Combination Regimens on the Rise in Mantle Cell Lymphoma

Michael E. Williams, MD

While no standard treatment approach is evident in the management of patients with mantle cell lymphoma (MCL), researchers are actively seeking to identify targeted approaches that could help solidify one.

For example, the phase II randomized ECOG-E1411 trial (NCT01415752) is seeking to determine whether the frontline triplet regimen of rituximab (Rituxan), bendamustine, and bortezomib (Velcade) followed by lenalidomide (Revlimid) and rituximab as maintenance therapy could dramatically improve outcomes for patients with MCL.

Additionally, a single-arm phase I/Ib study (NCT02419560) is currently exploring the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) for the treatment of relapsed/refractory patients with MCL. Patients will orally receive venetoclax at 100 to 400 mg/daily and ibrutinib at 280 to 560 mg/daily. The study is currently recruiting patients.

Results of a phase II study exploring the combination of lenalidomide and rituximab¹ found that patients had an objective response rate (ORR) of 92% when given as initial therapy—demonstrating that a chemotherapy regimen may not be a necessary treatment for MCL.

While such ongoing studies are helping agents potentially move down the pipeline to create novel approaches, Michael E. Williams, MD, says that the treatment options for patients with MCL have improved over the last 25 years.

“Mantle cell lymphoma has been, historically, been one of the more difficult non- Hodgkin lymphomas to treat,” Williams says. “However, that’s changed dramatically in recent years with newer chemoimmunotherapy combinations and the responsiveness in MCL to several new targeted agents.”

OncLive: What specific agents do you envision having potential in MCL?

In an interview with OncLive, Williams, who is the Byrd S. Leavell Professor of Medicine and a professor of Pathology at the University of Virginia Health System, discusses emerging regimens on the horizon, the potential of BCL-2 inhibition, and whether chemotherapy can be removed entirely from the treatment landscape of MCL.Williams: Right now, there is no clear standard of care for treating either younger or older patients with MCL. If they are younger, then the question is, “Is this a patient who is going to go through intensive therapy that includes high-dose cytarabine followed by autologous stem cell transplantation to consolidate that response?" Or, will there be more of a use of chemoimmunotherapy with or without maintenance treatment?

For older patients, it has typically been either rituximab plus CHOP—which we tend not to use—or rituximab plus bendamustine. Right now, for patients who are not transplant eligible from a standard approach and are looking at an extra duration of therapy, we are encouraging enrollment in the ECOG-E1411 trial, which is bendamustine and rituximab with or without bortezomib, followed by either rituximab alone or rituximab plus lenalidomide as maintenance therapy.

We are either looking at that existing background of standard regimens or that clinical trial to enroll in.

What has been the impact of some of these agents thus far?

We are now entering an era where we have other approved drugs for relapsed disease, including lenalidomide, ibrutinib, and bortezomib, which has been approved for a number of years in the United States. In the European Union, there is the mTOR inhibitor temsirolimus (Torisel) that is approved for relapsed disease. There is an interest in bringing 1 or more of those into the frontline setting, which is shown in the ECOG-E1411 trial, for select patients.In the relapsed setting, they clearly have activity, but the impact of these is potentially going to be profound. There was a multicenter study out of Weill Cornell Medicine and NewYork-Presbyterian looking at frontline treatment—without chemotherapy—using rituximab plus lenalidomide. The combination showed an impressive ORR and durable responses with ongoing maintenance therapy.

It sort of proves that, in the paradigm, you can use a nonchemotherapy-based approach and get very good responses. Interestingly, whether patients have low or high risk—as determined by the Mantle Cell Lymphoma International Prognostic Index—they seem to do equally well. It was a small study and the follow-up was relatively short, but it was very encouraging. It proves the principle that you can use a non-cytotoxic approach and get even better outcomes than we have in the past with our chemotherapy/immunotherapy combinations.

How do toxicities from lenalidomide compare with those associated with chemotherapy?

Do you think we can eventually move away from chemotherapy?

Is there potential for venetoclax in this space?

Other approaches to think about are consolidation or sequential treatments, incorporating novel agents such as ibrutinib or lenalidomide/rituximab after an initial cytoreduction surgery with bendamustine/rituximab or another regimen.Although there has not yet been a head-to-head comparison of those two in this disease, lenalidomide is likely better tolerated than the cytotoxic therapies. There are lenalidomide side effects, which can include cytopenia, gastrointestinal symptoms, and rash. Overall, they are somewhat different but balanced, but lenalidomide is a little better tolerated.I do think so. These new drugs have impressive single-agent activity, and there is merging evidence of the ability of combination regimens to get deep and fairly rapid responses. This may give us the opportunity to move away from cytotoxic drugs and use other approaches that are better tolerated and control the disease, perhaps even better than high-dose therapy and transplant.Venetoclax is a BCL-2 inhibitor that can have dramatic activity in CLL but also in a number of lymphomas, including MCL. As a single agent, responses occur in the relapse setting in the majority of patients. The complete remission (CR) rate is relatively low, but those are in typically heavily pretreated patients.

We are doing a lot of work at our center looking at preclinical models of ibrutinib plus other agents. We found that, if you combine ibrutinib with venetoclax in either preclinical models of CLL or MCL, we see a marked synergy.

You mentioned there is no standard of care. Are we moving toward figuring that out?

That has led to a phase I clinical trial, led by my colleague Dr Craig Portell, where patients with relapsed MCL receive the combination of venetoclax plus ibrutinib. It is still underway, but we are optimistic that we will see high response rates and that this may be a combination worthy of being moved earlier in the course of the disease if the safety, tolerability, and activity are what we hope it will be.There are a number of clinical trials that are in progress. I’m hopeful that the ECOG-E1411 trial will, in fact, establish the standard of care given the response rates and whether we can get to MRD negativity.

For younger patients, that is a challenge that is also being actively studied. The European Mantle Cell Lymphoma Network has done important work, as well as other groups in Europe, looking at induction regimens and the depth of response you can get either before or after stem cell consolidation.

Does that mean combinations are going to be the future in this space?

However, it is going to be a challenge, but a very important clinical research effort to figure out the way to compare a high-dose chemotherapy approach versus these newer agents or combinations, to see whether moving away from an intensive cytotoxic therapy to something that is more targeted gives a deeper response with less toxicity.Combinations of targeted agents will likely be the way we’ll need to go in MCL. For example, ibrutinib has certainly been a very important addition to our treatment landscape. However, only 2 out of 3 patients with MCL respond and only about 25% of patients will achieve a CR. The duration of response in the relapsed setting is typically 1 year to 1.5 years.

What are other next questions that need to be answered in this space?

When patients relapse, their disease can be aggressive, have rapid onset relapses, and they may not respond particularly well to subsequent therapy again. Because of that, we need to get more patients responding and in a deep remission. Combinations—whether it’s a targeted drug on a backbone of chemoimmunotherapy, or of targeted agents—is a priority for this next generation of studies in MCL.The other area of great interest, as is true for all lymphoproliferative malignancies, is to start tailoring treatment to individual patient subtypes. We know that MCL is not one disease; approximately 20% of patients have a very indolent phase and can be observed without treatment for a period of time.

How have you seen the MCL field evolve?

On the other end, there are patients with very high proliferative disease that has a very aggressive clinical course. That spectrum of disease is going to have to be taken into account as we craft therapy for individual patients, and it will not be a one-size-fits-all answer.It has been about 25 years since MCL was first defined as a specific clinical and molecular entity among the non-Hodgkin lymphomas. It has been an instructive disease that we have learned a lot from, and it’s exciting to see the link between the molecular and cellular biology and the logic and rationale for newer therapies. There is a lot to learn from that.

People should be excited about being in this field because there is so much going on. Participation in clinical trials and referrals of patients for these studies is how we will move the field forward as quickly as possible.

Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373:1835-1844.