Goy Shares Expertise on Exciting Progress in MCL

Andre Goy, MD

Novel regimens for mantle cell lymphoma (MCL) are on the rise, with researchers examining combinations with such treatments as ibrutinib (Imbruvica), lenalidomide (Revlimid), and bortezomib (Velcade), explains expert Andre Goy, MD.

For example, an open-label multicenter phase I/II trial is exploring the combination of ibrutinib and bortezomib in patients with relapsed/refractory MCL followed by ibrutinib maintenance therapy (NCT02356458).

Additionally, the phase II BATMAN trial is enrolling patients with relapsed/refractory MCL to treat them with the triplet regimen of bortezomib, cytarabine, and dexamethasone after 1 to 3 lines of prior therapy (NCT02840539).

In an interview with OncLive, Andre Goy, MD, chairman and director, chief of Lymphoma, and director of Clinical and Translational Cancer Research at John Theurer Cancer Center, Hackensack Medical Center, discussed the evolving treatment landscape in mantle cell lymphoma.

OncLive: How have you seen the landscape of MCL evolve over recent years?

Goy: There are a quite a few things changing. First of all—if you look clinically at MCL—it’s a very heterogeneous disease with its clinical presentation and biology, but also the comorbidities, given the fact that many patients at diagnosis are in the mid-60s to the early 70s. Therefore, that represents a very difficult presentation. This is probably one of the reasons why there are so many options in the NCCN guidelines—more than 12 options in the fourth-line setting now—and that gives you even more controversies in how to manage these patients.

The problem with MCL is that it can be sometimes difficult, in a rare disease, to accrue enough patients for a large study. What is happening after induction chemotherapy in MCL is that the vast majority of patients relapse and develop chemotherapy resistance. Over the years, we have developed approaches to try to improve the response and decrease relapse. When you look at real-world data and the impact of dose-intensity approaches with or without stem cell transplant consolidation in frontline, you reach a CR rate that is well over 80% compared with 30% in standard therapies. However, you also have a median PFS that is in excess of 6 to 7 years after those approaches of dose-intensive strategies with transplant, compared with some in the range of 14 months with standard therapy.

What is the relapse setting like currently?

In the relapse setting, it’s difficult. The novel therapies have offered an opportunity to try to treat these patients without chemotherapy. There are a lot of novel therapies. The first one approved is bortezomib and that became the first drug that was a biological targeted therapy, a proteasome inhibitor that has been combined with a number of different things.

It was studied in the frontline setting in non-transplant eligible patients in a large international study looking at R-CHOP versus R-CHOP replacing vincristine with bortezomib. It was a dramatic improvement—close to 60% improvement in PFS—and also a significant improvement in CR rate in favor of the bortezomib combination. This became the first novel regimen approved in MCL.

The second novel therapy approved was lenalidomide, which was approved in patients based on a large phase II study in patients who failed anthracyclines, rituximab, alkylating agents, and bortezomib. The response rate was 33% with an 8% CR rate; it was quite durable at up to 17 months. This was a population who had a median of 4 prior lines therapy. The rituximab combination with lenalidomide in the relapse setting has led to a response rate close to 60% and a CR rate near 40%, and that’s really quite durable. That’s really a step forward.

Finally, the third drug is ibrutinib that was approved in relapsed/refractory patients. The response rate was 68%, a 21% CR rate, and a median duration of about 17 months. That offers an option of also trying to combine rituximab with a CR rate that nearly reaches 40%.

Second-generation BTK inhibitors, proteasome inhibitors, and immunomodulatory agents are down the road. What are also very exciting are other antibodies, such as obinutuzumab (Gazyva), which will also be integrated as part of MCL management. However, BCL-2 inhibitors with venetoclax (Venclexta) had very impressive activity in relapse MCL.

What potential could immunotherapy have in this disease?

We cannot talk about novel therapies in a disease without talking about immunotherapy, right? Checkpoint inhibitors, BiTE antibodies, and chimeric antigen receptor (CAR) T cells will be important in MCL, particularly because the only way you can cure a patient with MCL who relapses is with transplant. Given the age, the non-transplant group is more than 50%. The only potential handicap in this situation is CAR T-cell therapy as something that will be very helpful.

The population is somewhat limited at 4000 to 5000 cases a year. Although most patients relapse, it is difficult to explore them in very large studies. There has been great effort particularly at United States and international groups now that are looking at induction therapy and randomizing patients after induction to hyper-CVAD transplant, stem cell transplant, versus maintenance.

What is the role of maintenance therapy in MCL?

Maintenance is really taking a big role in MCL, like in other hematologic malignancies across the board. The reason maintenance is very important is to achieve a minimal residual disease (MRD)­—negative status, which is something that is really critical.

This is very true regardless of regimens. You can achieve a molecular CR that has an impact on PFS and OS, regardless of therapy. A European trial is also going to look at integrating our novel therapies, such as ibrutinib with R-CHOP transplant, and then patients will be randomized after induction with high-dose therapy transplant versus maintenance with ibrutinib.

What’s interesting is now that we have these novel therapies and we can achieve a molecular CR or MRD-negative status after induction, maybe those patients do not need a transplant? There are a number of options that are really changing the field. The novel therapies also finally offer an opportunity to develop non-chemotherapy options in that setting.

Lenalidomide and rituximab in elderly patients could be an option that needs to be confirmed with longer follow-up. In both the relapse and frontline settings, it should allow us to reach the CR rate and MRD level that we potentially reached with high-dose therapy and dose-intensive strategies and that will be really important in the population where the median age at diagnosis is mid- to late 60s.

If you had to envision the future treatment landscape of MCL, what would it look like?

It is a great future for MCL. It’s important that we remind patients, caregivers, providers, and physicians to enroll patients on clinical trials so that we can dissect further. Given the landscape that we have, there has been 4 drugs approved in MCL in 10 years, and there are many more in the pipeline. We want to work together to try to move the needle forward.

The key point of what’s happening in the field is the impact of MRD and achieving a molecular CR. We have the tools finally to do so, and then we can treat them for a definite period of time to achieve a CR. Then, we can stop therapy and it will have an important aspect on cost control, as well. The combination of novel therapies will be very important both before chemotherapy or to use chemotherapy as maintenance—or instead of chemotherapy in patients who are not candidates for chemotherapy.