Lenalidomide/Rituximab Regimens Show Encouraging Responses in Relapsed/Refractory Follicular Lymphoma, But Slow Accrual Axes Study

The regimen of lenalidomide in combination with rituximab with bendamustine are effective therapies for relapsed/refractory follicular lymphoma, with high rates of overall and complete metabolic response by PET, according to data from the randomized phase 2 HOVON110/Rebel trial.

Marie José Kersten, MD, PhD

Marie José Kersten, MD, PhD

The regimen of lenalidomide (Revlimid) in combination with rituximab (Rituxan; R2) with bendamustine are effective therapies for relapsed/refractory follicular lymphoma (FL), with high rates of overall and complete metabolic response (CMR) by positron emission tomography (PET), according to data from the randomized phase 2 HOVON110/Rebel trial.

Results showed a complete response (CR) rate of 16% in the R2 arm and 22% in the R2-plus-bendamustine armat end of induction, reported Marie José Kersten, MD, 2022 ASH Annual Meeting. Ninety-two of a planned 150 patients were enrolled between 2014 and 2019, but the study was closed prematurely due to slow accrual.

“The patients with R2 plus bendamustine had more rapid responses and based on intention to treat however, the CMR rate was actually similar in the R2 and R2-plus-bendamustine arm,” Kersten, head, Department of Hematology at the Academic Medical Center, in Amsterdam, The Netherlands, said in a presentation. The ORR at the end of cycle 6 by PET scan was 64% in the R2 arm and 63% in the R2-plus-bendamustine arm, with rates of CMR of 48% and 50%, respectively, by PET scan.

In an intent-to-treat analysis, with a median follow-up of 48 months, the event-free survival rate was 39% in patients randomized to the doublet and 61% in those randomized to R2 plus bendamustine. Median EFS was 24.6 months and not reached (NR) in the doublet and triplet arms, respectively. “Importantly, 41% of the patients in R2 arm and 65% of patients treated with R2 plus bendamustine did not require any subsequent treatments for a prolonged period of time,” she said. The median time to next treatment was 9.2 months and NR, respectively.

There were 11 deaths in the R2 arm, 8 due to progressive disease and 3 due to toxicity; 5 deaths occurred in the triplet arm, due to progressive disease (n = 3) and toxicity (n = 1).

A landmark analysis at the 6-month assessment showed better discriminatory value of the PET scan over computed tomography for long-term EFS. This was true for prediction of CMR and overall survival.

In the international study, patients with grade 1 to 3a, CD20-positive FL that relapsed after up to 5 prior therapies were randomized 1:1 to R2 or R2 plus bendamustine. Patients in the R2 arm received 6 cycles every 28 days (lenalidomide 20 mg on days 1 to 21, and rituximab, 375 mg/m2 on day 1). Patients randomized to the triplet received the same dosing schedule of lenalidomide and rituximab, plus bendamustine at 90 mg/m2 on days 1 and 2. In both arms, patients with partial or complete remission received 2 years of rituximab maintenance, once every 3 months.

Thrombosis prophylaxis (aspirin or alternative anticoagulant) was advised during induction; antimicrobial prophylaxis with valaciclovir and cotrimoxazole was mandatory in the triplet arm.

Baseline characteristics were similar in both cohorts, with a median age of 63 years (range, 56-69). Most patients (82%) had stage III/IV disease and 84% had a Follicular Lymphoma International Prognostic Index score of 2 or higher. The median number of prior lines of treatment was 1.

The data cutoff date was June 11, 2022.

Some 80% of the patients in the R2 arm and 76% in the triplet arm completed the 6 cycles of induction therapy. Sixteen patients in the R2 arm and 11 in the triplet arm went off protocol due to progressive disease, and 3 patients in the R2 arm and 9 in the R2-plus-bendamustine arm went off protocol due to toxicity.

Grade 2 or higher adverse events (AEs) were more common with the triplet during induction, most notably infections and gastrointestinal (GI) toxicity. There were fewer AEs during maintenance and these also occurred more frequently with R2 plus bendamustine.

Severe toxicities occurred in 3 patients in the R2 arm (6.8%; 2 cases of fatal pneumonia) and in 6 patients in the R2-plus-bendamustine arm (13.0%); 43% and 66%, respectively, experienced grade 3/4 AE, with the rates of grade 4 being 2% and 7%, respectively. These comprised mainly of skin toxicity, infections, and GI toxicity. One patient in the triplet arm had Pneumocystis carinii pneumonia during rituximab maintenance.

“Although the ReBeL/HOVON110 study closed prematurely because of slow accrual, the study results are clinically meaningful and support ongoing R2 combination studies in FL,” concluded Kersten.


Kersten MJ, Dreyling M, Linton KM, et al. Lenalidomide-rituximab or lenalidomide-rituximab-bendamustine in patients with relapsed/refractory follicular lymphoma: primary analysis of the randomized phase II HOVON110/Rebel trial. Presented at: 2022 ASH Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 962.

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