Novel Treatment Strategies for Relapsed/Refractory MZL


A comprehensive review of novel therapies in relapsed/refractory marginal zone lymphoma and possible sequencing strategies in this setting.

Bijal D. Shah, MD, MS:
Brian, we’ve got some new agents in the relapsed setting. It seems like the list is growing, which is fantastic. This is 1 of those spaces where BTK [Bruton tyrosine kinase] inhibitors, PI3Ks, and Revlimid are starting to make their way into the treatment paradigm. How can you distinguish these?

Brian T. Hill, MD, PhD: Great question. [Those are] similar agents that we’ve been discussing, both for follicular lymphoma and for mantle cell lymphoma. In mantle cell, BTK inhibitors are much more active. In follicular, PI3 kinase inhibitors are more active. And in marginal zone lymphoma, it’s split more evenly. We don’t see the extremely high response rates with BTK inhibitors in marginal zone that we do in CLL [chronic lymphocytic leukemia] and mantle cell. We have ibrutinib as an option, for instance. We also have the newer agents, like umbralisib, an oral PI3 kinase. It’s well tolerated and very active in marginal zone. Of course there’s R2 [lenalidomide, rituximab], which we’ve been talking about today. I can’t tell you that there’s ever going to be head-to-head data comparing this, so it’s an individualized-patient decision when you look at the toxicity profile of each approach and patients’ need for treatment. But these are all active in this space.

Bijal D. Shah, MD, MS: Caron, when do you turn to something like CAR [chimeric antigen receptor] T cells in marginal zone? More specifically, from the original seemed like patients were progressing a little more rapidly.

Caron A. Jacobson, MD, MPH: CAR T isn’t approved for marginal zone lymphoma, but there was a cohort of patients on the ZUMA-5 study, which led to the approval of follicular lymphoma. They were all in the third line and beyond. Initially, it’s only 24 patients at this point, and the first 20 had been presented previously. The CR [complete response] rate was still quite high. It was 60% to 70%, instead of over 80%. But it looked like the durability of response and the progression-free and overall survival were going to be shorter. I had always cautioned that those patients had to have only 1 month of follow-up. Most of those patients had a very short 1 to 3 months of follow-up. Thus, the end of the curve was very immature.

[At the American Society of Hematology Annual Meeting] Sattva Neelapu presented the update to ZUMA-5, which shows an improvement in the duration of response, progression-free survival, and overall survival curves for marginal zone lymphoma, such that the duration of response has not been reached with a median of 12 months of follow-up at this point for that cohort. Hence, it’s looking much better, and I hope that the study leads to an approval of CAR T for marginal zone lymphoma because, as you heard from Brian and Ian [Flinn], responses to chemoimmunotherapy are short-lived. The responses we get to targeted agents are shorter than what we see in other therapies. I think this will be utilized for patients with marginal zone lymphoma.

Bijal D. Shah, MD, MS: That’s great.

Caron A. Jacobson, MD, MPH: Yes.

Bijal D. Shah, MD, MS: That’s good to hear. In the meantime, while we’re waiting on this approval, Michael, we’ve got the CHRONOS-3 study. Do you want to share some data that was developed from this trial?

Michael Wang, MD: First, I wanted to share some of my opinions on marginal zone lymphoma. It’s a fascinating lymphoma. We put the splenic marginal zone, the nodal, and the MALT [mucosa-associated lymphoid tissue] together for a lot of patients. But if you want to do trials, you obviously cannot put 3 of them in 1 trial; you have to do trials separately. We separated those groups, the numbers decreased, and that’s why not so many trials have been done in marginal zone lymphoma.

Nowadays, there’s a European marginal zone lymphoma consortium. People began to attack this disease. I worked on the R2 [lenalidomide, rituximab] therapy in mantle cell lymphoma. Then it was used not only in relapse but even in the frontline marginal zone lymphoma—a very effective combination. BTK inhibitors, such as ibrutinib, had a 50% response rate, which is not as high in mantle zone lymphoma. But when you use with rituximab, it’s another good option. Then we have all these PI3 kinase inhibitors.

Most recently, there was a trial with 458 patients by Dr [Muhit] Özcan, presented at ESMO [European Society for Medical Oncology Congress]. This was a phase 3 randomized study with Rituxan-copanlisib and Rituxan with placebo. They have several groups. They have nodal, they have extranodal. In all’s 22 months with the copanlisib arm and only 13 months in the placebo arm. Response rate was 75% in the overall for the experimental arm but only 50% in the placebo arm. The complete remission was 40% in the copanlisib but only 26% in the placebo arm. This is approving another combination for marginal zone lymphoma. With the CAR-T-cell therapy described by Dr Jacobson and many other therapies mentioned by Drs Ian and Hill, in marginal zone lymphoma we have more and more agents.

Bijal D. Shah, MD, MS: That’s wonderful.

Caron A. Jacobson, MD, MPH: There’s also the rare B-cell malignancy, where sequencing BTK inhibitors and PI3 kinase inhibitors seem to work. The resistance to BTK inhibitors in this disease doesn’t necessarily portend resistance to PI3 kinase inhibitors and vice versa. That’s another way you can increase life span.

Bijal D. Shah, MD, MS: Good point.

Michael Wang, MD: I want to say something about splenectomy. Splenectomy was used in the pretargeted therapy era. When we did splenectomy, not only did the disease regress, but 25% the bone marrow will become negative. That lasts for a period of time. Nowadays, I tend to use the novel agents more because this is a more elegant way of getting rid of the lymphoma. That’s my opinion.

Bijal D. Shah, MD, MS: That’s great. Brian, do you see BiTEs [bispecific T-cell engagers] and other novel agents marching their way into marginal?

Brian T. Hill, MD, PhD: Yes. The data we’ve seen with the bispecific agents in indolent lymphomas are really encouraging. There are low rates of low-grade cytokine release syndrome that will have to be worked out, but that class of drug is very exciting to see in development.

Michael Wang, MD: The beauty is that for marginal zone can borrow agents from large cell lymphoma, follicular lymphoma, and mantle cell lymphoma. Also, because the trials aren’t frequently done, the FDA has a low bar of allowing the data to be used for marginal zone lymphoma. Usually, marginal lymphoma doesn’t have many cases in the trial. It has its unique advantages.

Bijal D. Shah, MD, MS: It does. We learned really interesting things. As you pointed out earlier, Michael and Caron, the CR rates seem deeper in marginal zone lymphoma with PI3Ks than what we were seeing in follicular [lymphoma]. For me, that was a bit of a surprise.

Caron A. Jacobson, MD, MPH: Yes. This is a disease where perhaps those drugs, outside CLL, worked the best.

Bijal D. Shah, MD, MS: That’s wonderful.

Transcript edited for clarity.

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