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