Brad S. Kahl, MD, explains the evolution of mantle cell lymphoma treatment over the past decade and lays out the trajectory for future therapies, including the potential benefits of lenalidomide in the maintenance setting.
The continuation of rituximab (Rituxan) as maintenance therapy following frontline therapy with bendamustine plus rituximab (BR) remains an effective and tolerable treatment for older patients with mantle cell lymphoma (MCL), according to Brad S. Kahl, MD.
Maintenance rituximab following BR improves overall survival (OS) as well as progression-free survival (PFS) in this population, although the optimal duration of this therapy still needs to be determined, Kahl explained in a presentation on older patients with MCL who achieve remission, which he shared at the 2022 Pan Pacific Lymphoma Conference.1
“There is much to look forward to coming soon in MCL,” Kahl said in an interview with OncLive®.
In the interview, Kahl, a professor in the Department of Medicine, Oncology Division, Medical Oncology, at Washington University School of Medicine in St. Louis, and a medical oncologist at the Siteman Cancer Center, explained the evolution of MCL treatment over the past decade and laid out the trajectory for future therapies, including the potential benefits of lenalidomide (Revlimid) in the maintenance setting. He also emphasized the importance of exercising discernment when applying clinical trial data, such as the findings from the phase 3 SHINE trial (NCT01776840), to real-world, practice-based data on individual patient needs and characteristics.
Kahl: [The question I addressed] at the Pan Pacific meeting was: What do you do with an older patient with MCL who has completed induction therapy and is now in remission? What would be the best strategy to try to maintain that remission?
Some post-remission strategies could be influenced by what you did to get the patient into remission. The most commonly used induction strategy in the United States for older patients with MCL is probably BR. If you give BR for 6 cycles with no form of maintenance therapy, you can expect remissions lasting, on average, in the 3-year range, although some patients have shorter remissions, and some patients have longer remissions.
BR is well tolerated by older patients with MCL. [However, although this combination] is a useful way to induce remission, we would like to do better than 3 years. Is there anything we can do to extend that?
One of the more commonly utilized strategies, although without much evidence, has been the application of maintenance rituximab. Maintenance rituximab was shown to be beneficial after [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)] in [the phase 3 MCLelderly trial (NCT00209209)], a big European study published [in 2012]. However, whether that same benefit is derived after BR is not so clear. One small, randomized study that has been presented but not published suggested that rituximab maintenance after BR isn’t incredibly useful.
Recently, some larger datasets have become available. A recent important study from Peter Martin, MD, [of Weill Cornell Medicine,] and colleagues [was published] in the Journal of Clinical Oncology. Using the Flatiron [Health EHR-derived deidentified] database, they conducted a real-world analysis of 1,621 patients with MCL who had received induction therapy with [regimens such as] R-CHOP or BR and looked at patient outcomes based on whether patients had received maintenance rituximab. This large analysis showed that there is a major benefit of maintenance rituximab in terms of time to next treatment, which was seen in both the R-CHOP and the BR groups. This even translated into an OS benefit in this analysis.
[Although this was] not a randomized clinical trial, it [did gather information from a] large real-world database, and it’s the most powerful evidence we have indicating the benefit of maintenance rituximab after BR induction. That’s what I would recommend to patients right now outside of a clinical trial setting.
The big question before us right now is whether to add ibrutinib [Imbruvica] to the therapy. Just published in the New England Journal of Medicine were the results of the SHINE study, a big global study from Michael Wang, MD, of The University of Texas MD Anderson Cancer Center, and colleagues. This study randomized older patients with MCL. The control arm received BR for 6 cycles, followed by maintenance rituximab for 2 years, just like we do in standard practice.
The experimental arm added ibrutinib at a dose of 560 mg daily. Patients [in this arm] received ibrutinib throughout the induction, throughout the 2 years of maintenance, and beyond the maintenance rituximab, staying on the ibrutinib therapy until disease progression or intolerance. This important trial randomized 523 patients 1:1 to each arm.
This study showed that adding ibrutinib helps control the disease. Patients on ibrutinib were less likely to relapse. However, patients on ibrutinib were more likely to have significant adverse effects [AEs], and even more likely to have fatal AEs. Even though there’s a PFS benefit with the addition of ibrutinib, there is no OS benefit. This creates a bit of a quandary for practitioners. What do you do with this information?
When you look at the PFS curves from the SHINE trial, the absolute difference in terms of being in remission at 4 years is about 10%, [so a patient is] about 10% more likely to be in remission at 4 years [after ibrutinib therapy]. For instance, that’s like a 50% vs 60% likelihood [of being in remission at 4 years]. But again, there was no difference in OS.
Different practitioners will come to different conclusions about this dataset. I do not see myself recommending the incorporation of ibrutinib based on the SHINE data, because the PFS benefit is modest, and there’s no OS benefit. There’s also a significant toxicity risk that comes with the addition of ibrutinib.
Most importantly, you’re also using up your BTK inhibitor—currently our most commonly used second-line regimen—in the frontline. When your patient progresses through that BTK inhibitor, if you choose to use it, where do you go to next? We have CAR T-cell therapy and lenalidomide, but you have exhausted 1 of your best classes of options. For all those reasons, I don’t see myself recommending ibrutinib added to the BR plus rituximab maintenance regimen. [However, there will be] differing opinions about that dataset.
Where do we go from here? A couple of important datasets still need to be analyzed. The [phase 3] ECHO trial [NCT02972840] is designed exactly like SHINE, but it used the BTK inhibitor acalabrutinib [Calquence], which tends to have a better safety profile than ibrutinib. The ECHO readout, which will probably come in a year or 2, will be interesting. It may show a PFS benefit without the toxicity signal.
We hope to [present] data at [the 2022 ASH Annual Meeting and Exposition] from the [phase 2] E1411 trial [NCT01415752], in which patients received BR induction followed by rituximab maintenance, with half of the patients also receiving lenalidomide added to the rituximab. Maybe we’ll see how lenalidomide contributes to maintenance of remission.
Finally, the [phase 3] MANGROVE trial [NCT04002297] is currently enrolling patients. It’s testing the second-generation BTK inhibitor zanubrutinib [Brukinsa] combined with rituximab against BR, so half of the patients are going to receive a chemotherapy-free strategy. We don’t have any data on that yet, but it will be an interesting data set to analyze in a few years.
The biggest unmet needs remaining in MCL are options for the high-risk patients. Some of our frontline patients will have a p53 mutation, and they respond poorly to our standard treatments [such as] BR or high-dose chemotherapy and stem cell transplant. Hopefully, novel agents like BTK inhibitors or CAR T-cell therapy will turn out to be a better option for these high-risk patients.
In older patients who have highly proliferative disease without p53 mutations, our standard treatments still don’t work as well either. We need better options there. Maybe the addition of a BTK inhibitor would be valuable there, or maybe trying some novel combinations [would be helpful]. For example, there’s an interesting regimen that was developed in Italy called R-BAC, which is bendamustine, low-dose cytarabine, and rituximab. Those data look good now, with 7 years of follow-up. It’s possible that the addition of the low-dose cytarabine helps overcome the highly proliferative risk that [some of these patients have]. The R-BAC regimen could turn out to be a good option for older patients with highly proliferative MCL.
The standard of care for older patients ought to be BR with maintenance rituximab. We don’t know the optimal duration of maintenance rituximab; some studies have used 2 years, some studies have used 3 years, some studies have used an indefinite amount of time.
I worry about the toxicity of long-term maintenance rituximab, especially during the COVID-19 pandemic. [In my practice,] I’m choosing to stop the maintenance rituximab at 2 years, which will hopefully then allow some eventual B-cell recovery in those patients.
With the interesting SHINE dataset, some practitioners may opt to add ibrutinib to the regimen. I personally will not do that, but it’s reasonable to do it if you think those data are compelling enough. We have some interesting datasets around the corner with acalabrutinib in the ECHO trial, lenalidomide added to rituximab maintenance in the E1411 trial, and the chemotherapy-free arm in the MANGROVE study.