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Apoptotic-Regulatory and Complement-Protecting Protein Expression in Chronic Lymphocytic Leukemia: Relationship to In Vivo Rituximab Resistance

Rajat Bannerji, Shinichi Kitada, Ian W. Flinn, Michael Pearson, Donn Young, John C. Reed, John C. Byrd

From the Hematology-Oncology Service, Madigan Army Medical Center, Tacoma, WA; Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, MD; Burnham Institute, Cancer Research Center, La Jolla, CA; and Division of Hematology-Oncology, The Ohio State University, Columbus, OH.

Address reprint requests to John C. Byrd, MD, Division of Hematology-Oncology, Starling Loving Hall, The Ohio State University, Columbus, OH 43210; email: byrd-3{at}medctr.osu.edu.

Purpose: Rituximab has clinical activity in patients with chronic lymphocytic leukemia (CLL) and has a variety of proposed mechanisms, including apoptosis, complement-dependent cell lysis (CDC), and antibody-dependent cellular cytotoxicity (ADCC). Here we examine pretreatment biologic features that promote resistance to apoptosis and CDC in CLL patients and correlate it with clinical outcome to rituximab-based therapy.

Patients and Methods: Pretreatment samples from 21 CLL patients treated on a prospective, single-agent rituximab trial were examined for quantitative expression of apoptotic and CDC regulatory proteins, and the level of expression of these proteins was correlated with clinical outcome.

Results: Of the 21 patents for whom samples were available, 10 attained a partial response and 11 failed to respond to rituximab therapy. The mean pretreatment expression of Bcl-2, Mcl-1, XIAP, and the ratio of Bcl-2/Bax were higher but not statistically increased in nonresponding patients versus those responding to treatment. In contrast, the pretreatment Mcl-1/Bax ratio was significantly elevated (0.82 ± 0.28 v 0.39 ± 0.29, P < .016) in nonresponding patients compared with patients responding to rituximab therapy. Although pretreatment expression of CD55 and CD59 was not associated with response to rituximab therapy, significantly higher levels of CD59 were observed in the CLL cells that were not cleared from the blood at completion of therapy than the level observed at baseline levels (P = .02).

Conclusion: These data indicate that baseline expression of the Mcl-1/Bax ratio, but not CD55 and CD59, predict for clinical response to rituximab therapy in CLL patients. Further study of disrupted apoptosis in CLL as a potential mechanism of resistance to rituximab appears warranted.

This work was supported in part by the National Cancer Institute (P3016058, P01 CA81534-02 and CA98099), National Institutes of Health, Department of Health and Human Services, Bethesda, MD; the Sidney Kimmel Cancer Research Foundation; the Leukemia and Lymphoma Society of America; and the D. Warren Brown Foundation.

R.B. and S.K. contributed equally to the production of this work.

J.C.B. is a Clinical Scholar of the Leukemia and Lymphoma Society of America.

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