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Late-onset neutropenia following rituximab results from a hematopoietic lineage competition due to an excessive BAFF-induced B-cell recovery

¹ Department of Hematology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris V- René Descartes, Paris
² Department of Rheumatology, Institut National de la Santé Et de la Recherche Médicale (INSERM) U 802, Hôpital Bicêtre, AP-HP, Université Paris-Sud 11, Le Kremlin Bicêtre
³ Department of Immunology, INSERM U 567, IFR 116, Institut Cochin, Paris
⁴ INSERM U 362, IFR 54, Institut Gustave Roussy, Villejuif
⁵ Department of Immunology, INSERM U 653, Institut Curie, Paris;
⁶ Department of Biological Hematology, Hôtel-Dieu, AP-HP, Université Paris-Descartes, Paris
⁷ Department of Immunology, Hôpital Necker-Enfants Malades, AP-HP, Université Paris-Descartes, Paris
⁸ Department of Nephrology, Hôpital Necker-Enfants Malades, AP-HP, Université Paris-Descartes, Paris, France

Correspondance: Pr Agnès Buzyn, Service d’Hématologie Adultes, Hôpital Necker-Enfants Malades, 149-161 rue de Sèvres, 75743 Paris cedex 15, France. Tel: 33 1 44 49 52 86, Fax: 33 1 44 49 52 80, E-mail: agnes.buzyn{at}nck.aphp.fr

Rituximab is used in the treatment of lymphoma and autoimmune diseases, for which late-onset neutropenia (LON) were reported. LON-related mechanisms remain unclear. To obtain insights into the mechanisms, we assessed serum, peripheral blood and bone marrow (BM) samples of a patient with LON. Factors classically associated with neutropenia such as anti-neutrophil antibodies, T-LGL, soluble Fas Ligand were not detectable. We then evaluated the kinetics of various cytokines involved in B-cell and granulocyte homeostasis. We found that LON is related to a lack of granulopoiesis in the BM that coincides with a very high level of BAFF, a strong stimulator of B-cell recovery, and hypothesized a hematopoietic lineage competition due to an excessive B-cell recovery in the BM by promotion of B-cell lymphopoiesis over granulopoiesis within common developmental niches. Assessment of serum BAFF levels following rituximab could detect patients at risk of developing LON.

Key words: Neutropenia, rituximab, BAFF, niches, granulopoiesis, lymphopoiesis, lineage competition.