Future of MCL Treatment May Lie in Combinations, CAR T-Cell Therapy

Robert Dean, MD

Experts are hard-pressed to find impactful, long-lasting treatment regimens for patients with mantle cell lymphoma (MCL). Moreover, Robert Dean, MD, said that BTK inhibitors and chimeric antigen receptor (CAR) T-cell therapy may address the unmet needs of the difficult-to-treat patient population.

“We still face the problem of these patients having a very high risk of mortality at the time that they relapse. Initial remissions and survival have improved, but what we can do for patients after they relapse still leave a lot of room for improvement,” said Dean. “We need drugs that are going to be active against the hard cases to treat—we need drugs that will work well in tandem [with BTK inhibitors].”

OncLive: Could you discuss the current treatment landscape of MCL?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Dean, a staff physician at Cleveland Clinic, discussed the promise for new therapies in MCL.Dean: The treatment of [patients with] MCL has evolved in a step-wise manner over the past 20 years. Studies have gradually incorporated the monoclonal antibody rituximab (Rituxan) into frontline therapy. Our approaches to frontline therapy have diverged into a more intensive route that is more appropriate for younger, fit patents who receive combination chemotherapy, followed by consolidation with high-dose chemotherapy and autologous stem cell transplant (ASCT). Now, rituximab maintenance follows that course of treatment.

On the other hand, a pathway that is appropriate for patients who are less medically fit or older involves less intensive initial chemotherapy, typically with bendamustine and rituximab, and then rituximab maintenance without consolidation with ASCT. For those respective patient groups, frontline outcomes with the sequential improvements in those approaches have continued to [improve] over the years.

A number of drugs have been approved for the treatment of patients with relapsed MCL in particular. [These include] bortezomib (Velcade) and lenalidomide (Revlimid) here in the United States, temsirolimus (Torisel) over in Europe, and more recently, the BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence) [in the United States]. Both ibrutinib and acalabrutinib appear to be more active in patients with MCL than the earlier drugs that were approved in the relapsed setting. There is a slightly higher rate of significant adverse events (AEs) with ibrutinib, particularly issues related to atrial fibrillation and bleeding—most of which are minor, but can be clinically serious. Those 2 types of toxicities are relatively rare with acalabrutinib.

We have now seen some improvement in frontline treatment over time, but also gradual improvements with the advent of these drugs for our patients in the relapsed setting. We do not yet know whether combining these drugs in new ways or moving them earlier in the treatment course can provide better outcomes and longer remissions, or prevent relapse. If you look at the activity of bortezomib with lenalidomide and compare it with the activity of ibrutinib and acalabrutinib, the 2 former drugs have already been put to the test in a large phase III trial. Everyone wants to know about testing ibrutinib or acalabrutinib upfront because, in the relapsed setting, they work better. It stands to reason that they may do more if you move them to the frontline setting. We want to see studies that test that.

Are there any ongoing combination studies that could have potential?

Considering the incurable nature of the disease, what are the biggest challenges that need to be overcome in this treatment paradigm?

The other big question is, “For patients who do relapse, even when we throw our best treatment at them, is CAR T-cell therapy going to be something that not only is active, but actually changes the story?” We are hoping to find out if that is something that will change with the use of that treatment in the future.We know that venetoclax (Venclexta) has activity in patients with relapsed MCL, both from a small phase II study, and from anecdotal experience used off-label in those with relapsed disease after a BTK inhibitor. We are very excited to see some larger experiences in clinical trials with the combination of a BTK inhibitor, like ibrutinib, with venetoclax. That is a very rational combination because we know that BCL-2 overexpression is highly prevalent in MCL, so disrupting that pathway with a drug such as venetoclax should reap clinical rewards. That is a combination that I am interested in seeing developed further.We do not yet know about the curative potential of CD19-directed CAR T-cell therapy for MCL. Certainly, for other lymphoma histologies, such as large cell lymphoma, where there is already a larger clinical experience and longer follow-up, some patients are achieving durable remissions and are being cured through that approach. I am very excited to see how that is going to pan out with additional experience from the MCL trials using that treatment approach.

Allogenic bone marrow transplant or allogeneic stem cell transplant has, in the background, been considered a potential curative option for appropriately selected patients. I have gone that route with some patients over time who have experienced recurrence after other treatments and who were appropriately selected. It is certainly not an optimal treatment option for every patient because of the risks that are inherent to allogeneic transplant. If you have a younger, fit patient who has an appropriate donor and has already received treatment with a BTK inhibitor and has progressed after that, then I try to get them on a CAR T-cell trial as a next option.

Is there work being done to explore biomarkers?

Preliminarily, it looks like a very active approach to therapy. While the short-term toxicities are not trivial, the longer-term toxicity profile is more favorable than what you would see with allogeneic transplant. Barring that as an option, I would still consider allogeneic transplant as a reasonable approach to discuss with a patient who was medically fit, younger, and who I would expect to do relatively well.There is. One of the things that I referred to during my presentation is that there is a high degree of genomic instability in MCL. Cyclin D1 translocation is one of the hallmarks of the disease, and is the starter pack where the lymphoma cells get going.

However, additional acquired mutations on top of that are part and parcel of the biology of the disease. We do not yet have great data on using individual specific secondary mutations to predict outcome or select treatments, with the exception of p53 mutations, which are almost universally a poor prognostic indicator. I would consider that as an indicator to move to a more aggressive third-line treatment in a patient who has received and progressed on a BTK inhibitor after frontline treatment.