Addition of Bortezomib to Bendamustine/Rituximab Induction Therapy Does Not Significantly Improve PFS in MCL

Mitchell R. Smith, MD, PhD

The addition of bortezomib (Velcade) to frontline bendamustine plus rituximab (Rituxan; BR) did not significantly improve progression-free survival (PFS) or responses vs BR alone in patients with mantle cell lymphoma (MCL), and the high response and minimal residual disease (MRD) negativity rates observed with BR solidify its role as the standard backbone for induction treatment, according to Mitchell R. Smith, MD, PhD.

The phase 2 ECOG-ACRIN E1411 trial (NCT01415752) examined induction treatment with BV alone or BV plus bortezomib followed by maintenance treatment with rituximab (Rituxan) or lenalidomide (Revlimid) plus rituximab.

Data, which were presented during the 2021 ASCO Annual Meeting, showed that the 2-year PFS rate with BR alone was 74.8% (95% CI, 68.6%-81.6%) vs 79.7% (95% CI, 73.9%-85.9%) with BR plus bortezomib (HR, 0.83; 95% CI, 0.60-1.15), missing the primary end point of the trial. Additionally, the overall response rates (ORR) with BR and BR plus bortezomib were 89.8% and 89.2% respectively.

“BR with rituximab maintenance, which was our standard, had a [median] PFS of more than 5 years, which was far better than what we had hypothesized,” Smith explained. “As such, there was less of a chance that the bortezomib would provide added benefit. The take-home lesson is that BR with rituximab maintenance is quite a good option, and far better than what we had expected.”

In an interview with OncLive^®, Smith, the associate cancer center director for clinical investigations in the Division of Oncology and Blood Disorders at George Washington (GW) University Cancer Center, and a clinical professor of medicine at GW School of Medicine and Health Sciences, discussed the results of the ECOG-ACRIN E1411 trial examining BR-based induction treatment in patients with MCL and next steps for research.

OncLive^®: What was the rationale for the phase 2 ECOG-ACRIN E1411 study?

Smith: The genesis of this study began 10 years ago. At the time, and even now, the general approach to MCL treatment was that younger patients [would receive] more aggressive treatment and patients aged 60 years and older would generally receive less intensive chemotherapy. Ever since the phase 3 STIL trial [NCT00991211], BR has [served as] the basis [of treatment for these patients].

As such, back when this trial was designed, we decided to examine whether we could improve [the efficacy observed with] BR. One of the drugs that was approved at that time and had been combined with BR was bortezomib, so we examined whether 6 months of induction with BR with or without bortezomib [would provide added benefit].

Additionally, what was also coming along around that time was the use of rituximab maintenance therapy [as a way to] prolong remission. As such, we decided to add rituximab maintenance to all arms [of the study], as well as examine whether the addition of lenalidomide to rituximab [maintenance] would be beneficial.

The study ended up having 4 arms. Although BR [induction] with rituximab maintenance has not been formally studied in large groups, it was the de-facto standard that many of us were using. That is how the study was developed, and what we presented during the 2021 ASCO Annual Meeting were the induction data. The patients have been doing well enough that even with the follow-up, [we] have not seen enough events in the maintenance arm to report those data. Hopefully [we will have that information] in a year.

What did the trial population look like?

The study included all patients with previously untreated MCL. The strategy was developed 10 years ago in a separate trial for patients who were going to go on to receive autologous transplant, but our study was limited to patients over the age of 60 years. That other study ended early, so we then allowed patients of any age to [enroll]; that way, they could have an option for a study.

However, it turned out that only approximately 13% of the patients on the study were under 60 years, so the basic population was patients over the age of 60 years who were previously untreated and had adequate organ function and blood counts. However, many patients with lymphoma have low counts because of disease in the bone marrow. As such, we allowed low counts if it was thought to be on the basis of disease. There were no other significant exclusion [criteria], except for [those with] known disease in the central nervous system. Overall, this [trial enrolled] a broad patient population.

Could you expand on the regimens examined?

In terms of the regimen, the BR was fairly standard. Bendamustine was given on days 1 and 2, and rituximab was given on day 1, every 4 weeks for 6 cycles. The addition of bortezomib was initially given on days 1 and 4, but we found that that was challenging for many patients with extra visits. We changed it to day 1 only, at a slightly higher dose, as that had been documented to be equally effective and less toxic.

There was also a switch over from intravenous [IV] use, which had more neurotoxicity, to subcutaneous [administration]. As time went on, more patients received the weekly subcutaneous administration. In terms of rituximab, as treatment evolved, we did allow rituximab biosimilars [to be used] later in the study because they became available.

What were the key findings presented during the meeting?

The of bortezomib to BR was not [found to be] significantly beneficial. There seemed to be a slight trend toward better PFS vs BR [alone], but it was minimal and not [determined to be] statistically significant. With what we know now, that is not terribly surprising. The complete remission [CR] rate and the ORR were also not significantly improved [with the addition of bortezomib].

We also performed MRD analyses. The MRD at 10^-4 was over 90%, even by cycle 3, so BR was quite effective in achieving MRD [negativity]. This does factor into how we will design new studies, because BR is quite a good option. It is going to be hard to beat BR in terms of MRD and PFS [benefit].

What was learned in terms of safety?

The adverse effects [observed on the trial] were primarily cytopenias, as one would expect. [We did] not [observe] a big difference between the arms. Growth factor was allowed, and it was given to most patients, but it was not mandated. The only significant difference was [that there was] slightly more peripheral neuropathy with the bortezomib, which is also not surprising.

[Something we are currently examining is if safety differed between] the IV twice-weekly administration vs the subcutaneous [administration]. We will have to analyze that going forward. I suspect that giving bortezomib subcutaneously weekly is not going to [result in] much neuropathy. Only approximately 3% [of patients experienced this toxicity at] grade 3 or higher, and we expect that less [patients had this] later on in the trial. Again, that awaits further analysis.

What are the clinical implications of these findings?

BR with rituximab maintenance is quite effective as up-front therapy for patients with MCL. I do not think anyone was using bortezomib very much, although a randomized study replacing vincristine with bortezomib in cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab [R-CHOP], showed benefit. However, R-CHOP is falling out of favor.

The take home message is that, for our non-transplant patients, BR is [quite a good treatment option], and perhaps even [for] our transplant patients, it may be beneficial. We always counsel the idea of utilizing clinical trials, and many trials regimens [are BR-based. That is an exciting area [of research]. For example, we are awaiting [additional data on] BR with or without ibrutinib [Imbruvica]. We are looking forward to [examining] other agents [that we can potentially] add to the BR backbone.

What are the next steps with this research?

We need deeper analysis on the MRD question by next-generation sequencing at [a higher] sensitivity. Not surprisingly, MRD-positive patients do not do as well [with this approach] However, can we adjust therapy based on MRD status?

Also, PET scan has never really been validated as an end point in MCL. We have centrally-reviewed PET scans, and we often use these scans in lymphoma at the end of treatment to talk about CRs. However, in MCL we do not have solid data. We also have patient-reported outcome and quality-of-life data that we are looking forward to see.

[We need] to be patient and wait another year until the overall results, including the lenalidomide maintenance data, come out to really pick what the best treatment option is for [our] patients with MCL. That [information will help us inform] whether we add BTK inhibitors or other agents [into the mix]. In the meantime, we are coming away with the idea that BR is probably better than we would have thought, and that is comforting for our patients.

Reference

1. Smith MR, Jegede O, Martin P, et al. ECOG-ACRIN E1411 randomized phase 2 trial of bendamustine-rituximab (BR)-based induction followed by rituximab (R) ± lenalidomide (L) consolidation for mantle cell lymphoma: effect of adding bortezomib to front-line BR induction on PFS. J Clin Oncol. 2021;39(supp 15):7503. doi:10.1200/JCO.2021.39.15_suppl.7503