Rituximab exposure is influenced by baseline metabolic tumor volume and predicts outcome of DLBCL patients: a Lymphoma Study Association report

• Published in: Blood 2017-05, Vol.129 (19), p.2616-2623
• Main Authors: Tout, Mira, Casasnovas, Olivier, Meignan, Michel, Lamy, Thierry, Morschhauser, Franck, Salles, Gilles, Gyan, Emmanuel, Haioun, Corinne, Mercier, Mélanie, Feugier, Pierre, Boussetta, Sami, Paintaud, Gilles, Ternant, David, Cartron, Guillaume
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Kaplan-Meier Estimate; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; Male; Middle Aged; Positron-Emission Tomography; Rituximab - administration & dosage; Rituximab - metabolism; Rituximab - pharmacokinetics; Rituximab - therapeutic use; Treatment Outcome; Tumor Burden - drug effects; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2016-10-744292

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 TMTV0 and rituximab exposure on outcome in patients with diffuse large B-cell lymphoma (DLBCL). TMTV0 was measured by 18F-fluorodeoxyglucose-positron emission tomography-computed tomography in 108 previously untreated DLBCL patients who received four 375 mg/m2 rituximab 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 TMTV0 and 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 TMTV0 increased (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 TMTV0 was constructed, and the 375 mg/m2 classical dose would be suitable for patients with TMTV0