BTK Inhibitors in Mantle Cell Lymphoma

Harry P. Erba, MD, PhD:Let’s switch gears a little bit and turn to mantle cell lymphoma. You mentioned that the label indication for acalabrutinib is in mantle cell lymphoma. Can you tell us about the data that led to that approval?

Anthony R. Mato, MD, MSCE:Acalabrutinib has been studied as a single agent or in combination with rituximab. It’s approved, to my knowledge, as a single agent in patients with mantle cell lymphoma. This is one of those areas where I think cross-trial comparisons are very difficult to do, due to maybe subtle differences in prior lines of therapies, methodology of response assessment. But the drug appears to be active and well tolerated, with a high proportion of patients having very impressive rates as well as PFS [progression-free survival] and OS [overall survival].

Harry P. Erba, MD, PhD:And that’s in the relapsed/refractory setting?

Anthony R. Mato, MD, MSCE:Relapsed/refractory.

Harry P. Erba, MD, PhD:I’m an acute leukemia doctor, but if I remember right, the treatment of mantle cell lymphoma can include high-dose Ara-C—based regimens like DHAP [dexamethasone/Ara-C/cisplatin], hyper-CVAD [cyclophosphamide/vincristine/doxorubicin/dexamethasone].

Anthony R. Mato, MD, MSCE:Consolidative transplants

Harry P. Erba, MD, PhD:Right, and bendamustine/rituximab.

Anthony R. Mato, MD, MSCE:Yes.

Harry P. Erba, MD, PhD:Do you think that there are patients who could benefit from BTK inhibition as first-line therapy? Are there patients who wouldn't tolerate those intensive chemotherapies?

Anthony R. Mato, MD, MSCE:Absolutely, and I think it’s actually happening in clinical practice. I don’t know the proportion, but I would say at least 5% to 10% of frontline treatments are targeted agents now. There are high-risk patients. If you have a patient with ap53mutation or a 17p deletion with mantle cell lymphoma, they do equally poorly with chemotherapy as you would expect a CLL [chronic lymphocytic leukemia] patient to do. The same also may be true forIGHV-unmutated patients. They have prognostic significance in mantle cell lymphoma as well. And there, I do think there’s a role for a targeted agent. Or if you have someone who is extremely elderly or has multiple comorbidities where you really don’t see them tolerating high-dose cytarabine and a transplant or multiple cycles of hyper-CVAD [cyclophosphamide/vincristine/doxorubicin/dexamethasone], there is a strong argument to be made for a targeted agent. BTK inhibitors have certainly been studied. IMiDs [immunomodulatory drugs] have been studied. There’s aNew England Journal of Medicinepaper of R²[rituximab/lenalidomide] as a first therapy for mantle cell lymphoma that looked to be active and well tolerated. I think it is a shifting paradigm. We’re going to see that the proportion of patients treated with targeted agents for mantle cell lymphoma will increase a lot in the next couple of years.

Harry P. Erba, MD, PhD:Would you recommend using an oral targeted therapy in more than just infirm patients if they’re eligible for chemotherapy?

Anthony R. Mato, MD, MSCE:I think it’s a hard question.

Harry P. Erba, MD, PhD:That’s why I asked you. That’s why you’re here.

Anthony R. Mato, MD, MSCE:I think there’s a rationale for doing it in research. I think for individual patients, it’s a case-by-case basis. In order to avoid a standard of care with a lot of years or a long track record of what we could expect in terms of PFS, you’d have to have a biologically aggressive mantle cell case, such that you thought chemotherapy was more of a risk than a potential benefit to patients. I think those patients definitely exist. High-Ki-67, high-MIPI [mantle cell lymphoma international prognostic index] score patients, blastoid variant,p53, or 17p deleted: Those are the types of patients for which you could argue that you may not want to expose them to something that you think is destined to have a very short PFS. But otherwise, I do think the standard of care still remains to be rituximab-containing, cytarabine-containing therapies and consolidation with autotransplant.

Harry P. Erba, MD, PhD:So like everything else we do in oncology, we have to decide when we see that patient, are we on a curative path or are we on a path of just palliation and make the appropriate choices.

Anthony R. Mato, MD, MSCE:I think in mantle cell lymphoma, no matter what path you get on, you’re still on a palliative path.

Harry P. Erba, MD, PhD:Really?

Anthony R. Mato, MD, MSCE:I don’t think anyone is cured, with even stem cell transplantation. It just improves the PFS dramatically over standard-dose chemotherapy. But I don’t think anyone is really arguing that cure is the endpoint of dose-intensive therapies at this point.

Harry P. Erba, MD, PhD:And clearly more to do. How about ibrutinib in mantle cell lymphoma?

Anthony R. Mato, MD, MSCE:Same story. It is very active and is approved in the relapsed/refractory setting. Generally, it is well tolerated. Of course, all BTK inhibitors, if you pick CLL as the bar, are a little bit more of a disappointment in mantle cell lymphoma because the PFS is shorter in mantle cell lymphoma. So this is an area where combinations, for example, are potentially more exciting. The addition of anti-CD20 antibodies could potentially be more exciting for these patients. But certainly, ibrutinib in the relapsed/refractory setting is a go-to first therapy along with acalabrutinib when patients have been treated with standard of care, whatever you want to define that to be, as their first therapy. So I think very few patients are going from chemotherapy to chemotherapy at this point.

Transcript edited for clarity.