Ten Year Follow up of the MD Anderson Cancer Center Phase 2 Study of Rituximab in Combination with Lenalidomide (R2) for Patients with Low Tumor Burden Follicular Lymphoma
Authors: Chihara Dai , Nastoupil Loretta , Strati Paolo , Samaniego Felipe , Feng Lei , Rodriguez Maria Alma , Fayad Luis , Westin Jason R. , Hagemeister Fredrick B. , Wang Michael , Neelapu Sattva S. , Fowler Nathan H. 
Published: November 2021

Abstract
Background:
Patients with follicular lymphoma (FL) often present with asymptomatic low tumor burden (LTB) disease. Treatment with rituximab monotherapy for LTB disease may result in improved quality of life, and delay the need for cytotoxic therapy compared to watch and wait (WW) (Ardeshna et al. Lancet Oncol 2014), however, WW is still considered appropriate for patients due to a lack of survival benefit compared to rituximab monotherapy. Rituximab in combination with lenalidomide (R2) is superior to rituximab monotherapy resulting in significant improvement in progression-free survival (PFS) and overall survival (OS) for patients with relapsed/refractory FL (Leonard JP et al. J Clin Oncol 2019), and may be an appropriate option for some patients with previously untreated high-tumor burden FL based on the RELEVANCE study (Morschhauser et al. New Eng J Med 2018). Given R2 is generally well tolerated, we set out to report long term follow up of patients with LTB FL who received R2 on our phase 2 study.
Methods:
The original open label, phase 2 investigator-initiated study (NCT00695786) enrolled previously untreated patients with advanced stage indolent lymphoma between 07/2008 and 04/2012. Patients were treated with lenalidomide 20 mg/day on days 1-21 and rituximab 375 mg/m2 on day 1 of each 28-day cycle, continuing in responders for ≥6-12 cycles. The primary endpoint of the study was overall response rate (ORR). Secondary endpoint included complete response (CR) rate, PFS and OS. The 1999 International Working Group Criteria for Non-Hodgkin Lymphoma was prospectively used for response assessment, and the 2014 Lugano classification was used in this analysis to retrospectively define CR. The data cut-off date was 7/31/2021.
Results:
Overall, 40 patients with LTB FL based on the GELF criteria (Brice et al. J Clin Oncol 1997) were treated on the study. The median age of the patients was 57 years (range: 37-82 years). FLIPI risk was low in 14 (35%), intermediate in 18 (45%) and high in 8 (20%) patients. The median time from diagnosis of FL to R2 was 58 days (range: 16-1672 days). Twenty-three patients and 16 patients received six and 12 cycles, respectively. One patient stopped R2 at cycle 4 due to severe myocardial infarction. The ORR was 98% with 39 patients achieved CR (95%), one achieved partial response, ORR was (98%). With a median follow up duration of 9.8 years (range: 5.5-12.7 years), 15 patients experienced progression of FL, 10 patients required next line of treatment (3 rituximab monotherapy, 3 BR, 3 R-CHOP, 1 clinical trial) and 1 patient died with pancreatic cancer with FL in remission. Five patients (12.5%) experienced progression within 24 months, four of whom received next treatment and one was followed without treatment for over 7 years and lost to follow-up. The 10-year PFS, time to treatment failure (requires next treatment) and OS rates were 59%, 82% and 95%, respectively (Figure). Two patients experienced transformation at 9 months and 10.8 years, four patients experienced second cancers at 3.7 years (renal cell carcinoma), 4.3 years (melanoma), 8.7 years (pancreatic adenocarcinoma) and 9.3 years (bladder cancer). No significant difference was seen in PFS between patients who received 6 vs. 12 cycles (5-year PFS 67% vs 88%, p=0.33).
Conclusion:
With 10 years of follow up, R2 resulted in excellent OS without lymphoma related deaths in patients with low tumor burden FL although we continued to observe progression even after 10 years.
Figure 1 Figure 1.

Disclosures
Chihara: Astrazeneca: Honoraria. Nastoupil: TG Therapeutics: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Denovo Pharma: Other: DSMC; MorphoSys: Honoraria; Gilead/Kite: Honoraria, Research Funding; IGM Biosciences: Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Caribou Biosciences: Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Honoraria. Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. Samaniego: Arog: Research Funding; Imbrium: Membership on an entity's Board of Directors or advisory committees. Westin: AstraZeneca: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Umoja: Consultancy; Iksuda Therapeutics: Consultancy; Curis: Research Funding; Morphosys: Research Funding; 47 Inc: Research Funding; Genentech: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding. Wang: Juno: Consultancy, Research Funding; Imedex: Honoraria; Hebei Cancer Prevention Federation: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; CAHON: Honoraria; InnoCare: Consultancy, Research Funding; Oncternal: Consultancy, Research Funding; BioInvent: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Physicians Education Resources (PER): Honoraria; Mumbai Hematology Group: Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Celgene: Research Funding; Molecular Templates: Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; Clinical Care Options: Honoraria; Anticancer Association: Honoraria; Chinese Medical Association: Honoraria; Loxo Oncology: Consultancy, Research Funding; BGICS: Honoraria; Newbridge Pharmaceuticals: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; VelosBio: Consultancy, Research Funding; CStone: Consultancy; Genentech: Consultancy; Lilly: Research Funding; Bayer Healthcare: Consultancy; Moffit Cancer Center: Honoraria; OMI: Honoraria; Scripps: Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Dava Oncology: Honoraria. Neelapu: Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria. Fowler: Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company.