AUTHORS
Tony Zibo Zhuang, MD, Xiaowen Sun2, Lei Feng, MS3, Harshit Khosla, MD4, Amy A. Ayers5, Chijioke C Nze, MD, MPH6, Jonathon B. Cohen, MD, MS7, Umar Farooq, MD8, Brad S. Kahl, MD9, Izidore S. S. Lossos, M.D.10, Thomas M. Habermann, MD11, Yucai Wang, MD, PhD12, Jia Ruan, MD, PhD13, Richard Burack, MD, PhD14, Carla Casulo, MD15, Dai Chihara, MD, PhD16, Jonathan W. Friedberg, MD17, Eric Mou, MD18, Melissa Larson, MS19, Matthew E. Maurer, ScD20, Johanne Pierre21, Laurel Deaton22, Taylor Cain23, Minifrida Santiago24, James R. Cerhan, MD, PhD25, Christopher R. Flowers Jr, MD, MS26, Paolo Strati, MD27
AFFILIATIONS
1 University of Texas MD Anderson Cancer Center, Houston, Texas, United States, University of Texas MD Anderson Cancer Center, Houston, Texas, United States
2 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
3 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
4 University of Texas Health Science Center, Houston, Texas, United States
5 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
6 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
7 Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States
8 University of Iowa, Iowa City, Iowa, United States
9 Washington University in St. Louis, St. Louis, Missouri, United States
10 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States
11 Mayo Clinic, Rochester, Minnesota, United States
12 Mayo Clinic, Rochester, Minnesota, United States
13 Weill Cornell School of Medicine, New York City, New York, United States
14 Wilmot Cancer Institute, University of Rochester, Rochester, New York, United States
15 Wilmot Cancer Institute, University of Rochester, Rochester, New York, United States
16 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
17 Wilmot Cancer Institute, University of Rochester, Rochester, New York, United States
18 University of Iowa, Iowa City, Iowa, United States
19 Mayo Clinic, Rochester, Missouri, United States
20 Mayo Clinic, Rochester, Missouri, United States
21 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
22 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
23 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
24 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
25 Mayo Clinic, Rochester, Missouri, United States
26 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
27 University of Texas MD Anderson Cancer Center, Houston, Texas, United States
ABSTRACT
Introduction: The combination of rituximab plus lenalidomide (R²) is currently approved for the treatment of relapsed or refractory (R/R) follicular lymphoma (FL) based on results of the randomized phase 3 AUGMENT trial. In this study, performed between 2014 and 2017, that excluded patients with rituximab-refractory disease (defined as no response to rituximab-based regimens or relapsed within 6 months from the end of treatment), a median progression-free survival (PFS) of 30.4 months was reported at a 5-year follow-up. Recently, two randomized phase 3 trials, inMIND (2020-2025) and EPCORE-FL-1 (2022-2025), in which about 40% of patients had R/R FL refractory to an anti-CD20 monoclonal antibody, reported shorter median PFS for the R2 control arm of 13.9 months and 11.7 months, respectively, raising concerns about the real-world efficacy of this regimen. Only one real-world single center experience has been published to date that involved 69 FL patients, reporting a median PFS of 22 months. As factors impacting response to R2 are unknown, it is unclear what baseline characteristics may be responsible for such differences in these datasets.
Methods: To address this knowledge gap, a multi-center real-world retrospective analysis was performed in adult patients with R/R FL treated with R2 between May 2008 and July 2025 at 8 US-based academic centers participating in a multi-center Lymphoma Epidemiology of Outcomes (LEO) observational cohort study. Baseline characteristics were collected before initiation of R2. PFS was calculated from date of R2 initiation to progression, death or last follow-up. Median PFS and corresponding 95% confidence intervals (95% CIs) were estimated by the Kaplan-Meier method and differences between subgroups were compared using the log-rank test; univariate Cox proportional hazards model was fitted to evaluate the association between variables and PFS. Multivariable Cox proportional hazards model was fitted to assess the effects of covariates on PFS. Covariates which had a p-value less than 0.05 in the univariate analysis were included in the initial full model, and a stepwise selection method was used to reach the final model.
Results: One-hundred and sixty-nine patients were included in this analysis, and 51 (30%) were treated after 2020. The median age was 65 years (range, 33-92), 70 (41.4%) were female, 133 (84.7%) were White, and 10 (6.5%) had an ECOG performance status (PS) ≥2. Ninety-three (55%) patients had received at least 2 prior lines of systemic therapy, including an anthracycline-based regimen in 105 (62.5%) and a bendamustine-based regimens in 89 (52.7%). Fifty-seven (37.2%) had progressed within 24 months of frontline chemoimmunotherapy (POD24) and 32 (20.9%) were rituximab-refractory.
After a median follow-up of 40.7 months (95% CI: 34.9-55.6), the median PFS was 41.8 months (95%CI: 37.1-53.7). In univariate analysis, baseline characteristics associated with significantly shorter PFS included: older age as a continuous variable (HR 1.03, 95%CI: 1.01-1.05, p=0.002), ECOG PS ≥ 2 (median 11 months vs 44 months, p=0.0003), prior bendamustine (median 35 months vs 81 months, p<0.0001), POD24 (median 33 months vs 65 months, p<0.0001), rituximab-refractory disease (median 33 months vs 47 months, p=0.0003), and time from last treatment to R2 initiation (HR 0.9882, 95%CI 0.9806-0.9958, p=0.0023). Number of prior lines of systemic therapy as a continuous variable, FLIPI score at R2 initiation, prior anthracycline exposure, and time from initial FL diagnosis to R2 initiation were not statistically significantly associated with PFS.
In the multivariable analysis including all factors significant on univariate analysis, age (HR 1.03, 95%CI: 1-1.05, p=0.02), ECOG PS ≥ 2 (HR 2.6, 95% CI: 1.1-6.4, p=0.03) and prior bendamustine (HR 2.3, 95% CI: 1.3-3.8, p=0.003) remained independently associated with significantly shorter PFS, while POD24 status, rituximab-refractory disease and time from last therapy to R2 initiation lost their association with PFS.
Conclusions: Real-world activity of R2 for the treatment of patients with R/R FL is favorable, with a median PFS of approximately 3.5 years. R2 is associated with suboptimal outcomes in elderly patients, with poor ECOG performance status, and previously exposed to bendamustine. Further research is needed in these high-risk populations.
DISCLOSURES
Tony Zibo Zhuang, MD: No relevant conflicts of interest to declare.