Rituximab Maintenance for Advanced Follicular Lymphoma (FL) Patients - Comparison of Outcomes after First and Second Line Treatment in a Single Center Series
Authors: Viegas Diana , Lobato Joana , Esteves Susana , Coutinho Rita , Silva Maria Gomes 
Published: October 2019

Abstract
Standard approach to advanced stage FL patients in need of treatment is immunochemotherapy followed by rituximab maintenance (RM). Maintenance improves disease control after first line and overall survival in the relapse setting. The relative benefits of maintenance after first or subsequent treatment have not been directly compared.
Purpose: To compare the clinical outcome of patients receiving RM after first-line treatment with those who received RM for the first time after second line.
Patients and Methods: We retrospectively analyzed the outcomes (time to next treatment, TTNT, and progression free survival, PFS) of a single center series of advanced FL patients in remission after first or second treatment who received RM. Demographic and clinical characteristics before first or second induction (age, gender, FLIPI and FLIPI2) as well as induction chemotherapy, response rate, PFS and TTNT were retrieved from clinical charts. Patient characteristics at the beginning of induction were compared by Chi-squared test and time-to-event outcomes evaluated by the Kaplan Meyer method and compared by log rank test, with and without stratification for FLIPI; we calculated the adjusted hazard ratio controlled for FLIPI using Cox regression; p‹0.05 was considered significant.
Results: Among 371 advanced FL patients diagnosed and treated in a single center between 2001 and 2013, we identified 83 (45% male) who responded to first or second induction and received RM between 2005 and 2015 (59 after first line - M1 group - and 24 after second line - M2 group; 375 mg/m2 every 2 or 3 months for 2 years, respectively). M2 patients were older than M1 (median age 63 versus 55 yo). Other characteristics before induction were similar between the two groups, including FLIPI (low 14% and 13%, intermediate 42% and 33%, high 42% and 42% for M1 and M2, respectively; p=0.93) and FLIPI2 risk group distribution (low 10% and 4% , intermediate 49% and 38%, high 36% and 38% for M1 and M2, respectively; p=0.62). Median time from diagnosis was 5.1 years in M2 patients; M1 patients were treated at a median of 1.9 months after diagnosis.
First line treatment in the M1 group was mostly RCHOP (76%) while similar proportions of M2 pts received RCHOP (38%) and RCVP (46%) as second line. 20/24 of M2 pts (83%) had received Rituximab as part of first line treatment. CR/CRu rates after induction were comparable (48% and 42% in M1 and M2 pts respectively; p=0.17). After maintenance, with 13 pts not yet evaluable for response, ORR was 68% in M1 and 50% in M2 (p= 0.15). The frequency of CR/CRu was similar for first and second line patients (43% and 42% in M1 and M2, respectively) with 10/31 (32%) and 4/11 (36%) PR patients converting to CR after M1 and M2, respectively. At a median follow-up of 2.3 in M1 and 2.5 years in M2, relapse/progression occurred in 16 (27%) and 8 (33%) patients, respectively. A new treatment was started in 19% and 29% of patients in the M1 and M2 groups. Accordingly, TTNT after M1 (not reached) was significantly longer than after M2 (33.2 months), p=0.04. This difference was not significant in stratified analysis by FLIPI. However, when controlling for FLIPI, the hazard of subsequent therapy in M2 was twice as M1 (HR=2.1; 95% CI: 0.8-5.4). Two-year PFS was also superior in M1 (80% [95% CI 70-92%] versus 62% [95% CI 44-87%] in M2) although not statistically significant (p= 0.19). Indeed, there was a 50% increase in the risk of progression or death adjusted for FLIPI in M2 compared to M1 (HR=1.5; 95%CI: 0.6-3.8).
Conclusion: In this series, although patients receiving RM both after first and second induction therapy benefited from the treatment, longer treatment-free intervals and disease control were seen in the first line setting. The benefits of repeating Rituximab maintenance have not been prospectively evaluated; in countries where economic constraints impose restrictions to its repeated use, our results suggest that advanced FL patients should preferentially receive RM after first line.

Disclosures
Silva: Roche Pharmaceutics: Consultancy.