Post-ASCT Consolidative Immunotherapy with RITUXIMAB, rINF-a2b and rIL2 In Poor-Risk DLBCL: Results of a Phase II Study

A minority of patients with diffuse large B cell lymphoma (DLBCL) can really be cured and the early or late relapse rate remains a subject of major concern. The occurrence of 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 eradicate them. Thus, it has been postulated that post-autologous stem cell transplantation (ASCT) consolidative immunotherapy might eradicate minimal residual disease and, therefore, reduce relapse rate and even improve overall survival (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 setting of post-ASCT low tumor burden.

We conducted a phase II study to compare OS, relapse-free survival (RFS), death rate and overall relapse rate between patients with poor-risk DLBCL 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 patients with poor-risk DLBCL treated with ASCT alone.

On 180 patients, 27 with DLBCL from Brest, autografted in complete remission (CR) ≥ 1 or partial remission (PR), were considered eligible for the study. They received, on adequate post-ASCT hematologic reconstitution, 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. One hundred and fifty three patients from Brest, Lille and Tours did not receive any additional treatment after ASCT and served as controls.

The two groups were comparable, except for age, which was older in the study group (p=0.018) and for pre-ASCT response pattern, which was better in the control group. There was no influence of recruitment center, sex, disease Ann Arbor stage, IPI score, RITUXIMAB administration before ASCT, graft source or ASCT conditioning regimen on the final results. Median OS and RFS were not reached in any group and are still under study. The median follow-up was 54.9 months in the study group and 48.8 months in the control group. In univariate analysis, the prevalence of death rate was 7.4% and 26.2% in the study group and the control group, respectively (OR = 0.23, 95%CI [0.05-0.99], p=0.03), and the overall relapse rate was 11.1% (3 patients) and 22.9% (35 patients), respectively (OR=0.42, 95%CI [0.12-1.48], p=0.17). In multivariate analysis, the risk of death was significantly decreased (OR 0.196; 95%CI [0.046-0.827] p=0.027) and there was a trend toward a decreased relapse rate (OR 0.348; 95%CI [0.104-1.168], p=0.088) in the study group compared to the control group. In addition, older age was independently associated with an increased risk of death (OR=1.053, 95%CI [1.02-1.09], p=0.002).

Adverse events were generally mild, consisting essentially of fever and chills with the rIL-2 and rINF-α-2b subcutaneous injections responding well to PARACETAMOL, fatigue, grade 2 abnormal liver function tests in one third of patients, grade 3 neutropenia in 45% of patients and hypothyroidism in one patient.

We found that post-ASCT immunotherapy with rIL2, rINF-α-2b and RITUXIMAB has a statistically significant favorable impact on death rate and a positive, although not statistically significant, effect relapse rate. In view of its toxicity profile, it appears to be quite feasible and safe and might be considered as a promising line of treatment designed for post-ASCT minimal residual disease and worth being evaluated within the frame of a prospective randomized trial.

No relevant conflicts of interest to declare.