Lenalidomide plus rituximab in patients with rituximab-resistant indolent B-cell and mantle cell lymphomas: 10-year follow-up.
Authors: Gupta Aditi , Schuster Stephen J. , Svoboda Jakub , Nasta Sunita , Napier Ellen , Walsh Kristy , Chong Elise A. 
Published: June 2021

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Background: Lenalidomide (len) plus rituximab is now a standard-of-care option for indolent B-cell non-Hodgkin lymphomas (iNHL) and mantle cell lymphomas (MCL). We previously demonstrated the efficacy of len plus rituximab in patients (pts) with rituximab-refractory iNHL and MCL (Chong et al. Clin Can Res 2015). We now report the longest experience to date with this regimen. Methods: We conducted an open-label phase II trial in pts with iNHL or MCL and rituximab resistance, defined as failure to respond or progression of disease within 6 months (mo) of rituximab or a rituximab-containing regimen. Pts received len 10 mg daily for 8 weeks, followed by 4 weekly doses of rituximab 375 mg/m2 and continued len maintenance until disease progression, toxicity or pt choice. Results: 50 pts (30 FL, 14 MCL, 2 MZL, 4 SLL) were treated between 2008-2012. Median follow-up was 10.5 years (yr). Pts received a median of 3 prior therapies (range: 1–7). Progression free survival (PFS) for all pts at 5 and 10 yrs was 20.0% [95%CI 8-35] & 13% [95%CI 3-30%]; 5- and 10-yr response duration (RD) was 27% [95% CI 12-46] and 18% [95% CI 4-40], respectively; 5- and 10-yr overall survival (OS) was 58% [95%CI 43-70] and 45% [95%CI 30-58], respectively. 5-yr OS from the time pts were deemed rituximab-resistant is 64.0% and 10-yr OS 51.9%. For pts with FL, 5- and 10-yr PFS were both 13%, and 5- and 10-yr OS were 60% and 40%. For MCL, 5- and 10-yr PFS were both 25% and 5- and 10-yr OS were 50% and 36%. At 10.5 yr, 4 pts (2 FL, 1 MCL, 1 MZL) remain in complete remission (CR), 3 of whom discontinued len at 7.0-yr, 8.8-yr and 10.1-yr in CR. 1 pt with FL discontinued study in CR after 11.6-yr but continues on commercial len at 5 mg daily. The most common grade 1–2 adverse events (AEs) requiring dose reductions were neuropathy (n = 3) and diarrhea (n = 5), which all resolved with dose reduction. The most common grade 3–4 AEs requiring dose reductions were neutropenia (n = 6, 12%) and tumor flare (n = 3, 6%). Pts discontinued therapy due to toxicity at a median of 4.9 mo (range 0.3–25.7) from len start due to grade 3–4 rash (n = 2), grade 2 abdominal pain (n = 1), and grade 3–4 thrombocytopenia (n = 2). Only 1 patient discontinued len after > 1 yr (25.7 mo) due to persistent diarrhea. The pt who developed grade 2 abdominal pain was retreated with len without recurrence of pain and sustained a second CR for 5 yrs. 5 (10%) pts developed secondary cancers at a median of 15.5 mo (range: 0.8–50.5) from starting len, including 2 hematological (acute myeloid leukemia, B-acute lymphoblastic leukemia) and 3 solid cancers (NSCLC, renal cell carcinoma, prostate cancer). Prior to enrollment, 4/5 of the patients with secondary cancers had received alkylating agents and 3/5 had received anthracyclines. Conclusions: These data represent the longest reported outcomes for len plus rituximab in NHLs. We demonstrate durable responses and a manageable safety profile with rituximab plus low-dose len. Clinical trial information: NCT00783367.