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

Abstract

Late-onset neutropenia following rituximab results from a hematopoietic lineage competition due to an excessive BAFF-induced B-cell recoveryRituximab 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.Haematologica 2007; 92:(2)e20-e23 IntroductionRituximab, an anti-CD20 monoclonal antibody, is increasingly used in the treatment of lymphoma and autoimmune diseases. CD20 is expressed on malignant B-cells, normal differentiated B-cells and pre-B-cells, but not on stem cells and granulocyte precursors. Late-onset neutropenia following rituximab (LON) have been reported, 1-7 occurring 1 to 6 months after last rituximab infusion, as being severe (<0.5x10 9 /L), spontaneously reversible and without life-threatening infections.Several studies suggest that LON could be related to an excess of T-Large Granular Lymphocyte (LGL) in the bone marrow (BM) and peripheral blood (PB) which express and secrete large amounts of Fas and Fas Ligand (FasL) leading to apoptosis of mature neutrophils, 4 or to a production of autoantibodies binding to the neutrophil surface during recovery of a new immune repertoire. 2,6 On the other hand, a recent study suggests that LON is not related to circulating factors but to perturbations of Stromal-derived Factor 1 (SDF-1) and granulopoiesis homeostasis during B-cell recovery.7 This is reinforced by previous studies showing the hypocellularity of the marrow at the time of LON [1][2][3]6 and the absence of anti-neutrophil antibodies in the serum or T-LGL in the PB., 2,6,7 We report here that LON is related to a lack of granulopoiesis in the BM that coincides with the time of maximum B-cell depletion in PB, and proposed the hypothesis that LON is due to a hematopoietic lineage competition in the BM by promotion of B-cell lymphopoiesis over granulopoiesis within common developmental niches. Study designCase report. /L). At admission on day 84, blood tests revealed a severe neutropenia (0.2x10 9 /L), with normal hemoglobin level and platelet count, but the exact time from last treatment to the development of neutropenia could not be precisely determined with the available data. The serum monoclonal component...

Late-onset neutropenia associated with rituximab therapy: evidence for a maturation arrest at the (pro)myelocyte stage of granulopoiesis

“…Maturation arrest at the (pro)myelocyte stage of myelopoiesis is a characteristic feature of severe congenital neutropenia (SCN) of either autosomal dominant or recessive inheritance [15] and is related to mutations in the HAX1 or ELA2 genes [21,22], which in turn is associated with increased myeloid apoptosis at the (pro)myelocyte stage [16,17]. Our current investigations, therefore, provide evidence of similarities in the pathogenesis of LON and SCN.…”

“…In further support of this notion, Voog et al [14] identified eight patients with LON and detected antineutrophil antibodies in two of these patients. However, the absence of anti-neutrophil antibodies in other studies [8,10,11,21,22] suggests that additional factors are also involved in LON.…”

“…Some authors have hypothesized that the balance between granulopoiesis and lymphopoiesis in the BM could be disturbed following rituximab treatment [10,22]. LON could also result from B-cell depletion-induced variations of growth and retention factors, including stromal-derived factor-1 (SDF-1) and B-cell-activating factor (BAFF).…”

Late‐onset neutropenia following rituximab therapy in rheumatic diseases: Association with B lymphocyte depletion and infections

“…However, the relationship of late-onset neutropenia to B lymphocyte depletion is intriguing, as patients with late-onset neutropenia had a longer and deeper B lymphocyte depletion and lower serum IgM levels than controls. This phenomenon may be related to a more pronounced B lymphocyte depletion reported in SLE patients with the Fc␥ receptor IIIa 158 V allele after rituximab treatment (10) and to lack of granulopoiesis coinciding with high levels of B lymphocyte-activating factor (11).…”

Unexpected Hematologic Effects of Biotherapeutics in Nonclinical Species and in Humans

“…One theory is that neutropenia arises from impaired myelopoiesis due to altered growth factors and/or competition between cell lineages in the marrow niche during homeostatic restoration of B cells (Dunleavy et al 2005;Terrier et al 2007). Alternatively, Fas-mediated apoptosis of neutrophils by increased Fas associated with expansion of reactive granular T lymphocytes has been demonstrated by one group (Stamatopoulos et al 2008) but has not been confirmed by other investigators (Fukuno et al 2006;Terrier et al 2007;Tesfa et al 2008).…”