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(1‐trough)) 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(1‐trough) and achieving a CR was confirmed by matched‐pair logistic regression analysis (odds ratio, 0.79; p = 0.0020). In addition, a higher C(1‐trough) (≥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(1‐trough) less than or equal to 18.40 μg/ml, compared with 12.35% and 6.17% for patients with C(1‐trough) greater than 18.40 μg/ml. Disease stage was found to be the most significant influencing factor of C(1‐trough), with 51.02% of patients at stage IV with an observed C(1‐trough) 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(2) may help to improve clinical outcomes.