The role of BAFF and G-CSF for rituximab-induced late-onset neutropenia (LON) in lymphomas.

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.