MCL Landscape Rapidly Evolving With Promising Approaches on Horizon

Ann S. LaCasce, MD, MMSc

Although the FDA approval of ibrutinib (Imbruvica) marked the first major advance in mantle cell lymphoma (MCL) in several years, the emergence of effective agents, such as acalabrutinib (Calquence), venetoclax (Venclexta), bispecific antibodies, and CAR T-cell therapies, has investigators excited for the future, said Ann S. LaCasce, MD, MMSc.

In 2013, the FDA granted an accelerated approval to ibrutinib for the treatment of patients with MCL who have received ≥1 prior therapy. The regulatory decision was based on data from a phase II trial, which demonstrated that use of the agent led to an overall response rate (ORR) of 68%.¹ This approval was followed by that of acalabrutinib in 2017, an agent that has been shown to induce comparable ORRs with potentially less risk for atrial fibrillation and bleeding, toxicities known to be associated with the use of ibrutinib.

Venetoclax is another agent that has made headway in the space, showing an ORR of 75% at a median follow-up of 27 months, according to data from a dose-escalation phase I trial that had been presented at the 2018 ASH Annual Meeting.²

“Venetoclax is an extremely well tolerated drug with the exception of the risk of tumor lysis with initiation,” said LaCasce, director of Dana-Farber/Partners CancerCare Hematology-Medical Oncology Fellowship Program, institute physician, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School.

Due to the promise of this agent, it was also evaluated in combination with ibrutinib in a single-group phase II trial.³ Treatment with the combination resulted in a complete response (CR) rate of 42% at week 16; this was significantly higher than the historical result of 9% at this time point that had been seen with ibrutinib alone (P <.001).

“There are some novel bispecific antibodies and other approaches [such as CAR T-cell therapies are] in clinical trials as well that are likely to have good activity in MCL,” said LaCasce. “The field is rapidly evolving in a very exciting way.”

In an interview with OncLive, LaCasce highlighted recent progress made in MCL, exciting approaches under investigation, and provided insight into where future research should focus.

OncLive: What are some of the key advances made in MCL in recent years?

LaCasce: The first real advance we’ve seen in some time was the FDA approval of ibrutinib, which has a good ORR of over 70%. However, as we have seen in patients with chronic lymphocytic leukemia (CLL), its use can be associated with bleeding and the risk of atrial fibrillation. Because MCL is another disease that tends to affect our older patients, this can be quite problematic.

Therefore, we were, as a field, very happy with the approval of acalabrutinib, which has shown a similar overall response rate in phase II studies. The patients [included in these studies] were less heavily pretreated than those who had been initially included in the ibrutinib study. Therefore, that is a very good option; we also believe that it has lower rates of atrial fibrillation and bleeding. Although there have been fewer patients treated [with acalabrutinib], there is not as much long-term follow-up. Also, there are some infectious events that we sometimes see with ibrutinib, including risk of fungal infections. We haven’t seen that with acalabrutinib, but again, we need longer-term follow-up.

Then, [there is the data with] venetoclax as a single-agent from a small phase II study [that included] multiple different subtypes of lymphoma, which showed a response rate of about 75%; this is very appealing. There was also a paper published in the New England Journal of Medicine, which showed that the combination of ibrutinib and venetoclax had significantly higher rates of CR. The ORR was similar to that of single-agent ibrutinib, but the CR rate was longer. We need some ongoing studies to define whether [this agent is] going to be a better option for our patients in first relapse. In addition, these drugs are now being incorporated upfront, so the whole landscape is kind of changing.

Could you expand on the work being done with next-generation BTK inhibitors?

Acalabrutinib is the one that’s FDA approved, but there are multiple other “me-too” drugs that may be more selective. There’s a noncovalent one, but I don’t know a lot about where these agents are in development; they’re all in clinical trials. We’ll need to see whether they are more effective and less toxic. At the end of the day, that’s going to be the question to answer. We already have 2 approved drugs in this space with that target.

Is there work being done to combat resistance to these inhibitors?

We need to better understand the patterns of resistance to BTK inhibitors in MCL. There are documented mutations that arise in CLL and I honestly don’t know how well that has been studied in mantle cell. I don’t believe that’s thought to be the typical mechanism of resistance in MCL. The other thing that’s worth mentioning is that whenever you switch a patient off of a BTK inhibitor, in CLL or MCL, you have to be very, very careful; patients can get significant flare of disease that can be very clinically important.

Is there a role for immunotherapy in this space?

There really is no great data indicating that this is going to be a good effective therapy in MCL. There may be some data out there that I’m not aware of, but in general, checkpoint inhibitors in non-Hodgkin lymphoma have been quite disappointing in terms of their activity as single agents. There is the exception of primary mediastinal B-cell lymphoma, maybe testicular lymphoma, and maybe primary central nervous system lymphoma if you’re not using a lot of steroids.

However, for MCL, I don’t think that this is going to be a significant approach, in terms of PD-1 inhibitors. There are bispecific antibodies and other [agents] that are more similar to CAR T cells that are hopefully going to be active, but I don’t believe that we have any good evidence to support PD-1 inhibitors.

What is the hope for CAR T-cell therapy?

CAR T-cell studies are ongoing in MCL and everyone is pretty excited about this option, given that we do have patients who relapse after autologous stem cell transplant (ASCT). In the past, we haven’t had great options for those patients. We have patients in whom ASCT is not effective, so having an option like CAR T-cell therapy is great. We look forward to seeing data [with that approach]. We do have allogeneic stem cell transplant, but that is obviously associated with significant risk. We’re hoping that the CAR T-cell data will look good.

Do you believe that this approach possesses curative potential?

It’s still very early in terms of the [CAR T-cell therapy] trials in MCL. There’s nothing that has yet been presented or published to my knowledge looking at durability [of this approach]. However, given the results that we’ve seen in some B-cell lymphomas, and the fact that there are a good proportion of patients who remain in remission now several years out, we hope that it may be curative. With MCL, you have to follow patients for a very long time to really know whether they may recur. Using circulating tumor DNA or other ways to look for minimal residual disease (MRD) negativity may help us figure it out sooner, rather than 20 years later, whether patients are truly cured. Long-term remission is a viable goal now.

Where should future research efforts focus?

We need to incorporate MRD approaches to really understand how to predict who is going to relapse. Again, I believe that we need to look at CAR T cells. There is a very important upfront study ongoing, a US Intergroup study, which is looking at for patients who have MRD-negative disease after initial induction therapy. They are trying to determine the benefit of ASCT plus maintenance rituximab (Rituxan) versus rituximab alone.

That is a very, very important study in the era of rituximab and some better therapies, because it would be great to get away from high-dose chemotherapy approaches and ASCT if we can demonstrate that there isn’t a huge benefit. Right now, those studies with upfront ASCT in first remission show very long [median] PFS—at 5, 6, 7 years—so it is a very effective strategy.

However, for our older patients, the toxicities can be quite significant, so I can’t overemphasize how important that study is. It’s not a “sexy” study because it’s not looking at novel agents, but it’s an extremely important study that is going to set the groundwork for how we think about the disease in the future.

References

1. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-516. doi: 10.1056/NEJMoa1306220.
2. Davids MS, Roberts AW, Wierda WG, et al. Long-term follow-up of patients with mantle cell lymphoma treated with venetoclax monotherapy. Blood. 2018;132:2883. doi: 10.1182/blood-2018-99-117210.
3. Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211-1223. doi: 10.1056/NEJMoa1715519.