Maintenance Rituximab Linked to Improved Outcomes in MCL

Talal Hilal, MB, BCh, associate professor of oncology and urology at Johns Hopkins Medicine

Talal Hilal, MB, BCh

In a meta-analysis of rituximab (Rituxan) maintenance for patients with mantle cell lymphoma (MCL), investigators concluded that this approach improves progression-free (PFS) and overall survival (OS) following induction chemoimmunotherapy.

“Overall, patients who are young, fit, and eligible for transplant who start with an induction chemoimmunotherapy that includes cytarabine-based regimens and rituximab maintenance in that setting appear to have a benefit in terms of PFS and OS,” said lead study author Talal Hilal, MB, BCh.

Through PubMed, Embase, Scopus, Web of Science, and Cochrane, investigators gathered 697 records, and 28 full-text articles were used after exclusions. Overall, 1050 patients met the inclusion criteria, with 455 patients in the rituximab maintenance arm and 595 in the non-rituximab maintenance arm.

PFS (HR, 0.39; 95% CI, 0.31-0.50) and OS (HR, 0.47; 95% CI, 0.27-0.83) were improved with rituximab maintenance. Additionally, those who had undergone autologous stem cell transplant experienced a slightly better PFS (HR, 0.34; 95% CI, 0.25-0.47) and OS (HR, 0.38; 95% CI, 0.22-0.65) benefit.

OncLive: Can you provide an overview of this trial?

In an interview with OncLive^®, Hilal, an assistant professor of Medicine at Mayo Clinic, discussed the findings of this meta-analysis, and the approach to maintenance therapy in patients with MCL.Hilal: This was a meta-analysis where we aimed to answer the question of what the benefit of maintenance rituximab is in patients who have MCL. There are not many studies, so we thought that a systematic review would be a good way to start. We found about 700 studies that were screened by about 7 meta-inclusion criteria, which were pretty broad. They did not specify whether it was a first-line treatment, relapse, or posttransplant. The main thing was that they must have had induction chemoimmunotherapy. We also included randomized trials and observational studies with comparative arms. Randomized trials were included, and 4 observational studies were included.

What else needs to be understood about rituximab in this setting?

We found that in the overall population, there was a benefit in terms of PFS and OS. In the prospective studies only, the benefit was mainly PFS, and there was no OS benefit. There are only 3 prospective trials, and 2 of them did not use transplant. That is the main driver of the OS benefit in terms of prospective studies. Retrospective studies have their own limitations—there is a lot of heterogeneity and differences in how patients were treated. When we looked at transplant only, there were a couple that were excluded because they did not do transplants, so we were left with about 5. In those studies, there was a benefit in PFS, but not OS.There was a study presented at the 2016 ASCO Annual Meeting, which was a subgroup of the [StiL NHL7-2008] MAINTAIN trial, which looked at bendamustine/rituximab induction followed by maintenance versus observation. That is not published yet as a paper; however, in that trial, there was no benefit in PFS or OS. Those are patients who did not receive a transplant and were not fit for transplant. They received the most common induction regimen that we use, which was not reflected in this meta-analysis. A lot of clinicians don't offer maintenance rituximab in the setting of no transplant. They'll receive chemoimmunotherapy and get a response, but then it is sort of unknown.

Are there any other agents you would like to see explored?

A lot of it is unknown because this abstract did not show a benefit. That is a place that [rituximab] could be explored further. Could a more intensive chemotherapy regimen be more useful and [deliver] some sort of benefit in terms of PFS in this setting? Using cytarabine induction in patients who are younger may be a population that benefits from maintenance rituximab. It would be nice to see that paper get published, but for now, there is a consensus on offering rituximab maintenance for patients after transplant. There is a little controversy for patients without transplant.There are data in follicular lymphoma using obinutuzumab (Gazyva) that has not been replicated in MCL. The data in follicular lymphoma are not convincing; there are limitations to using obinutuzumab, such as a high risk for infection and toxicity. Unless we can show some benefit to rituximab in OS or quality of life, it will be hard to move to a different anti-CD20.

What about lenalidomide (Revlimid)?

Is there anything else going on in the space that you find particularly exciting?

Agents such as ibrutinib (Imbruvica) and acalabrutinib (Calquence) can be explored, but then you are subjecting patients to long-term therapy, which also has more toxicity than rituximab or obinutuzumab. We still need earlier, smaller data to be optimistic about using these agents.That is a reasonable approach. Lenalidomide is one of the more tolerated drugs used in the second- and relapsed settings. A lot of patients have prolonged benefit with lenalidomide. The issue there becomes taking pills everyday versus an infusion every 2 to 3 months. Cost and toxicity also may limit its use.There are earlier studies looking at BTK and PI3K inhibitors in MCL, follicular lymphoma, and chronic lymphocytic leukemia. They seem to have good activity in terms of response rate, but we do not yet know long-term efficacy.

Is there anything else that you would like to add?

In terms of the use of agents that are active in MCL, we have a few. The main question is, how do we use less [drugs] and have patients be better for longer? The less toxic regimens that can be used in the maintenance setting would be preferred, and a more toxic regimen in the induction setting would probably confer some benefit as well.Our study highlights that there is a PFS benefit. If you look at all the studies that were included, the overall message is that there is a PFS benefit whether you use it after induction with or without transplant. OS benefit is supported only in 1 prospective trial after transplant. There is an OS benefit in 1 prospective trial in non-transplant [patients] using R-CHOP induction. Patients who get cytarabine induction can also benefit in that setting. Outside that, it is hard to tell patients that they will have an OS benefit without transplant or an intensive induction regimen.

The main message is that there might be a PFS and OS benefit in transplant, but we cannot know for sure in that third population.

Hilal T, Wang Z, Almader-Douglas D, et al. Rituximab maintenance for mantle cell lymphoma: a meta-analysis. J Clin Oncol. 2018;36 (suppl; abstr e19557).