Recurrence of persistent polyclonal B lymphocytosis (PPBL) after rituximab treatment

Dear Editor, Persistent polyclonal B lymphocytosis (PPBL) is a rare entity with a polyclonal increase of marginal zone-like B lymphocytes in the peripheral blood [1, 2], most prevalent in smoking middle-aged women [3]. Patients display elevated immunoglobulin M (IgM) and sometimes decreased IgG levels in the serum [4–6]. Splenomegaly and/or polyclonal lymphocytic infiltration of the bone marrow may be present [7, 8]. The disease has been associated with HLA-DR7 positivity and chromosomal abnormalities [6], but its etiology remains elusive. Herein, we report its recurrence after rituximab treatment, revealing interesting aspects of its putative pathophysiology. A 44-year-old Caucasian womanwith a history of Sudeck’s dystrophy and hysterectomy presented with epigastric pain. The patient was an active smoker. Awork-up revealed splenomegaly (3.6×16.5 cm) in the absence of enlarged lymph nodes. A differential blood count showed normal leukocyte count (9440/μl) with lymphocytosis (4863/μl, normal 1000– 2800/μl), and blood smear showed atypical, agranular large lymphocytes with bilobated nuclei (Fig. 1a). IgM was elevated (3.18 g/l, normal 0.4–2.3 g/l, Fig. 1b) without monoclonal bands in immunofixation, and IgG was reduced (4.09 g/l, normal 7–16 g/l). A bone marrow biopsy showed normal hematopoiesis and mild lymphocytosis without blasts or light chain restriction. Relative lymphocytosis in the peripheral blood was traced back to a B lymphocytosis (3457/μl, normal 100–500/μl, Fig. 1c) with no detectablemonoclonality in flow cytometry and IgH clonality analysis (Fig. 1d). The patient was HLA-DR7 negative. Albeit a watch-and-wait strategy is generally indicated in this situation, the patient was treated four times with 375 mg/ m rituximab resulting in the normalization of her spleen size (3.7×10.8 cm) and IgM level (2.1 g/l), as well as an eradication of her peripheral blood B lymphocytes (0/μl). Eighteen months after rituximab treatment, her B cell counts were back to normal (307/μl) and a mild polyclonal IgM elevation had returned (2.47 g/l). B cell numbers continued to rise over the next months (Fig. 1c), lymphocytes with bilobated nuclei reappeared, and B cell subpopulation analysis 2 years after the rituximab treatment showed an expansion of marginal zone-like B lymphocytes in the peripheral blood (52.1 % of B cells, normal <30.8 %) indicating recurrence of PPBL. However, her spleen size was still normal. FISH analysis revealed one or two 3q gains in 3.5 % of B cells, respectively (Fig. 1e, cutoffs for non-B cells 0.5–1.0 %). The recurrence of the PPBL phenotype after eradication of the recirculating B cell pool is remarkable and gives rise to various speculations on the etiology of PPBL. Given the high cellular burden in PPBL, an insufficient eradication and re-expansion of affected B cells in peripheral tissues is a possible explanation; however, the eradication from peripheral blood was complete. Alternatively, as CD20 expression is C. Wehr : L. Houet : S. Gutenberger :K. Warnatz (*) Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg, Breisacherstrasse 117, 79106 Freiburg, Germany e-mail: klaus.warnatz@uniklinik-freiburg.de