Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 22, No 14S (July 15 Supplement), 2004: 2529
© 2004 American Society of Clinical Oncology

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Abstract

Synergistic interaction between rituximab and 2-chlorodeoxyadenosine (2-CdA) against Waldenstrom's Macroglobulinemia preclinical model

Wayne State University, Detroit, MI

2529

Background: Waldenstrom's Macroglobulinemia (WM) is an incurable malignant disorder. Rituximab represents a new therapeutic modality for B-cell tumors and has modest activity in WM. Among cytotoxic agents, 2-CdA has significant activity. In this study, Rituximab and 2-CdA combination was used in pre-clinical SCID mouse xenograft model of human WM (WSU-WM-SCID) (Blood 81:3034, 93). Methods: Subcutaneous (sc) tumor-bearing ICR-SCID mice were randomly assigned to one of four groups (8 animals each): Group 1 (control); Group 2 received Rituximab intravenously (iv) via tail vein daily x 5 days at a dose of 150 mg/kgm/day; Group 3 received 2-CdA injections sc daily x 5 days at MTD of 30 mg/kg/d; Group 4 received a combination of Rituximab and 2-CdA, as in groups 2 and 3, concurrently. Two treatment cycles were given with one week rest in between. Subsequent experiments focused on biological studies and involved removing tumors following therapy for flow cytometry and deoxycytidine kinase (dCK) activity. Results: Both agents showed modest activity in this model [Rituximab T/C = 30%, T-C = 13 days, Log₁₀kill 1.9; 2CdA T/C = 36.9%, T-C = 14 days, Log₁₀kill 1.33] but tumors progressed within 1 week. Residual tumors following Rituximab therapy preserved original phenotype except were CD20(-) due to Rituximab binding as confirmed by anti-Rituximab antibody. When used in combination, 8/8 animals were cured (no tumor development for 120 days). Treatment was well tolerated. Rituximab therapy increased dCK activity by 170%, 210%, and 258% after 1, 3, and 5 injections respectively. dCK is key to the phosphorylation of 2-CdA to its active metabolite 2-CdATP. Conclusions: there is synergistic interaction between Rituximab and 2-CdA leading to cure in this WM model. Enhancing dCK activity is one mechanism of interaction between the two agents. The WSU-WM-SCID is a model of resistant WM where no cures were achieved using standard agents until now. Clinical use of the combination against WM is recommended.

Author Disclosure

Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration International Waldenstrom's Macroglobulinemia Foundation

Abstract presentation from the 2004 ASCO Annual Meeting