Rituximab exposure-response in triweekly R-CHOP treatment in DLBCL: A loading dose is recommended to improve clinical outcomes.

Previous exposure-response analyses for rituximab suggest that higher rituximab concentrations were associated with an improvement in efficacy, however, clinical studies investigating a higher rituximab dose had mixed results. To further explore the exposure-response relationship of rituximab, a prospective observational analysis was performed involving 121 newly diagnosed patients with diffuse large B-cell lymphoma treated with triweekly rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The trough concentration in the first cycle (C ) was significantly higher in patients achieving complete response (CR) compared with patients that did not achieve CR (22.00 μg/ml vs. 16.62 μg/ml, p = 0.0016), however, this difference between the two groups disappeared in later cycles. The relationship between rituximab C and achieving a CR was confirmed by matched-pair logistic regression analysis (odds ratio, 0.79; p = 0.0020). In addition, a higher C (≥18.40 μg/ml) was associated with longer progression-free survival (p < 0.0001) and overall survival (p = 0.0038). The percentages of patients that did not achieve a CR and had recurrence after CR within 24 months were 35% and 22.50%, respectively, for patients with a C less than or equal to 18.40 μg/ml, compared with 12.35% and 6.17% for patients with C greater than 18.40 μg/ml. Disease stage was found to be the most significant influencing factor of C , with 51.02% of patients at stage IV with an observed C less than 18.40 μg/ml. For these advanced patients, population pharmacokinetic simulations using an established model suggest that a loading dose of 800 mg/m  may help to improve clinical outcomes.