title: Rituximab exposure is influenced by baseline metabolic tumor volume and predicts outcome of DLBCL patients: a Lymphoma Study Association report.
abstract: High variability in patient outcome after rituximab-based treatment is partly explained by rituximab concentrations, and pharmacokinetic (PK) variability could be influenced by tumor burden. We aimed at quantifying the influence of baseline total metabolic tumor volume (TMTV0) on rituximab PK and of TMTV0and rituximab exposure on outcome in patients with diffuse large B-cell lymphoma (DLBCL). TMTV0was measured by18F-fluorodeoxyglucose-positron emission tomography-computed tomography in 108 previously untreated DLBCL patients who received four 375 mg/m2rituximab infusions every 2 weeks in combination with chemotherapy in 2 prospective trials. A 2-compartment population model allowed describing rituximab PK and calculating rituximab exposure (area under the concentration-time curve; AUC). The association of TMTV0and AUC with metabolic response after 4 cycles, as well as progression-free survival (PFS) and overall survival (OS), was assessed using logistic regression and Cox models, respectively. Cutoff values for patient outcome were determined using receiver operating characteristic curve analysis. Exposure to rituximab decreased as TMTV0increased (R2= 0.41,P< .0001). A high AUC in cycle 1 (≥9400 mg × h per liter) was associated with better response (odds ratio, 5.56;P= .0006) and longer PFS (hazard ratio [HR], 0.38;P= .011) and OS (HR, 0.17;P= .001). A nomogram for rituximab dose needed to obtain optimal AUC according to TMTV0was constructed, and the 375 mg/m2classical dose would be suitable for patients with TMTV0<281 cm3In summary, rituximab exposure is influenced by TMTV0and correlates with response and outcome of DLBCL patients. Dose individualization according to TMTV0should be evaluated in prospective studies. These studies were registered at www.clinicaltrials.gov as #NCT00498043 and #NCT00841945.
authors.affiliation: Université François-Rabelais de Tours, National Center for Scientific Research (CNRS), Genetics, Immunotherapy, Chemistry, and Cancer (GICC), UMR 7292, Tours, France.
authors.forename: Mira
authors.initials: M
authors.lastname: Tout
authors.affiliation: Department of Clinical Hematology, Centre Hospitalier Universitaire (CHU) Dijon, INSERM Lipids, Nutrition, Cancer (LNC) UMR 866, Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Casasnovas
authors.affiliation: Lymphoma Study Association (LYSA) Imaging, Henri Mondor University Hospital, Créteil, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Meignan
authors.affiliation: Department of Clinical Hematology, CHU Rennes, U917, Rennes 1 University, Rennes, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lamy
authors.affiliation: Department of Clinical Hematology, CHU Lille, Groupe de Recherches sur les formes Injectables et les Technologies Associées (GRITA), Université de Lille 2, Lille, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Morschhauser
authors.affiliation: Department of Hematology, Hospices Civils de Lyon, Université Claude Bernard Lyon-1, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.affiliation: Department of Hematology and Cell Therapy, Clinical Investigations Center INSERM U1415, CHU Tours, Tours, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gyan
authors.affiliation: Lymphoid Malignancies Unit, Henri Mondor University Hospital, Assistance Publique - Hôpitaux de Paris and Universités Paris-Est Créteil (UPEC), Créteil, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Haioun
authors.affiliation: Department of Hematology, CHU Angers, Angers, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Mercier
authors.affiliation: Department of Hematology, CHU Nancy, Nancy, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Feugier
authors.affiliation: Lymphoma Academic Research Organization, CHU Lyon-Sud, Lyon, France.
authors.forename: Sami
authors.initials: S
authors.lastname: Boussetta
authors.affiliation: Université François-Rabelais de Tours, National Center for Scientific Research (CNRS), Genetics, Immunotherapy, Chemistry, and Cancer (GICC), UMR 7292, Tours, France.|Laboratory of Pharmacology-Toxicology, CHU Tours, Tours, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Paintaud
authors.affiliation: Université François-Rabelais de Tours, National Center for Scientific Research (CNRS), Genetics, Immunotherapy, Chemistry, and Cancer (GICC), UMR 7292, Tours, France.|Laboratory of Pharmacology-Toxicology, CHU Tours, Tours, France.
authors.forename: David
authors.initials: D
authors.lastname: Ternant
authors.affiliation: Department of Hematology, CHU Montpellier, Montpellier, France; and.|University of Montpellier, CNRS UMR 5235, Montpellier, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cartron
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D000069283:Rituximab / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000069283:Rituximab