Clinical trials of a mouse-human chimeric anti-CD20 monoclonal antibody (rituximab) for B cell non-Hodgkin's lymphoma in Japan

Rituximab, a mouse-human chimeric antiCD-20 monoclonal antibody, induces apoptosis in B cell non-Hodgkin's lymphoma (B-NHL) cells, in addition to lysis by complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. A group of 12 patients with relapsed CD20(+) B-NHL were enrolled in a phase I study; 4 received rituximab 250 mg/m(2) and 8 375 mg/m(2) once weekly for 4 weeks. Grade I or 2 infusion-related toxicity such as 'flu-like symptoms and skin reactions were observed. Of the 11 patients eligible for study enrollment, 2 achieved a complete response (CR) and 5 a partial response (PR). The T-1/2 of rituximab was 445 +/- 61 h, and serum rituximab levels were measurable at 3 months. Thereafter, 90 relapsed patients with indolent B-NHL or mantle cell lymphoma (MCL) were enrolled in a phase II study and received rituximab 375 mg/m(2)x4 weekly infusions. A central pathology review and an extramural review disclosed that 13 patients were ineligible for final analysis. Factors affecting response and progression-free survival (PFS) were analyzed in the remaining 77 patients. The overall response rate (ORR) in indolent B-NHL and MCL was 61% (37/61, 95% CI 47-73 %) and 46% (6/13, 95 % CI 19-75 %), respectively. The median PFS time was 245 days in indolent B-NHL and 111 days in MCL patients. Multivariate analysis revealed that the ORR was affected by the number of prior regimens (P = 0.018) and that the PFS was affected by the following three factors: disease type (P = 0.000), presence of extranodal lesions (P = 0.001), and number of prior regimens (P = 0.007). The PFS times of patients with higher serum rituximab concentrations at day 14 (greater than or equal to 70 mug/ml) and at 3 months ( greater than or equal to 10 mug/ml) were significantly longer than those of patients with lower concentrations (P = 0.006 and P = 0.0001, respectively). In conclusion, rituximab is more effective in indolent B-NHL than in MCL. Several prognostic factors and serum rituximab concentrations are useful for predicting the therapeutic efficacy.