Favorable Impact of Post-ASCT Consolidative Immunotherapy with RITUXIMAB, rINF-a2b and rIL2 on Overall Survival and Progression-Free Survival in Advanced Stage or Relapsed/Refractory Follicular Lymphoma: Results of a Phase II Study

Advanced stage III/IV or relapsed/refractory follicular lymphoma (FL) can hardly be cured with conventional chemotherapy and patients, even after autologous stem cell transplantation (ASCT), experience innumerable relapse events occurring at decreasing progression-free intervals. Important progress was made since the introduction of RITUXIMAB as part of frontline chemoimmunotherapy or as maintenance after frontline treatment with or without ASCT. But, whatever the policy applied, no plateau is observed regarding overall survival (OS) and progression-free survival (PFS). Disease relapse, even in patients with documented complete remission (CR), is thought to be induced both by resistant minimal residual tumor cells and the lack of immunocompetent mechanisms to contain or eliminate them. Thus, it has been postulated that post-ASCT consolidative immunotherapy might eradicate minimal residual disease, based on antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism, and have a favorable impact on relapse rate and even OS. This view has led to a considerable interest in immunotherapy as a promising therapeutic line to restore and enhance the impaired anti-tumor immune surveillance in the context of post-ASCT low tumor burden.

We conducted a phase II study to compare OS and PFS between patients with advanced or relapsed/refractory FL receiving consolidative immunotherapy combining recombinant interleukine-2 (rIL-2), recombinant interferon- α-2b (rINF- α-2b) and RITUXIMAB after ASCT, with the aim of controlling minimal residual disease, and other counterparts with FL receiving no further treatment after ASCT.

From August, 1995, to October, 2009, 139 patients with FL were autografted in complete remission ≥1 or partial remission. Of these patients, 66 were considered eligible for immunotherapy. On adequate post-ASCT hematologic reconstitution, they received 4 weekly IV injections of RITUXIMAB administered on an outpatient fashion. This was followed by a home-based program of subcutaneous injections of rIL2 (6 million UI × 3 / week in 1st cycle; 9 million × 3 / week in 2d) and rINF- α-2b (1.5 million UI × 3 / week in 1st cycle; 3 million × 3 / week in 2d) administered over two 7-week cycles. These two cycles were separated by a two-week free interval. The other 73 patients did not receive any additional treatment after ASCT and served as controls.

The two groups were comparable regarding demographic characteristics, disease profile and treatment course, except that the control group had significantly less transformed FL (p =0.0156) and a higher mean treatment line number (p =0.018). Median OS and PFS were not reached in either the study group or the control group. OS, initially not different between the 2 groups (p =0.21), was found significantly higher in the study group after a cut-off follow-up time point of 86.6 months (p =0.017). A significantly higher PFS was also noted in favor of the study group over the control group (p =0.0131). With a median follow-up of 60 months (10 to 136) in the study group and of 82 months (0.7 to 174) in the control group, survival rate was 90.9% and 71.2%, respectively (p= 0.0034) and the overall relapse rate was 19.7% (13 patients) and 41.1% (30 patients), respectively (p= 0.0064). Adverse events were generally mild, consisting essentially of fever and chills with the rIL-2 and rINF- α-2b subcutaneous injections (rapidly controlled with PARACETAMOL), fatigue, grade 2 abnormal liver function tests in one third of patients and grade 2 or 3 cytopenias (anemia or neutropenia) in 40% of patients.

These results confirm that post-ASCT immunotherapy with rIL2, rINF- α-2b and RITUXIMAB has a statistically significant impact on OS and PFS. In view of its tolerability, it appears to be quite feasible and safe and might be seen as a promising line of treatment designed for eradicating post-ASCT minimal residual disease and worth being tested within the frame of a randomized trial for validation as an essential step in the treatment algorithm of FL.

No relevant conflicts of interest to declare.