Lenalidomide Plus Rituximab Continues to Improve PFS With Manageable Safety in Lymphoma Subtypes


The addition of lenalidomide to rituximab continued to improve survival outcomes with durable responses among patients with indolent B-cell non-Hodgkin lymphomas and mantle cell lymphomas.

Treatment with lenalidomide (Revlimid) and rituximab (Rituxan) continued to improve progression-free survival (PFS) with durable outcomes and a manageable safety profile in patients with indolent B-cell non-Hodgkin lymphomas (iNHL) and mantle cell lymphomas (MCLs), according to 10-year follow-up data presented at the European Hematology Association (EHA) 2021 Congress.1

“With median follow up of 10.5 years, we report the longest outcomes data to date for lenalidomide and rituximab in patients with rituximab refractory iNHL and MCL,” the study authors wrote. “Our long-term follow-up demonstrates that durable responses can be achieved with this combination and maintained with a tolerable side effect profile.”

In the retrospective review of the single-center, prospective, open-label phase 2 trial (NCT00783367), investigators aimed to evaluate 5- and 10-year outcomes for patients with iNHL and MCL with rituximab resistance (defined as failure to respond to or progression of disease within 6 months of rituximab or a rituximab-containing regimen) who were treated with lenalidomide and rituximab to identify adverse events (AEs) that led to dose discontinuation.

At a median follow-up of 10.5 years, 5- and 10-year PFS for all patients (N = 50) was 20.0% (95% CI, 8%-35%) and 13% (95% CI, 3%-30%), respectively. For those with follicular lymphoma (FL; n = 30), the 5- and 10-year PFS rates were 13% for both. For patients with MCL, 5- and 10-year PFS rates were 25% for both.

Response duration rates at 5 and 10 years for all patients were 27% (95% CI, 12-46) and 18% (95% CI, 4%-40%), respectively. For the FL and MCL subgroups, 10-year PFS rates were 18.1% and 21.5%, respectively. The median response duration for patients who initially responded to the combination regimen (n = 28) was 2.1 years.

The five- and 10-year overall survival (OS) rates were 58% (95% CI, 43%-70%) and 45% (95% CI, 30%-58%), respectively. Moreover, 5- and 10-year OS rates from the time patients were deemed rituximab-resistant were 64.0% and 51.9%, respectively. For patients with FL, 5- and 10-year OS rates were 60% and 40%, respectively; corresponding rates were 50% and 36% for those with MCL.

At the 10.5-year follow-up, 4 patients – including 4 with FL, 1 with MCL, and 1 with marginal zone lymphoma (MZL) – remained in complete remission. Three of the 4 patients discontinued lenalidomide at year 7.0, 8.8, and 10.1 in complete remission. One patient with FL discontinued the study in complete remission after 11.6 years but continues on commercial lenalidomide at 5 mg daily.

The most common grade 1 to 2 AEs requiring dose reductions were neuropathy (n = 3) and diarrhea (n = 5), all resolving with dose reduction; the most common grade 3 to 4 AEs were neutropenia (n = 6) and tumor flare (n = 3).

Overall, 4% of patients discontinued lenalidomide at > 6 cycles of therapy and 22% discontinued lenalidomide at < 6 cycles of therapy. Patients discontinued lenalidomide treatment due to AEs at a median of 4.9 months (range, 0.3-25.7) after patients started on therapy.

Discontinuations of lenalidomide were due to grade 3 to 4 rash (n = 2), grade 2 abdominal pain (n = 1), and grade 3 to 4 thrombocytopenia (n = 2). The patient who developed grade 2 abdominal pain was retreated with lenalidomide without recurrence of pain and sustained a second complete remission for 5 years.

One patient discontinued treatment after 25.7 months after starting lenalidomide because of persistent diarrhea.

Six patients (12%) developed a secondary cancer after a median duration of 11.5 months (range, 0.8-50.5) of lenalidomide therapy, including 3 hematologic malignancies (acute myeloid leukemia at 7.5 months and 50.5 months, and B-cell acute lymphocytic leukemia at 0.8 months) and 3 solid malignancies (renal cell carcinoma at 6.8 months, non–small cell lung cancer at 26.0 months, and prostate cancer at 15.5 months).

Gupta and colleagues previously showed the efficacy of the combination regimen in patients with rituximab-refractory iNHL and MCL who were enrolled between 2008 to 2012.2

In the trial, 50 patients – including 30 with FL, 14 with MCL, 2 with MZL, and 4 with small lymphocytic lymphoma – were treated with lenalidomide 10 mg daily for 8 weeks, followed by 4 weekly doses of rituximab 375 mg/m2 and continued lenalidomide maintenance until disease progression, toxicity, or patient choice.

Inclusion criteria included patients having CD20-expressing small B-cell lymphomas and a history of rituximab-resistant lymphoma. Patients were excluded from the trial if they had previous treatment with lenalidomide and central nervous system involvement by lymphoma.

Patients had received a median of 3 prior lines of therapy (range, 1-7).

In the previous analysis, the overall response rate after 8 weeks of lenalidomide was 30.2%. Moreover, 12 weeks after the addition of rituximab to lenalidomide, ORR increased to 62.8%.

After a median follow-up of 39.2 months, median PFS was 22.2 months and PFS after lenalidomide plus rituximab was significantly longer (22.2 months vs 9.13 months; P = .0004).

“Lenalidomide plus rituximab produces synergistic results in indolent B-cell non-Hodgkin lymphomas and mantle cell lymphomas,” the study authors wrote.

For future direction, they would like to “optimize lenalidomide dosage and length of treatment duration.”


1. Gupta A, Schuster S, Svoboda J, et al. Lenalidomide plus rituximab in patients with rituximab-resistant indolent b-cell and mantle cell lymphomas: 10-year follow-up. Presented at: European Hematology Association 2021; June 9-17, 2021; Virtual. Abstract EP800. doi: 10.1097/HS9.0000000000000566.

2. Chong EA, Ahmadi T, Aqui NA, et al. Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas. Clin Cancer Res. 2015;21(8):1835-1842. doi: 10.1158/1078-0432.CCR-14-2221.

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