B cell reconstitution after rituximab treatment of lymphoma recapitulates B cell ontogeny

doi:10.1016/j.clim.2006.08.009

Clinical Immunology

Volume 122, Issue 2, February 2007, Pages 139-145

https://doi.org/10.1016/j.clim.2006.08.009 Get rights and content

Abstract

The long-term immunologic effects of B cell depletion with rituximab and the characteristics of the reconstituting B cell pool in lymphoma patients are not well defined, despite the widespread usage of this therapy. Here we report that during the B cell reconstitution phase a majority of the peripheral blood B cells have an immature transitional phenotype (47.8% ± 25.2% vs. 4.4% ± 2.4% for normal controls, p < 0.0001), similar to what has been described during the original ontogeny of the immune system and following bone marrow transplantation. Moreover, the recovery of the CD27+ memory B cell pool was delayed compared to normal B cell ontogeny, remaining below normal controls at 1 year post-rituximab (4.4% ± 3% vs. 31% ± 7%, p < 0.0001). Expansion of functionally immature B cells and decreased memory B cells may contribute to an immunodeficient state in patients recovering from rituximab mediated B cell depletion, particularly with repeated treatment.

Introduction

Rituximab is a monoclonal antibody directed against the B cell specific antigen CD20, an integral membrane protein believed to function in B cell cycle initiation and differentiation. Owing to its high and relatively sustained expression on neoplastic and normal B cells, CD20 represents an ideal target for immunotherapy of an ever-growing variety of B cell disorders, both malignant and nonmalignant. Indeed, since its approval in 1997 for the treatment of non-Hodgkin's lymphoma, the use of rituximab has expanded into additional malignant conditions as well as autoimmune diseases [1], [2].

Despite the widespread use of this therapeutic modality, the phenotype of the B cells emerging after rituximab treatment has only recently been described and not in lymphoma [3], [4]. We questioned whether lymphoma patients undergoing B cell reconstitution post-rituximab experience a recapitulation of B cell ontogeny, similar to the post-transplant setting. In the latter situation, the emerging B cells have an immature phenotype [5] that may account for the prolonged B cell dysfunction seen in these patients [6], [7], [8]. This has important implications, particularly given the increasing use of rituximab “maintenance” schedules [9], [10]. Thus, as part of two clinical trials of rituximab combined with either a CpG oligonucleotide or an anti-idiotype vaccine in the treatment of follicular NHL, we evaluated the phenotype and kinetics of returning B cells after rituximab therapy.

Section snippets

Clinical samples

All patients had a diagnosis of follicular non-Hodgkin's lymphoma, grades 1–3, confirmed with hematopathology review at University of Rochester (Table 1). Two cohorts of lymphoma patients were examined: [1] patients with relapsed follicular non-Hodgkin's lymphoma participating in a phase II trial of rituximab and CpG oligonucleotide (n = 7, patient numbers 1–7) receiving standard dose rituximab on day 0, 7, 14, and 21 and CpG on day 7, 14, 21, and 28 and [2] patients with de novo, previously

The kinetics of B cell reconstitution

With rituximab treatment, all patients had profound depletion of peripheral blood B cells to less than 5 cells/μl. Consistent with prior reports, this level of B cell depletion persisted for 6–9 months in most patients (Table 1) [11]. B cell recovery to pre-treatment levels occurred by 12 months, although the median peripheral B cell counts (28 cells/μl) remained well below the normal lower limit of 50 B cells/μl. Our results are in accord with a recent study that found repeated courses of

Conclusions

Key findings of the present manuscript include the demonstration in rituximab treated lymphoma patients of: [1] a substantial peripheral expansion of both T1 and T2 B cells at immune reconstitution [2], functional immaturity of these transitional B cell subsets based on extensive in vitro assays not previously utilized to define these populations post-rituximab [3], the prolonged dominance of the peripheral B cell pool by transitional B cells suggestive of a maturation block [4], a correlation

Acknowledgments

We acknowledge Ray Felgar and Arnaldo Arbini for hematopathology review and Chungwen Wei for expert review of the manuscript. We appreciate the assistance of Sally Quataert of the Human Immunology Center in the early flow cytometry analysis of the lymphoma cohorts.

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^☆: Supported in part by grants to JHA from NIH-NIAMS K08AR048303, the Lupus Foundation of America, and the Alliance for Lupus Research; and RO1 AI049660-01A1 and U19 Autoimmunity Center of Excellence AI56390 to IS. JWF was supported in part by a career development award from the National Cancer Institute (CA-102216).

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Rapid CommunicationB cell reconstitution after rituximab treatment of lymphoma recapitulates B cell ontogeny☆

Abstract

Introduction

Section snippets

Clinical samples

The kinetics of B cell reconstitution

Conclusions

Acknowledgments

Blood

Blood

Exp. Hematol.

Blood

Blood

Ann. Oncol.

Blood

B cells as therapeutic targets for rheumatic diseases

Curr. Opin. Rheumatol.

Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis

Arthritis Rheum.

Regeneration of B cell subsets after transient B cell depletion using anti-CD20 antibodies in rheumatoid arthritis

Arthritis Rheum.

B cell reconstitution after human bone marrow transplantation: recapitulation of ontogeny?

Bone Marrow Transplant.

Abnormal CD4:CD8 ratios and delayed germinal center reconstitution in lymph nodes of human graft recipients with graft-versus-host disease (GVHD): an immunohistological study

Exp. Hematol.

Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma—a randomized phase II trial of the Minnie Pearl Cancer Research Network

J. Clin. Oncol.

Rapid Communication
B cell reconstitution after rituximab treatment of lymphoma recapitulates B cell ontogeny☆