Questions remain about best front-line treatment in mantle cell lymphoma
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As new therapeutic options for mantle cell lymphoma emerge, physicians are learning where they best fit into the treatment armamentarium.
Chemotherapy, often followed by stem cell transplant, remains the cornerstone of front-line treatment for patients with mantle cell lymphoma. However, many of the newer agents, such as Bruton tyrosine kinase (BTK) inhibitors and chimeric antigen receptor T-cell therapy, have found homes as second- and third-line therapies. As the field moves forward, physicians expect to have even more refined treatment options, according to Craig A. Portell, MD, associate professor of medicine at the University of Virginia School of Medicine.
“A lot of investigation for mantle cell lymphoma is ongoing, and our hope is that we continue to find ways to improve patients’ outcomes and keep the treatments as safe as possible,” Portell said.
In an interview with Healio, Portell further discussed important questions regarding novel therapies, how the various treatments are being used in clinical practice and future areas of investigation in the treatment of mantle cell lymphoma.
Healio: What are the primary concerns with respect to treatment for mantle cell lymphoma?
Portell: One of the primary questions is: What are the best upfront treatments? We’re still trying to figure this out, particularly for patients who are not transplant-eligible after achieving a first remission. The amount of chemotherapy necessary, the incorporation of novel agents and the safety of combining chemotherapy with these novel agents are all still areas of investigation.
After the front-line setting, other concerns pertain to the relapse setting. Can some of our novel agents be combined and provide better outcomes than the single agents alone for a longer period? We are starting to get data, but we’re still questioning whether combining novel agents is the best strategy in the relapse setting.
Healio: As the newest treatment to become available for mantle cell lymphoma, how is CAR T-cell therapy being used in clinical practice?
Portell: The data show that CAR T-cell therapy is best used after a BTK inhibitor failure, and we have been successful in getting some of those patients through CAR T-cell therapy. We would like to see it used a little bit earlier, but the data are lacking in that space, and it is still a question if CAR T-cell therapy will provide long-term disease-free treatment in mantle cell lymphoma as it does for diffuse large B-cell lymphoma in some patients.
So, typically, we’re giving novel agents first and then the CAR T-cell therapy. However, we have hope that the reverse will happen at some point.
Healio: What are some of the concerns with CAR T-cell therapy? How can they be mitigated?
Portell: With CAR T-cell therapy, patients certainly have more cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome with mantle cell lymphoma than with some of the other lymphomas, particularly follicular lymphoma. One of my concerns is the long-term disease-free interval after CAR T-cell therapy. Most patients are going to experience some degree of toxicity with CAR T-cell therapy and the question is whether that is worth the long-term benefit we’re hoping for with the treatment, which hasn’t been shown yet. The data available are currently in multiply relapsed patients, so that target extrapolates just to those patients who are in the third-line setting or so. It may be that it will work better if we use CAR T-cell therapy earlier.
Healio: Where do BTK inhibitors fall on the spectrum of treatment for mantle cell lymphoma?
Portell: As of right now, they fall in the second-line treatments. Ongoing clinical studies, which have been fully enrolled, moving BTK inhibitors, in combination with chemotherapy, to the front-line setting, but we don’t have any readouts on that yet. So, we are mostly using them in the second-line setting. There are rare instances where they would be used after that, but now, we would typically use a BTK inhibitor after chemoimmunotherapy failure.
Healio: Would you say newer therapies, such as BTK inhibitors and CAR T-cell therapy, have changed the treatment paradigm for mantle cell lymphoma?
Portell: They definitely have.
Before the advent of BTK inhibitors, patients after failing front-line treatment. Now, BTK inhibitors are a chronic treatment and need to be taken for as long as they work. They really are a good option for some of these patients with mantle cell lymphoma.
With CAR T-cell therapy, the impact may be a little less, but we didn’t have this line of therapy before 2 years ago, so it certainly is a new treatment option that will hopefully prolong patients’ lives.
Healio: Are there any novel treatments currently under investigation for mantle cell lymphoma?
Portell: We have found success using venetoclax (Venclexta; Abbie, Genentech) as both a single agent and in combination with monocolonal CD20 antibodies in mantle cell lymphoma relapse after ibrutinib (Imbruvica; Janssen, Pharmacyclics). Is it a homerun? No, but it does seem to provide some activity. Ongoing are combining ibrutinib with venetoclax and the jury is still out on whether that combination will be as effective as two single-agent sequences alone.
Other novel agents, including ROR1 antibody seem to be very active in mantle cell lymphoma. Novel BTK inhibitors appear to be active in mantle cell lymphoma that are noncovalently bound to BTK, so they kind of mitigate some of the resistance mechanisms to BTK inhibition.
We also do have some hope for phosphatidylinositol 3 (PI3)kinase inhibitors in mantle cell lymphoma. Currently, however, they are mostly used in later-line settings, so it is hard to see how active they actually are, particularly the newer, safer PI3 kinase inhibitors as opposed to the earlier generation of PI3 kinase inhibitors that are associated with quite a bit of toxicity.
Healio: What areas do you think require further research?
Portell: This is pure speculation, but one might hypothesize that CAR T-cell therapy may be the better choice for patients with mantle cell lymphoma instead of autotransplant in the first remission. There are ongoing clinical investigations to see if minimal residual disease-negative remission needs the stem cell transplant in the first remission. That study is being undertaken by the ECOG group.
Another important question is: Can novel agents overtake chemotherapy or be added to chemotherapy in the front-line setting? We have the studies available, but they haven’t been read out yet, so hopefully we’ll have data from those soon.
We also have unanswered questions in the relapse setting. Can we combine agents to get deeper remissions so we can do treatment-free intervals as opposed to continuous BTK inhibitor treatments? Can we take people off these therapies that are well tolerated but sometimes cost-prohibitive and associated with some toxicity? Can we get to this treatment-free interval while still keeping patients in remission? We hope that novel agents in combination will get to that point.
Finally, further investigation into the agents that are coming out would also add to the treatment landscape in mantle cell lymphoma.
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Healio Interview
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