Phase II Trial of lenalidomide plus rituximab (R2) in previously untreated follicular lymphoma: 15-year follow up data from MDACC Trial

Abstract Introduction: Lenalidomide with rituximab (R2) as first line treatment for patients with previously untreated follicular lymphoma (FL) has shown its efficacy in former trials, however, long-term outcomes of this treatment are unknown. Here, we report 15-year follow up data of the pivotal phase 2 trial at MD Anderson Cancer Center. Methods: A total of 79 patients with previously untreated FL were included in the original clinical trial. Patients received rituximab 375 mg/m2 on day 1 of each cycle and lenalidomide 20 mg/day on days 1-21 of each 28-day cycle for 6 cycles (Schedule A), or rituximab 375mg/m2 IV x1 weekly on cycle 1 and day 1 of every subsequent cycle with lenalidomide 20 mg/day on days 1-21 of each 28-day cycle for 6 cycles followed by lenalidomide 10 mg/day on days 2-22 for cycles 7-12 for 12 cycles treatment (Schedule B). The primary endpoint was overall response rate (ORR); secondary endpoints were complete and partial response (CR, PR), safety, and progression free survival (PFS). PFS was defined as time from starting treatment to disease progression or death, event free survival included time from starting treatment to discontinuation due to any cause and overall survival (OS) was defined from the time of initial diagnosis of FL to death/last follow up. The data cut-off date was 7/20/2025. Results: Median age of patients at the time of starting R2 was 56 years (range: 29-84), 51% were males. Schedule A was administered in 49 patients and schedule B in 30 patients. Forty and 39 patients had low tumor burden and high tumor burden disease by GELF criteria, respectively. Sixteen patients (20%) had low risk, 42 patients (53%) had intermediate and 21 patients (27%) had high risk disease by FLIPI. Thirty-three patients (45%) had low risk, 30 patients (41%) had intermediate and 10 patients (14%) had high risk disease by FLIPI24 risk model. Seventy-six patients were evaluable for initial response assessment and 75 (99%) responded. The best complete response rate was 87%. The median follow-up duration of this update was 14.2 years (range: 2.0-16.5 years). Of note, 36 patients (46%) of patients were lost to follow up at the time of data cut off, patients stopped coming to routine clinic visit particularly during COVID pandemic. At the time of last follow up, 30 patients experienced disease progression and the median PFS was 16.5 years (95%CI: 9.9 years-not reached), and 10-year PFS was 61% (95%CI: 49-71%). Sixty patients (76%) were in complete response at 30 months (CR30), and those who achieved CR30 had significantly longer PFS compared to those who progressed before 30 months (hazard ratio: 0.04), although no significant difference was seen in OS. Patients who had low tumor burden disease compared to high tumor burden disease (10-year PFS: 66% vs 56%), and patients who received longer treatment with Schedule B showed longer PFS compared to Schedule A (10-year PFS: 70% vs 57%), but without statistical significance. Overall, nine patients died at the last follow up and only one patient confirmed due to lymphoma (1 AML, 1 COVID, 1 endocarditis, 1 pancreatic cancer, 1 pneumonia, 3 unknown). The median OS was not reached, and 10-year OS was 95% (95%CI: 86-98%). Eleven patients experienced progression of disease within 24 months (POD24), and those patients who experienced POD24 had numerically shorter OS (10-year OS: 97% vs 80%) but without statistical significance. Subgroup analysis showed no significant differences in PFS with FLIPI or FLIPI24 risk score. Five patients developed transformation and time to event ranged from 9 months to 15 years. Conclusions: This long-term follow up study confirmed durable responses of first line treatment of R2 in patients with FL, even without 2-years of maintenance given in RELEVANCE trial. At a follow up of 15 years, the majority of patients remain in remission and patients who achieved CR30 had the best outcomes. As we continue to develop R2-based first line treatment of FL, this trial will continue to provide long-term outcome references for future trials.