Interferon Maintenance Prolongs Remission Duration After Rituximab-Containing Induction In First-Line Advanced Stage Follicular Lymphoma Patients – a Retrospective Analysis of the German Low-Grade Lymphoma Study Group (GLSG)

Rituximab (R) maintenance in first remission of follicular lymphoma (FL) has recently been shown to improve remission duration as compared to observation only (Salles et al., ASCO 2010). During the nineties of the last century, maintenance using interferon alpha (IFN) had been shown to be effective in indolent lymphoma (Solal-Celigny et al., NEJM 1993, Hagenbeek et al., JCO 1998). Therefore IFN-maintenance became a standard in GLSG trials after 1995. However, data on the impact of IFN after R-containing chemotherapy are rare. We performed a retrospective analysis of GLSG trials in which we compared the outcome of patients who received IFN-maintenance and patients who did not start any form of consolidation or maintenance therapy after achieving a partial or complete remission. We adjusted the analysis for potential confounders that might have influenced the decision not to start IFN-maintenance.

In the GLSG first-line trials “CHOP vs. MCP” and “CHOP vs. R-CHOP” patients younger than 60 years had been randomized between consolidating high-dose radiochemotherapy followed by autologous stem cell transplantation (ASCT) and IFN-maintenance. For all responding patients older than 60 years, IFN-maintenance was intended. All patients with FL achieving a partial or complete remission after MCP, CHOP, or R-CHOP who did not start ASCT were included in the current analysis. Patients intended for IFN who did not start IFN-maintenance were compared to patients who started IFN-maintenance. We compared patient and treatment characteristics between these groups in order to detect possible reasons why IFN-maintenance was not started. Remission duration (RD) was calculated from the end of induction to relapse or death. RD was censored at the latest follow-up date in patients without event, but also when a new antilymphoma therapy was initiated without any sign of progression. No censoring was done for any form of dose reduction or stopping of IFN, which was recommended in the trials if inacceptable side effects were observed. We compared RD with IFN-maintenance to observation only by Kaplan-Meier-curves and log rank test and we adjusted for the potential confounders FLIPI, performance status, R-containing induction and remission status in multiple Cox-Regression. In order to assess the impact of IFN-maintenance after R-containing induction, we performed a subgroup analysis of R-CHOP treated patients.

Of 1306 FL patients with clinical remission, ASCT was started in 306 patients and documentation concerning postremission therapy was missing in 21 patients. In 719 (73%) of the remaining 979 patients IFN-maintenance was started, whereas 260 patients did not receive IFN-maintenance. Patients in which IFN-maintenance was started were not more frequently younger than 60 years (59% vs. 55%, p=0.24), and not more frequently in a better performance status (ECOG 0–1: 93% vs. 91%, p=0.33). There was only a trend to better FLIPI (LR/IR/HR 13%/41%/46% vs. 15%/34%/52%, p=0.10) as compared to patients with observation only. Patients with IFN-maintenance had not more frequently achieved a CR (19% vs. 21%, p=0.65), but more patients had been treated without Rituximab during induction (57% vs. 37%, p<0.0001). According to our analysis patients with IFN-maintenance had a significantly prolonged RD (hazard ratio 0.73, 95% CI 0.59 to 0.91, p=0.0045) which was even more pronounced after adjustment for FLIPI factors, performance status, Rituximab containing induction, and remission status (adjusted hazard ratio 0.59, 95% CI 0.47 to 0.74, p<0.0001). In 309 (65%) of 473 patients treated with R-CHOP IFN-maintenance was started. RD after 3 years was 78% vs. 64% (p=0.0007) and the adjusted hazard ratio for IFN-maintenance was 0.57 (95% CI 0.39 to 0.84 p=0.0042).

Although this is not a randomized comparison, our analysis shows that the impact of IFN, which was observed before using R-containing therapy may still be valid in the era of immunochemotherapy. Since R-maintenance seems more effective and has less side effects, IFN-maintenance will no longer be the first choice for maintenance therapy in FL. However, it seems relevant to keep in mind that IFN is still an active substance in lymphoma therapy and may be a therapeutic option when rituximab maintenance is not possible. It may also be relevant for future investigations in lymphoma therapy.

Dreyling:Johnson & Johnson:.Hiddemann:Roche: Honoraria, Research Funding.