title: Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response.
abstract: BACKGROUND
  Treatment of follicular lymphoma with rituximab is currently recommended at a dose of 375 mg/m(2). We aimed to provide a rationale for optimal dosing and scheduling of this anti-CD20 antibody based on pharmacokinetics.
  
  
  METHODS
  Clinical efficacy of immunochemotherapy with rituximab, fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial (AGMT-NHL9). Pharmacokinetic analysis was assessed in 17 patients.
  
  
  RESULTS
  Induction treatment resulted in high clinical response rates (complete remission 66%; ORR 100%). Significantly higher complete remission rates were observed in female patients (86 vs. 47%; Odds Ratio 6.8, 95% CI: 1.12; 41.82; P=0.05). Rituximab pharmacokinetic analysis showed a high variability ranging over almost 1 order of magnitude at maintenance cycle 1 (area under the curve 1,540-12,025 g/L*days). Median area under the curve was lower in men (81%) and in patients with initial bone marrow infiltration (76%). Higher rituximab serum concentrations before next therapy (C(trough)) were associated with female sex (P=0.04) as well as with absence of initial bone marrow infiltration (P=0.001). C(trough) correlated with remission quality (complete vs. partial remission; P=0.005) and progression-free survival (P=0.03). A decline in rituximab C(trough) below 25,000 ng/mL was observed 9.5 to 62 months before clinical relapse (P=0.008).
  
  
  CONCLUSIONS
  The results of this pilot trial suggest that more differentiated dosing schedules based on gender and bone marrow infiltration should be explored for rituximab therapy for lymphoma. This study was registered in ClinicalTrials.gov (Identifier: NCT01560117).
authors.affiliation: Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna Währinger Gürtel 18-20 A-1090 Vienna, Austria. ulrich.jaeger@meduniwien.ac.at
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jäger
authors.forename: Michael
authors.initials: M
authors.lastname: Fridrik
authors.forename: Markus
authors.initials: M
authors.lastname: Zeitlinger
authors.forename: Daniel
authors.initials: D
authors.lastname: Heintel
authors.forename: Georg
authors.initials: G
authors.lastname: Hopfinger
authors.forename: Sonja
authors.initials: S
authors.lastname: Burgstaller
authors.forename: Christine
authors.initials: C
authors.lastname: Mannhalter
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Oberaigner
authors.forename: Edit
authors.initials: E
authors.lastname: Porpaczy
authors.forename: Cathrin
authors.initials: C
authors.lastname: Skrabs
authors.forename: Christine
authors.initials: C
authors.lastname: Einberger
authors.forename: Johannes
authors.initials: J
authors.lastname: Drach
authors.forename: Markus
authors.initials: M
authors.lastname: Raderer
authors.forename: Alexander
authors.initials: A
authors.lastname: Gaiger
authors.forename: Monique
authors.initials: M
authors.lastname: Putman
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
mesh_terms: D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D010865:Pilot Projects; D011379:Prognosis; D011446:Prospective Studies; D012074:Remission Induction; D000069283:Rituximab; D012737:Sex Factors; D015996:Survival Rate; D014018:Tissue Distribution; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D008942:Mitoxantrone; D014740:Vidarabine; C024352:fludarabine