Rituximab-Induced Changes in Hematolymphoid Tissues Found at Autopsy

Adina M. Cioc, MD; Steven M. Vanderwerf, MD; Bruce A. Peterson, MD; Valentin G. Robu, MD, PhD; Colleen L. Forster; Stefan E. Pambuccian, MD

Disclosures

Am J Clin Pathol. 2008;130(4):604-612. 

In This Article

Abstract and Introduction

The effect of rituximab on malignant B cells and normal circulating B cells has been previously studied. In contrast, data on the degree of depletion of nonneoplastic B cells induced by rituximab in lymph nodes and spleen is limited. For this purpose, clinical charts, autopsy records, lymph node and spleen sections, and immunoperoxidase stains were reviewed from 10 patients who had received 1 to 40 doses of rituximab before death. The percentage of nonneoplastic B cells was lower in the lymph node and spleen in rituximab-treated patients when compared with cyclophosphamide, doxorubicin, vincristine, and prednisone–treated patients and patients without lymphoma. The effect of rituximab on nonneoplastic B cells was observed as soon as 1 month after administration and with as few as 3 doses. Reappearance of normal numbers of B cells was not observed 1 to 12 months after the last dose of rituximab was administered. We conclude that rituximab induces prompt, consistent, profound, and prolonged depletion of B lymphocyte populations in human lymphoid tissue.

Rituximab is a chimeric mouse/human IgG1 κ antibody that reacts specifically with the CD20 antigen found on the surface of malignant and normal B cells.[1,2] Rituximab is widely used as a single agent or in combination with conventional chemotherapy for treatment of low- and high-grade, relapsed, or refractory CD20+ B-cell non-Hodgkin lymphoma (NHL).[3,4] Rituximab has several effects on B cells, such as antibody-dependent cellular cytotoxicity, inhibition of cell proliferation, and apoptosis.[1,5] It also sensitizes malignant B cells to chemotherapy through disruption of antiapoptotic pathways, creating synergy with chemotherapeutic agents.[1,5] Recent studies suggest improved progression-free and overall survival rates with addition of rituximab to chemotherapy regimens for follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL).[6,7,8]

Rituximab also has a substantial effect of depleting normal circulating B cells.[1,2,9,10] The prospect that CD20 targeting might modulate normal or nonneoplastic B-cell function has led to testing of rituximab therapy for a variety of autoimmune disorders such as immune thrombocytopenic purpura, rheumatoid arthritis, and cryoglobulinemia.[11] Data on the degree of normal B-cell depletion in solid tissues, including bone marrow, lymph nodes, and spleen, are limited. Animal studies suggest that B-cell depletion in solid tissues is significant, but not complete, and that it varies from site to site and from individual to individual even when the same doses are used.[10] The main purpose of this study was to assess the influence of rituximab therapy on nonneoplastic B cells in hematolymphoid organs in patients with NHL. For this purpose, we examined tissue procured at autopsy in patients with NHL who were treated with rituximab as a single agent or in combination with chemotherapy.

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