Other Approved Agents and Treatment Strategies for MZL


Moving beyond BTK inhibition in marginal zone lymphoma, expert panelists review other therapies and drug classes with indications in this setting.


Bhavesh Shah, RPh, BCOP: Let’s move to the next part and talk about some of the clinical trials in marginal zone lymphoma. Amit, you mentioned that we now have 1 PI3 [phosphoinositide 3] kinase inhibitor that we didn’t have before and there are actually 4 out there. We know that just like the BTKs [Bruton tyrosine kinase inhibitors], there’s going to be differences in umbralisib being more delta selective. The thought is that you’d have fewer immune-mediated adverse events. There’s also the whole concept of Tregs [regulatory T cells]. It may preserve a number and function of the regulatory T cells that lead to these the immune-mediated adverse effects. What’s your experience with umbralisib and some of the data in terms of its response in marginal zone lymphoma?

Amitkumar Mehta, MD: Umbralisib is a highly specific PI3 delta inhibitor, and it also has casein kinase 1 epsilon inhibition. This is in addition to the delta inhibition like we have in the others. Copanlisib [Aliqopa] is a little different. It and duvelisib [Copiktra] have alpha and delta inhibition. But all are active in B-cell lymphomas, especially follicular lymphoma and marginal zone lymphoma. Umbralisib was approved based on the UNITY-NHL study. It included other indolent lymphomas, but the main group was follicular and marginal zone lymphoma. The overall response, which was the primary end point, was about 15%. But impressively, about 16% of patients had complete response rates in that study.

The adverse effect profile was similar to other PI3 kinase inhibitors, but with less diarrhea and less transaminitis. If you look at grade 3 or higher toxicities, the more common were neutropenia, diarrhea, and elevation of ALT [alanine transaminase] and AST [aspartate transaminase]. They were the more important ones. I always highlight that whenever I start. That’s where my pharmacist’s role comes in. On the PI3 kinase inhibitor, they have a high risk of infection, especially PJP [pneumocystis jirovecii pneumonia] infections. They also reactivate some of the viruses like CMV [cytomegalovirus].

As soon as I start this protocol with any PI3 kinase inhibitor, it’s important that I start with prophylaxis like acyclovir, Bactrim, or sulfa to prevent PJP. That’s where my pharmacist’s role comes in. They will make sure that the patient isn’t allergic to sulfa. If they’re allergic to sulfa [sulfamethoxazole], then we switch to other anti-PJP prophylaxis. This is important. Umbralisib is now FDA approved for marginal zone lymphoma based on UNITY-NHL for patients who have seen more than 1 line of therapy, especially with prior anti-CD20 therapy.

Bhavesh Shah, RPh, BCOP: Thank you. The UNITY-NHL trial also tested rituximab [Rituxan] and lenalidomide [Revlimid]. I wanted to also get your perspective on that.

Amitkumar Mehta, MD: R-squared, or rituximab/lenalidomide, is also very active in various lymphomas, but it’s more active in follicular lymphoma than marginal lymphoma. In the AUGMENT study that compared R-squared [rituximab/lenalidomide] vs R [rituximab], those were rituximab-sensitive patients. The responses and PFS [progression-free survival] weren’t as great in marginal zone lymphoma as they were in follicular lymphoma. Interestingly, the survival was a little lower compared with just the rituximab arm. So I’d be a little cautious. It’s a very active agent. The caveat is that the sample size of patients was very small. It’s very difficult to interpret in that setting. But it’s a very active combination. It’s listed in the NCCN [National Comprehensive Cancer Network] guidelines, but you have to be very careful with R-squared.

Bhavesh Shah, RPh, BCOP: Absolutely. There’s a pretty significant REMS [Risk Evaluation and Mitigation Strategy] program associated with using Revlimid, which requires patients who are women with childbearing potential to have a negative pregnancy test, and you have to be very proactive in making sure appropriate contraception is being used, with a lot of education to prevent any pregnancies in patients. Javier, in terms of the landscape of marginal zone lymphoma, we talked about maintenance therapy. Do you do maintenance therapy? Amit already shared his perspective. What’s your perspective on maintenance therapy?

Javier Munoz, MD, MBA: I echo previous comments from Amit. There’s no overall survival benefit for maintenance rituximab. There is a PFS benefit. I have the discussion with the patients. For patients with bulky disease or patients who have an incomplete response, I may be slightly more tempted to use it. But overall, I’m not a maintenance person in the way that I don’t push patients to go in that direction. I have the discussion with them and present the options, but particularly in this COVID-19–ridden world, I’m trying very hard to not prescribe treatment altogether. When I have to prescribe therapies, I’m trying to shy away a little more when it comes to monoclonal antibodies because they seem to decrease your chances of building antibodies against the COVID-19 vaccination. If you’re not prolonging their survival by doing the maintenance rituximab, then I don’t see strong benefit from prescribing it.

Transcript edited for clarity.

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