infusions in all 12 patients, the first 30 mg of RTX promoted clearance of >75% leukemic cells. Four of six patients receiving 20 mg/m² RTX retained 50% CD20, and additional RTX infusions promoted further cell clearance. However, four of six patients receiving 60 mg/m² had CD20 levels <20% baseline 2 days after initial infusions, and additional RTX infusions were less effective, presumably due to epitope loss. Our results suggest that when a threshold RTX dose is exceeded, recrudesced RTX-opsonized cells are not cleared, due to saturation of the mononuclear phagocytic system, but instead are shaved of RTX-CD20 complexes by acceptor cells. Thrice-weekly low-dose RTX may promote enhanced clearance of circulating CLL cells by preserving CD20.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Commonwealth Foundation for Cancer Research and a University of Virginia Cancer Support Grant.

² Address correspondence and reprint requests to Dr. Ronald P. Taylor, Box 800733, University of Virginia Health Sciences Center, Charlottesville, VA 22908-0733. E-mail address: rpt{at}virginia.edu

³ Abbreviations used in this paper: RTX, rituximab; CLL, chronic lymphocytic leukemia; NHL, non-Hodgkin’s lymphoma; ALC, absolute lymphocyte count; Al, Alexa Fluor; MESF, molecules of equivalent soluble fluorochrome; FcR, receptors specific for the Fc portion of IgG; MPS, mononuclear phagocytic system; HEL, hen egg white lysozyme.

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