Bendamustine/Rituximab Represents a Backbone for Therapeutic Development in MCL

Brad S. Kahl, MD

The combination of bendamustine and rituximab (Rituxan; BR) as induction therapy with bortezomib (Velcade) did not demonstrate improved 2-year progression-free survival (PFS) vs BR alone in patients with mantle cell lymphoma (MCL), according to data from the phase 2 ECOG-ACRIN E1411 trial (NCT01415752).1 However, the notable 2-year PFS outcomes with BR alone have paved the way for a standard to build upon in the MCL treatment landscape, according to Brad S. Kahl, MD.

For example, the phase 3 ECHO trial (NCT02972840), which evaluated BR combined with acalabrutinib (Calquence) vs BR alone in patients with previously untreated MCL ineligible for autologous hematopoietic stem cell transplantation (HSCT), supported the January 2025 FDA approval of BR plus acalabrutinibin this patient population.2

Furthermore, in the phase 2 study, investigators evaluated the addition of lenalidomide (Revlimid) to rituximab as maintenance therapy.1

“The addition of lenalidomide to maintenance [therapy] also did not improve PFS,” Kahl said in an interview with OncLive®. “[We concluded that] it was a negative trial, disappointingly, because we hoped we would improve outcomes. Bortezomib did not improve the induction [outcome], and lenalidomide did not improve the maintenance [results].”

The median PFS independent of the induction regimen was 5.9 years vs 7.2 years in patients treated with maintenance rituximab and rituximab/lenalidomide, respectively (HR, 0.84; 90% CI, 0.62-1.15).

During the interview, Kahl detailed the phase 2 study rationale and design, key efficacy data, and how BR has opened the door for future regimens in the MCL treatment landscape.

Kahl is a professor in the John T. Milliken Department of Oncology in the Division of Oncology at the Washington University School of Medicine in St. Louis, Missouri.

OncLive: What was the background and rationale for evaluating BR with or without bortezomib in MCL?

Kahl: We began designing the study back in 2011, and at that time, we were struggling with managing MCL and how to improve outcomes. We knew that for younger patients who could handle intense treatments the best strategy was some semi-intensive induction followed by HSCT. Our older patients weren’t candidates for that kind of strategy. We had recently learned that BR was a very good and tolerable strategy for these older patients. The United States practice was starting to latch on to this idea of BR for 6 months of induction. Other data also showed that maintenance rituximab could be useful in extending those remissions, which we used as our backbone. [For the study] we were trying to decide how we could improve outcomes beyond that. At the time of the study, the newer agents on the scene and worth testing were bortezomib and lenalidomide, both of which had been FDA approved for [patients with] relapsed/refractory MCL. Therefore, we decided to design a study for older patients with MCL, in which we would test the addition of bortezomib to BR induction and the addition of lenalidomide and rituximab as a maintenance strategy.

How was the study designed, and what were the key patient characteristics for enrollment?

It was a 4-arm study, where [patients in] 1 arm received BR plus maintenance rituximab, and then another arm added bortezomib to the induction [regimen]. The third arm added lenalidomide to the maintenance [regimen], and then the fourth arm added bortezomib and lenalidomide [to the induction and maintenance regimens, respectively]. This was a randomized phase 2 study, and for the analysis the 2 bortezomib-containing arms were pulled together and compared with the 2 non-bortezomib arms. The 2 lenalidomide arms were paired together and compared with the 2 non-lenalidomide arms. As a secondary analysis, we analyzed all 4 arms separately.

The trial was designed for older patients with MCL aged 60 years and older [whose disease] would not be considered appropriate for more intensive treatments. The primary end point of the study was PFS. We were identifying whether the addition of these novel agents improved PFS compared with the control arm of BR followed by rituximab maintenance.

What were the key efficacy findings?

The study showed that adding bortezomib to BR induction did not improve the 2-year PFS [rate]. It came in around 75% to 80% for both arms, and it didn’t improve the complete remission rates either. We learned that just the baseline regimen of BR was very effective; the median PFS was over 5 years, which was a promising result in these older patients. It cemented that regimen as the backbone upon which to build and test. So even though our trial was negative, not long after our trial was initiated, newer drugs came along like the BTK inhibitors ibrutinib [Imbruvica] and then acalabrutinib. If you look at the design of those subsequent trials like SHINE [NCT01776840] and ECHO, the investigators took the backbone of BR that we had established and evaluated the addition of a BTK inhibitor to that induction regimen.

Although the study was negative, are there any future research directions?

This regimen we selected—BR followed by rituximab maintenance—became a North American and worldwide standard upon which to build. Groups are now comparing that regimen with the addition of BTK inhibitors. There’s [an ongoing] trial called MANGROVE [NCT04002297], which is evaluating BR vs a chemotherapy-free approach of zanubrutinib and rituximab. There are also some [completely] chemotherapy-free approaches being tested. The next step will be to see if a chemotherapy-free approach, like all novel agents, can perform better than BR with rituximab maintenance—that’s the next frontier for older patients with MCL.

References

1. Smith MR, Jegede OA, Martin P, et al. Randomized study of induction with bendamustine-rituximab ± bortezomib and maintenance with rituximab ± lenalidomide for MCL. Blood. 2024;144(10):1083-1092. doi:10.1182/blood.2024023962
2. FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma. FDA. January 16, 2025. Accessed May 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-bendamustine-and-rituximab-previously-untreated-mantle-cell-lymphoma