Rituximab Maintenance Treatment of Relapsed/Resistant Follicular Non- Hodgkin’s Lymphoma: Long-Term Outcome of the EORTC 20981 Phase III Randomized Intergroup Study

Background. In 2005 we analyzed the results of a prospective randomized phase III intergroup trial evaluating the role of rituximab (R) both in remission induction and maintenance treatment of 465 relapsed/resistant follicular lymphoma (FL) patients. Major conclusions were that addition of R to CHOP induction yielded an increased ORR and CR rate, and that R maintenance strongly improved median progression free survival (PFS), both after induction with CHOP and R-CHOP, and overall survival (OS (

Study design. Patients with stages III or IV FL at initial diagnosis and relapsed after or resistant to a maximum of two non-anthracycline containing systemic chemotherapy regimens, were randomized to remission induction with either 6 cycles of standard CHOP (once every 3 weeks) or CHOP + R (375 mg/m² at day 1 of each cycle of CHOP). Those with a complete or partial remission after 6 cycles of therapy underwent a second randomization to no further treatment (observation) or maintenance treatment with R (375 mg/m² once every 3 months) until relapse or for a maximum period of two years.

Results. 465 patients were randomized to induction with either CHOP (231) or R-CHOP (234). As reported, CHOP and R-CHOP induction yielded similar partial response rates (57% vs.56%), but significantly different CR rates (16% and 29%; p=0.0001). 334 patients were randomized to either R maintenance treatment (167) or observation (167). R maintenance resulted in a highly significant improvement of PFS: median 3.7 years versus 1.3 years in the observation arm (p<0.0001; hazard ratio 0.55). The advantage of R maintenance was observed both after CHOP induction (p< 0001: HR 0.37) and R-CHOP induction (p= 0.003; HR 0.69). The 5 years OS was 74% in the R maintenance arm and 64 % in the observation arm (p=0.07). That the highly improved PFS after R maintenance did not translate into a significant OS advantage might partially be explained by the fact that 41% of progressing patients received R as salvage therapy. This varied according to treatment arm: from 59% after CHOP followed by observation to 26% after R-CHOP followed by R maintenance. R maintenance was associated with a significant increase in grade 3/4 infections: 9.7% vs.2.4% (p= 0.01). 7 of the 167 patients had to discontinue R maintenance because of toxicity, mostly recurrent infection.

Conclusion. With long term follow-up we confirm the superior PFS with R maintenance. The improvement of OS did not reach statistical significance, possibly due to the abundant use of R in post-protocol salvage treatment.