Expert Explains Treatment Approaches for MCL

Simon Rule, MD, PhD

For young, fit patients with mantle cell lymphoma (MCL), the best frontline treatment approach could be observation, according to Simon Rule, MD, PhD.

Rule, a professor of hematology at Plymouth University Medical School in the United Kingdom, acknowledged that BTK inhibitors have positively changed the landscape in the relapsed/refractory setting. However, he stressed that these novel approaches are potent, and physicians should save these types of therapies for more aggressive stage disease.

In patients who present with low-volume, asymptomatic MCL, Rule noted, the “watch and wait approach” is appropriate because there is no benefit to treating them early in their disease.

There is an ongoing trial in the United Kingdom testing the efficacy of this strategy. In the study, newly diagnosed patients with MCL go into a biobank and researchers follow the course of their disease. Of the patients who were clinically eligible to be watched and waited on, over 30% did not progress after 1 year. Rule says this is important because hematologists won’t know if a patient’s disease is indolent if they are immediately treated.

In patients who do require active treatment, agents such as bortezomib (Velcade) and lenalidomide (Revlimid) have been studied as first-line therapy for patients with MCL. Some of the most highly anticipated data, though, are with the BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence).

Additionally, the SHINE study (NCT01776840) is a two-arm phase III trial of ibrutinib in combination with bendamustine plus rituximab (BR) in patients with newly diagnosed MCL. The first arm is placebo, given orally once daily plus 90 mg/m² of bendamustine intravenously (IV) on days 1 to 2 of cycles 1 to 6, plus rituximab at a dose of 375 mg/m² IV on day 1 of cycles 1 to 6. If complete or partial response (PR) is achieved, 375 mg/m² of rituximab is given on day 1 of every second cycle for a maximum of 12 cycles. The second arm contains 560 mg of oral ibrutinib once daily plus the same BR dosing regimen.

OncLive: What is the current management for patients with MCL?

What regimens are in development?

In an interview with OncLive, Rule discussed the observational and active therapeutic approaches for patients with MCL.Rule: For younger patients, it is pretty well established that it is a high-dose cytarabine-based regimen. It is usually followed by a stem cell transplant, followed by rituximab maintenance. That is pretty much the standard. There are a number of different ways you can give high-dose cytarabine. Of course, the drugs that have made the biggest impact in this disease are the BTK inhibitors. The question is if we need these drugs for the frontline treatment of younger patients. These patients are off drugs and living a normal quality of life. When they relapse—because everyone relapses—that is when we introduce these novel therapies.

Please explain the watch and wait approach.

There are a number of ongoing studies in the United Kingdom that are going to challenge the traditional paradigm. Specifically, do we need transplant? That is something for the future. It is difficult in the younger patients to use anything other than the traditional chemotherapy. When I give presentations about this disease, I always say, "Don't forget that chemotherapy works." There is a lot of excitement about new drugs, obviously. However, the odd thing about these drugs is that they will probably be more valuable for the older, frailer patients. Be cautious about using new drugs early. I have been watching and waiting MCL for a long time—over a decade. People thought I was mad when I first started doing it, and now it is becoming pretty well established. Watching and waiting does not disadvantage patients. If they are asymptomatic with low-volume disease, there is no benefit in treating someone early in treatment if they are in good health. It sounds counterintuitive with an aggressive cancer, but the answer is that when you treat this disease, it inevitably relapses. When it relapses, it is a much more difficult disease to treat. You won't know if someone has indolent disease unless you leave them alone.

What are your thoughts on moving BTK inhibitors upfront?

We have patients who we know are indolent because we have been watching them for 2 years—this is what we are defining as truly indolent. We will compare them with treated patients and compare biological material. A common challenge is whether we treat patients differently after watching and waiting on them and now they need treatment. It is an interesting question and you could argue it 1 or 2 ways. However, I would treat everybody the same. It is the obvious thing to do. The earlier BTK inhibitors are used in the relapsed setting, the better the outcome. At first relapse, you get the best benefit from the BTK inhibitors, so it seems like the logical thing to do. A trial I am running in the United Kingdom is a frontline study of ibrutinib/rituximab versus bendamustine/rituximab or CHOP/rituximab. It is chemotherapy versus nonchemotherapy. We know from recent data that nonchemotherapy has been very active. We have 150 patients enrolled in this study and progression-free survival is our endpoint.

We also recognize a group of patients who do very badly: the p53-mutated group. The Nordic Group looked at this subset. These are young, fit patients receiving high-dose cytarabine and an autograft in clinical trials. Basically, their survival is under 2 years if they have p53 mutations. We also know these patients don't do well with BTK inhibitors. These patients struggle getting into remission in the first place.

What is the take-home message from all of this?

Again, it comes back to what I said about the excitement with new drugs—we have to remember what already works. Stem cell transplant can cure these patients. If patients have a blastoid presentation, I will do an upfront stem cell transplant if they are young and fit enough. We also know that venetoclax works very well in this group. In a trial, over 50% of p53-mutated patients got a complete response with venetoclax. I would say that if you have a young patient with a good prognosis, they can be left untreated. You might be surprised by the results. If they need treating, I would look for p53 mutations. If they present these, start thinking about a more aggressive strategy because you won't get them into remission. Ibrutinib won't work. For the majority, use your favorite high-dose cytarabine regimen.