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.

Effect of FCGR polymorphism on the occurrence of late-onset neutropenia and flare-free survival in rheumatic patients treated with rituximab.

BACKGROUND: The causes and mechanisms of late-onset neutropenia (LON) following rituximab treatment in patients with rheumatic diseases are not known. In this study, we aimed to investigate the role of established Fcγ receptor gene (FCGR) polymorphisms and B-cell-activating factor (BAFF) gene promoter polymorphisms for the development of LON and for the efficacy of rituximab in patients with rheumatic diseases. METHODS: A single-center case-control retrospective study was nested in a cohort of 214 consecutive patients with rheumatic diseases treated with rituximab. Eleven patients presented with LON. Fifty non-LON control subjects were matched by diagnosis, age, sex, and treatments. Single-nucleotide polymorphisms of FCGR (FCGR2A 131H/R, FCGR2B 232I/T, FCGR3A 158V/F) and BAFF promoter polymorphism -871C/T were analyzed with polymerase chain reaction-based techniques, and serum immunoglobulin M (IgM) and BAFF levels were analyzed by enzyme-linked immunosorbent assay. Flare-free survival was related to LON occurrence and polymorphisms. RESULTS: The FCGR3A V allele, but not other FCGR polymorphisms, correlated with the occurrence of LON; each V allele conferred a fourfold increased OR for LON (p = 0.017). FCGR3A 158V/V and presentation with LON were associated with a longer flare-free survival (p = 0.023 and p = 0.031, respectively). FCGR3A 158V/V was related to lower IgM levels (p = 0.016). Serum BAFF levels showed no relationship with LON and BAFF -871C/T promoter polymorphism. There was a tendency toward longer flare-free survival in patients with the BAFF -871T/T allotype compared with the C/T or C/C allotypes (p = 0.096). CONCLUSIONS: The results of the present study suggest that presentation with LON may be a result of the intrinsic efficacy of rituximab in patients with rheumatic diseases. LON could indicate a longer biological and therapeutic activity of rituximab modulated by a certain genotypic polymorphism: the high-affinity FCGR3A V allele. This genotype and the occurrence of LON are both related to longer flare-free survival, suggestive of common mechanisms for LON and duration of response to rituximab. The role of the BAFF -871C/T promoter polymorphism in LON occurrence is unclear.

Late-onset neutropenia following rituximab therapy: incidence, clinical features and possible mechanisms.

Late-onset neutropenia (LON) is emerging as a common adverse effect to rituximab therapy owing to widespread use of this drug in the treatment of B-cell lymphomas and autoimmune diseases. However, the true incidence and mechanisms are not fully understood. LON has been reported in 5?27% of rituximab-treated lymphoma patients. Similar figures apply for autoimmune patients but they appear to have more infections during the neutropenic period. Recent reports imply that host factors may play an intriguing role for development of LON, for example, polymorphisms in FCGR3. Pronounced B-lymphocyte depletion and lower serum IgM, as reported in LON patients during the period of neutropenia compared with matched controls, may play a role for understanding the mechanisms and risk stratification for emergence of LON.

Late-onset neutropenia following rituximab therapy in rheumatic diseases: association with B lymphocyte depletion and infections.

OBJECTIVE: Late-onset neutropenia following rituximab therapy is a well-recognized side effect in lymphoma patients, but only a few cases of late-onset neutropenia have been reported in patients with autoimmune disorders. The purpose of this study was to define the incidence, clinical features, and some of the underlying mechanisms of late-onset neutropenia in relation to rituximab use in several rheumatic diseases. METHODS: We conducted a retrospective analysis of a cohort of 209 consecutive patients with rheumatic diseases who had been treated with rituximab at a university hospital between June 2003 and March 2009. RESULTS: Eleven patients with late-onset neutropenia were identified. The highest incidence was observed in granulomatosis with polyangiitis (Wegener's) and systemic lupus erythematosus patients (23% and 20%, respectively), whereas the incidence in rheumatoid arthritis patients was 3%. The median time to onset of neutropenia was 102 days (range 40-362 days) and coincided with the entire period of B lymphocyte depletion; this depletion was more pronounced in patients with late-onset neutropenia (P = 0.002) than in a control group of 20 matched patients without late-onset neutropenia. Serum IgM levels decreased during the same time and to a significantly greater amount in patients with late-onset neutropenia than in controls (P = 0.027). No patient with late-onset neutropenia displayed specific antineutrophil antibodies. Seven patients were hospitalized because of infections (6 with sepsis and 1 with febrile neutropenia) that required intravenous antibiotics. Six were treated with granulocyte colony-stimulating factor. CONCLUSION: In patients treated with rituximab for rheumatic diseases, late-onset neutropenia is a clinically significant adverse event associated with marked B lymphocyte depletion and severe infections. The incidence of late-onset neutropenia appears to vary with autoimmune disease type.

Idiosyncratic drug-induced agranulocytosis: possible mechanisms and management.

The incidence of drug-induced neutropenia has not changed in the western hemisphere over the last 30 years. Yet, the drug panorama has changed considerably. This implies that host factors may play an intriguing role for this idiosyncratic reaction. The knowledge as to mechanisms for the reaction has advanced with emerging understanding of neutropoiesis and immune regulation. Nonetheless, it is still remarkably difficult to pinpoint why and how a drug causes this unexpected, severe adverse event in a patient. Patient characteristics, e.g. genetics, appear to be keys for better understanding, predictions and prevention. Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc.

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

Late-onset neutropenia, i.e. an absolute neutrophil count of <1.5 x 10(9)/l, may follow 4 weeks or more after therapy with rituximab for lymphoma. However, incidence, predisposing factors, and pathogenic mechanisms are still poorly defined. In a retrospective study of 113 consecutive lymphoma patients treated with rituximab, with or without chemotherapy, we found eight patients (7%) with late-onset neutropenia (LON). Median time to onset was 88 days (range, 1-9 months) after last rituximab dose. Median duration of LON was 54 days (range, 1-17 weeks). Four of the eight patients underwent stem cell transplantation. Three patients developed febrile neutropenia and two required treatment with granulocyte colony-stimulating factor. In four subsequently identified patients with severe LON, a maturation arrest at the (pro)myelocyte stage was observed in the bone marrow, similar to that found in severe congenital neutropenia or Kostmann disease. However, none carried mutations in HAX1, thus ruling out such mutations in the development of the maturation arrest in these patients. Nevertheless, our data suggest that rituximab-related LON and congenital neutropenia might share similar neutropenia-causing mechanisms resulting in maturation arrest.