title: Tumor necrosis factor alpha release is a major biological event associated with rituximab treatment.
abstract: BACKGROUND
  In patients with low-grade non-Hodgkin's lymphoma, rituximab (MabThera) produces infusion-related toxicity, including fever, rigors, and chills in greater than 50% of those treated. The majority of these reactions are grade 1 or 2.
  
  
  METHODS
  In the GELA study LNH98-5, a total of 400 elderly patients with previously untreated diffuse large B-cell lymphoma were randomized to treatment with CHOP or with rituximab plus CHOP (R-CHOP). In a detailed investigation of biological events which may be associated with adverse reactions specific to rituximab infusion, a subgroup of 55 patients (26 in the CHOP group and 29 in the R-CHOP group) were selected for measurement of several biological parameters at baseline and at 1, 4 and 8 h (H1, H4 and H8, respectively) after commencing therapy. For 27 patients, measurements included cytokine and complement levels.
  
  
  RESULTS
  Baseline demographic and disease characteristics were similar for patients in both treatment groups. Compared with the CHOP treatment group, patients in the R-CHOP group had significantly higher post-treatment changes in neutrophil, lymphocyte, and monocyte counts, LDH levels, C3a levels, and TNF-alpha levels. In the R-CHOP group, neutrophil levels increased at H4 (P<0.05), lymphocyte levels decreased at H1 (P<0.05), H4 (P<0.001) and H8 (P<0.05), monocytes levels decreased at H1 (P<0.01), LDH levels increased at H4 (P<0.05) and H8 (P<0.01), and C3a decreased at H1 (P<0.01). The most statistically significant changes were observed for TNF-alpha levels: Mean values of TNF-alpha increased more than 250% at H1 and H4 and were still increased by 170% at H8 (P<0.001 at all timepoints). Since only six of the 55 evaluated patients had severe adverse events, it was not possible to correlate severe toxicity with these biological variations.
  
  
  CONCLUSIONS
  This analysis demonstrates that rituximab infusion was rapidly followed by activation of complement, B-lymphocyte cytolysis, and TNF-alpha release.
authors.affiliation: Laboratoire d'immunologie, CH Lyon-Sud, Pierre-Benite and Jeune Equipe 2267 from University Claude Bernard, Lyon, France.
authors.forename: J
authors.initials: J
authors.lastname: Bienvenu
authors.forename: R
authors.initials: R
authors.lastname: Chvetzoff
authors.forename: G
authors.initials: G
authors.lastname: Salles
authors.forename: C
authors.initials: C
authors.lastname: Balter
authors.forename: H
authors.initials: H
authors.lastname: Tilly
authors.forename: R
authors.initials: R
authors.lastname: Herbrecht
authors.forename: P
authors.initials: P
authors.lastname: Morel
authors.forename: P
authors.initials: P
authors.lastname: Lederlin
authors.forename: P
authors.initials: P
authors.lastname: Solal-Celigny
authors.forename: B
authors.initials: B
authors.lastname: Audhuy
authors.forename: B
authors.initials: B
authors.lastname: Christian
authors.forename: J
authors.initials: J
authors.lastname: Gabarre
authors.forename: O
authors.initials: O
authors.lastname: Casasnovas
authors.forename: G
authors.initials: G
authors.lastname: Marit
authors.forename: C
authors.initials: C
authors.lastname: Sebban
authors.forename: B
authors.initials: B
authors.lastname: Coiffier
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects; D001772:Blood Cell Count; D003167:Complement Activation / Q000187:drug effects; D015926:Complement C3a / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000097:blood / Q000187:drug effects; D016393:Lymphoma, B-Cell / Q000188:drug therapy; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy; D008875:Middle Aged; D000069283:Rituximab; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D000069283:Rituximab; D015926:Complement C3a; D007770:L-Lactate Dehydrogenase