Next Steps in Relapsed/Refractory Mantle Cell Lymphoma


Jonathon Cohen, MD, MS: We are lucky, at the current time, to have 3 approved BTK [Bruton tyrosine kinase] inhibitors for patients with relapsed/refractory mantle cell lymphoma. Ibrutinib was the first to be approved, but we now also have acalabrutinib as well as zanubrutinib. It’s important to recognize that at least as of right now, these have not been compared head to head. So it’s difficult to really draw firm comparisons between the 3 with regard to their efficacy and tolerability. Having said that, we have seen some themes emerging. It does appear that some of the newer BTK inhibitors may have some decreased toxicity, although it’s also important to recognize that acalabrutinib, for example, has been associated with an increased risk of headaches. This has not necessarily been seen with ibrutinib.

I think 1 of the key facts to keep in mind is that the other BTK inhibitors were developed after some of the initial trials with ibrutinib showed promise. In addition, many of the toxicities that we have come to identify with ibrutinib were already described at that point. Maybe patients who were at risk for some of these toxicities might not have been put on acalabrutinib or zanubrutinib studies. Really, to tell the difference among these groups, we’ll need head-to-head studies. Many are being considered and are under way, but it will be some time before we can really make any definitive comparisons.

When I’m evaluating a patient in clinic, I often take into account a number of factors, not the least of which is the ease in obtaining the medication and whether one might be associated with a lower co-pay. In my own practice, I’ve seen a difference in co-pay of up to $100 a month, and it’s not always the same drug that is cheaper. So it’s important to work with your pharmacy staff to see if you can get 1 of these medications at a lower rate based on the patient’s prescription drug coverage.

Also, although there hasn’t been direct head-to-head comparison, it does seem as if there may be fewer bleeding complications and cardiac complications with some of the newer BTK inhibitors. For a patient with a history of atrial fibrillation, for whom I think a BTK inhibitor is critical, I might consider 1 of the newer versions of the medication.

At the end of the day, I really can’t definitively state that there are significant differences among these therapies. It often comes down to more practical matters like cost, for example; some require twice-daily administration while others are daily administration.

Despite the fact that we now have a number of effective therapy options and that patients with relapsed/refractory mantle cell lymphoma are living longer than in the past, the overwhelming majority will unfortunately still die from their disease. Ibrutinib, as good as it is, is unfortunately still associated with an ongoing risk for relapse the further out you go. And we know that there can be ongoing toxicity. For a patient with relapsed/refractory mantle cell lymphoma, it’s important to really balance this toxicity with long-term goals of care and long-term efficacy.

Fortunately, we do have some other more intensive options. Allogeneic transplantation can, in some instances, be curative for a highly selective group of patients. It’s important, especially for our younger patients or those who have relapsed early or multiple times, to at least have this discussion about the potential role of allogeneic stem cell transplantation.

In addition, many of you are likely familiar with the fact that CAR [chimeric antigen receptor] T-cell therapy, currently approved for large B-cell lymphoma, has been evaluated in mantle cell lymphoma and looks very promising. I don’t know exactly where CAR T-cell is ultimately going to fit into the management algorithm of patients with mantle cell lymphoma, but it will certainly require discussion and will be an excellent therapy option for patients in the future.

Finally, it’s important to recognize that many of these therapies work very well as monotherapy but could work even better in the setting of a combination. The hope would be that they remain quite well tolerated. One good example is lenalidomide, which has been approved for mantle cell lymphoma in patients who have progressed after bortezomib. We know that lenalidomide monotherapy is not nearly as effective as lenalidomide in combination with rituximab. For example, I often think about using rituximab with lenalidomide in patients with relapsed mantle cell lymphoma. My expectation is that there will be ongoing studies of combinations, and we may find that particular BTK-containing combinations are more effective than BTK inhibitors as monotherapy.

I think the future is very bright. A lot of discussion and a lot of testing will be needed to figure out the right sequence of therapies, right combinations, and where some cellular therapies fit in. These are all the subject of intense debate and clinical trials in the current time.

Transcript edited for clarity.

Case: A 68-Year-Old Male with Mantle Cell Lymphoma

Initial presentation

  • A 68-year-old man presented with generalized lymphadenopathy, fatigue and an unintentional 8-lb weight loss
  • PMH: HTN, medically controlled
  • PE: abdominal distention, splenomegaly

Clinical workup

  • LDH 345 U/I, ANC 3500/mm3, beta-2-microglobulin 4.4 µg/L, leukocytes, 5.98 X 109/L, hemoglobin 9.6 gm/dL
  • FISH: t (11;14)
  • Immunocytochemistry: cyclin D1+, CD5+, CD20++
  • BMB positive for lymphoid cells with cyclin D1
  • PET/CT scan showed widespread lymphadenopathy in numerous nodal regions including left mesenteric (3.4 cm), bilateral axillary (3.9 cm, 5.3 cm), and cervical (5.1 cm)
  • Ann Arbor stage IV; MIPI score 6.3; ECOG PS 1


  • Patient was started on bendamustine + rituximab
    • Achieved PR
    • Continued on maintenance rituximab q8W
  • At 9 months the patient had clinical disease relapse
    • He was started on ibrutinib 560 mg PO qDay
    • Imaging at 12-week follow-up showed no evidence of disease

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