Abstract
Mechanisms for late-onset neutropenia (LON) after rituximab treatment are poorly defined both for non-Hodgkin lymphoma (NHL) and for autoimmune disorders. We performed a case–control analysis of a prospective cohort of 169 evaluable consecutive rituximab-treated NHL patients to assess cytokines involved in neutro- and lymphopoiesis (G-CSF, SDF1, BAFF, APRIL) and inflammation (CRP) as possible LON mechanisms. Fifteen patients (9%) developed LON (peripheral blood /PB/ absolute neutrophil counts /ANC/ < 0.5 G/L, all with marked depletion of CD20+ B-lymphocytes in bone marrows); they were compared with 20 matched NHL controls without LON. At start of LON, significantly higher PB G-CSF and BAFF levels (P = 0.0004 and 0.006, respectively), as well as CRP rises were noted compared to controls; these G-CSF and BAFF and most CRP values returned to levels of the controls in post-LON samples. G-CSF (but not BAFF) changes correlated to CRP rises (but not to ANC levels). BAFF levels correlated significantly to absolute monocyte counts and PB large granular lymphocyte counts (but not to ANC, C-CSF or CRP values). No changes of SDF1 or APRIL levels were noted. Neither LON cases nor controls displayed anti-neutrophil autoantibodies. Collectively, LON in NHL patients was timewise related to transient bursts of blood G-CSF and BAFF concentrations, suggesting that these neutro- and lymphopoiesis growth factors play a role in emergence of rituximab-induced LON, and that inflammation may be a trigger for G-CSF production during LON.
Highlights
Late-onset neutropenia (LON), following rituximab therapy for autoimmune diseases or lymphomas, is an unusual type of drug-induced neutropenia (NP), because it occurs between 1 and 12 months after completing rituximab therapy [1,2,3]
C D20+ B-lymphocytes are rapidly depleted and they reappear to the peripheral blood (PB) after 5–12 months [6, 11, 12], preceded by an elevation of peripheral blood (PB) levels of BAFF [4].Elevated BAFF levels have been reported in LON in rheumatic diseases, with a return to basal levels after LON [6], yet its role in LON development is unclear, as well as the underlying mechanisms involved in BAFF elevation
We and others reported that LON in lymphoma and rheumatic patients is related to the possession of certain BAFF and FCGR3 gene polymorphisms [13, 14], suggesting possible genedrug interactions
Summary
Late-onset neutropenia (LON), following rituximab therapy for autoimmune diseases or lymphomas, is an unusual type of drug-induced neutropenia (NP), because it occurs between 1 and 12 months after completing rituximab therapy (and not during or shortly after intake as with most agranulocytosis-inducing drugs) [1,2,3]. The role of BAFF (B-cell activating factor) has attracted attention in relation to rituximab treatment for rheumatic diseases [4,5,6,7]. C D20+ B-lymphocytes are rapidly depleted and they reappear to the peripheral blood (PB) after 5–12 months [6, 11, 12], preceded by an elevation of peripheral blood (PB) levels of BAFF [4].Elevated BAFF levels have been reported in LON in rheumatic diseases, with a return to basal levels after LON [6], yet its role in LON development is unclear, as well as the underlying mechanisms involved in BAFF elevation. We and others reported that LON in lymphoma and rheumatic patients is related to the possession of certain BAFF and FCGR3 gene polymorphisms [13, 14], suggesting possible genedrug interactions
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