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Combination Regimens on the Rise in Mantle Cell Lymphoma

Gina Columbus @ginacolumbusonc
Published: Friday, May 06, 2016

Michael E. Williams, MD

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.”

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.

OncLive: What specific agents do you envision having potential in 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.

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.

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

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.

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