A comprehensive discussion on ways to approach treating patients with high-risk mantle cell lymphoma.
Alexey V. Danilov, MD, PhD: One subtype of MCL [mantle cell lymphoma] that I still have trouble with, with the BTKis [Bruton tyrosine kinase inhibitors], is blastoid disease. Bijal, how do you address a patient? How do you treat a patient when they have this type of MCL?
Bijal D. Shah, MD: We’re still stuck with chemotherapy now. With that said, the question that comes to mind immediately is TP53 or not. We know we’re going to highly enrich for TP53 mutations in that subset of patients, and we also know the benefit from chemotherapy is going to be less. I’m thinking about what can I do if it’s explosive disease, chemotherapy plus, so this might be a scenario where I think about bendamustine plus ibrutinib. Or another chemotherapy regimen like R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] plus ibrutinib. But it’s a bridge; it’s a bridge to CAR [chimeric antigen receptor] T-cell therapy in this instance for me, because I know the durability of that is going to be very short lived. Or if you can get an allogeneic transplant. But at least in Florida, allogeneic transplants are seldom covered for our patients.
Alexey V. Danilov, MD, PhD: Yes, and you mentioned that many of these patients would have TP53 aberrations. I would say that in the SHINE study, it seemed to me that the BR [bendamustine and rituximab] plus ibrutinib combination was still not moving the needle enough in this patient population. Boyu, you when you see a patient who has a TP53 mutation, how do you approach them? And do you test 100% of patients for TP53 abnormalities?
Boyu Hu, MD: Yes, I definitely do now. I think it’s really important for treatment decisions. What SHINE has given us is a BTK inhibitor in the frontline setting. Whether you choose to use BR with ibrutinib is up to you. But at least we have ibrutinib now that can be covered for Medicare patients, for example, because of the SHINE study. I try to get a BTK inhibitor for these patients who have TP53 mutations in the frontline setting. I’ve had a really hard time getting that approved. What I end up doing is trying to “burn through” a line of treatment to get them to a more effective BTK inhibitor. But again, like Matt said, the most effective treatment is the one you can get for the patients. So I’m excited to see a lot of these new clinical trials that are using targeted agents, especially for high-risk patients with TP53 mutations.
Alexey V. Danilov, MD, PhD: Is this the patient subtype you would be [setting] up for CAR T early?
Boyu Hu, MD: Yes, an early referral to a cellular therapy group so they can get in quickly with them and collect their T cells quickly is definitely something I would consider. I have been able to get CAR T in the second-line setting many times. If they relapse after a BTK inhibitor, you should try to get them to CAR T as soon as you can.
Alexey V. Danilov, MD, PhD: Yes, I agree with that. Maybe an alternative approach which would be combination therapies. There are multiple combination trials ongoing in MCL. There is, for example, BOVEN, which combines zanubrutinib, obinutuzumab, and venetoclax. There is SYMPATICO, which combines ibrutinib and venetoclax. There are also acalabrutinib and venetoclax combination studies. Matt, do you think venetoclax BCL2 inhibition has a role in MCL?
Matthew J. Matasar, MD: I do. Venetoclax monotherapy in patients with relapsed/refractory mantle cell lymphoma at best has idiosyncratic activity. It does work in a subset of patients, too small of a subset of patients. But when it works, you can have dramatic, rapid, and quite prolonged activity. We have no great biomarker for that. So it’s a bit of a shot in the dark right now as monotherapy. But it tells us that it’s a drug that we can incorporate into combination treatment approaches and leverage that activity to augment a combination or combinatorial strategy. We’re seeing good success with BOVEN and other programs that are incorporating venetoclax into a multitargeted approach.
Alexey V. Danilov, MD, PhD: What do you think about lenalidomide? Does it also still have a role?
Matthew J. Matasar, MD: Yes, lenalidomide still has a potential role. I would say that there are data to support its use across lines of therapy. [Jia] Ruan, [MD, PhD,] and colleagues have shown us that you can use it in the first-line setting safely. It has activity.
Alexey V. Danilov, MD, PhD: I’m sorry, that was in combination with acalabrutinib and rituximab, right?
Matthew J. Matasar, MD: Or even just the older R-squared [rituximab and lenalidomide] data that she and colleagues reported now some years ago. We’ve seen lenalidomide has activity across lines of therapy. It’s combinable, it has a clear toxicity profile. I take personal umbrage when people talk about the use of lenalidomide as chemotherapy free. That’s an unfair descriptor of the patient experience of receiving lenalidomide. But IMiDs [immunomodulatory imide drugs] in general clearly do have some activity in mantle cell lymphoma. I’m encouraged by some early work with other targets that have related activity, such as CELMoD [cereblon E3 ligase modulator] platforms.
Transcript edited for clarity.