The addition of rituximab (R) therapy significantly improves PFS in patients with relapsedl/refractory disease responding after CHOP as well as responders after R-CHOP induction (van Oers, 2005). The aim of this study was to assess, in patients with previously untreated indolent NHL, the safety, efficacy and PK of additional R therapy in responders to R-CHOP induction. Between 10/01 and 08/06, 102 patients aged 28–84 (mean 57 yr) yrs with Ann Arbor Stage III (28.4%) or IV (71.6%) indolent NHL were treated on this Phase II single-arm, open-label, multi-center, community-based trial. Baseline LDH and β2 microglobulin were above normal in 20.6% and 66.3% of patients, respectively. Treatment consisted of 6 cycles of R-CHOP (cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, and doxorubicin 50 mg/m2 all IV on Day 1 of each 21-day cycle; prednisone 100 mg/d po Days 1–5; and R 375 mg/m2 IV 2–3 days prior to first dose of CHOP and thereafter on Day 1 of each cycle). Patients with ongoing response (CR/CRu or PR) received R 375 mg/m2 weekly x 4, repeated every 6 months x 2 yrs, for a total of up to 16 R doses, within 28 days after completion of R-CHOP. Median follow-up was 39 mos. ORR after R-CHOP was 86.3% (95% CI: 78.3, 92.1), with CR/CRu 48% (95% CI: 38.0, 58.2). As measured from initiation of R-CHOP, PFS at 2 and 3 yrs was 75.2% (95% CI: 64.0, 83.3) and 67.3% (95% CI: 54.6, 77.2), respectively. OS at 2 and 3 yrs was 92.9% (95% CI: 85.7, 96.6) and 89.4% (95% CI: 81.2, 94.2), respectively. Infusion-related toxicity with R given after R-CHOP was less frequent than seen with R-CHOP in this study. The overall incidence of serious adverse events during R therapy given after R-CHOP was 8.5%, including 3 NCI-CTC grade 3/4 events: viral encephalitis (n=1), patellar fracture (n=1) & development of colon cancer (n=1). Serum R concentrations were collected over serial timepoints from 12 patients. Both pre- and end of infusion serum R concentrations were similar across cycles 2–4 of R therapy given after R-CHOP. R concentration was higher just prior to infusion of the first R dose given after R-CHOP due to residual concentration from the R-CHOP treatment. Concentrations were very low (< 10 ug/mL) just prior to initiation of the subsequent R cycles. During R therapy given after R-CHOP, serum R concentrations were similar to those previously reported during R monotherapy treatment (Berinstein, 1998). In summary, this study demonstrated that R therapy given after R-CHOP to be generally well-tolerated, and associated with 75.2% PFS and 92.9% OS at 2 yrs, and 67.3% PFS and 89.4% OS at 3 yrs. Moreover, the current study demonstrates that PK data from R induction can be extrapolated to R given after R-CHOP. The benefit of adding additional R therapy to responders to R-chemotherapy will be addressed in the analysis of the ongoing Phase III PRIMA study, wherein patients with advanced follicular lymphoma who respond to R-chemotherapy induction are randomized to receive further R therapy vs. observation.
Disclosure:Employment: Jean Bjerke is a contractor for Genentech, Inc. and David Loecke is a biostatistician for Genentech. Research Funding: Lowell Hart is the recipient of research funds from Genentech, Inc. for some studies in his practice. Off Label Use: The label includes treatment of patients with previously untreated follicular CD20-positive B-cell NHL with rituximab plus CVP chemotherapy, rather than rituximab plus the study-mandated CHOP chemotherapy. The label includes treatment of patients with previously untreated low-grade CD20-positive B-cell NHL with the same study-mandated regimen of rituximab following response to CVP chemotherapy, but not after response to R-CHOP