Treatment options for MZL: second-line and beyond

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Tycel Jovelle Phillips, MD: This ties in with some of the options we can use in a second-line setting, which in some ways still mirror some of the things we’ve discussed before with follicular lymphoma patients in a first-line setting. When patients relapse with marginal zone lymphoma, as we know, this incurable cancer will relapse in most patients at some point. Again, what they used in the first row can sometimes be reused in the second row, especially if it’s in a single area, and again, something that’s sensitive to radiation. Or if it’s a more diffuse disease, if it’s a low burden, again, if they’ve had a very long-lasting response to rituximab, that’s something we can do. also reuse in a second-line setting without having significant concerns about long-term toxicities.

Things are obviously different when we start talking about chemoimmunotherapy, but again, if these agents weren’t used in the first line, options like bendamustine and rituximab, bendamustine and obinutuzumab are things that we can use as a second line with the expectation of a very lasting response. R-CVP [rituximab, cyclophosphamide, vincristine, and prednisone] or O-CVP [obinutuzumab, cyclophosphamide, vincristine, prednisolone] is something that can be used in a second-line setting, if you want to avoid re-using a bendamustine chemotherapy regimen. If you want to avoid the use of an anthracycline this will bring us to CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], which we usually send back to patients, unless we have other really viable chemoimmunotherapy options or there is a concern for transformation.

More recently, new agents have been approved in this framework, and we have had a lot of them in recent years. Ibrutinib is the first generation BTK [Bruton tyrosine kinase] inhibitor which has an indication in marginal zone lymphoma. Zanubrutinib is a second generation BTK inhibitor that was recently approved by the FDA. The main takeaway from zanubrutinib compared to ibrutinib is that zanubrutinib in some of these more recent studies appears to have a better safety profile compared to ibrutinib. It has a different dosage in that it can be administered either 160 mg BID [twice a day] or 320 mg per day, while ibrutinib is a daily dose. But the toxicity profile of zanubrutinib seems to indicate that it is a much better option when one wishes to use a BTK inhibitor in marginal zone lymphoma, particularly based on the MAGNOLIA study, which was recently presented.

Lenalidomide and rituximab also have an indication in marginal zone lymphoma based on the AUGMENT study, although responses in patients with marginal zone lymphoma have not been at the level we have seen. with patients with follicular lymphoma with R² [lenalidomide and rituximab]. And then umbralisib, which is a delta PI3 kinase inhibitor that we talked about earlier, has an indication in marginal zone lymphoma. Again, umbralisib compared to some of the other delta inhibitors appears to have a better toxicity profile. But again, without a direct comparison, it’s hard to say if there is a real difference between these patient populations, as we don’t like the comparison between studies of these agents.

That being said, Dr Danilov, what is your preferred treatment regimen for patients on the second line and beyond who have marginal zone lymphoma, if even you have a preferred option in this situation?

Alexey Danilov, MD, PhD: It’s hard to talk about the preferred option, as you said Dr Phillips, it depends on what they got on the front line and how long the response lasted, how durable the response was and, this stage, of the kind of toxicity I might anticipate. But indeed, in addition to lenalidomide and rituximab and chemoimmunotherapy, we have umbralisib, zanubrutinib, and ibrutinib as all good options. Once that goes beyond that, we have additional agents that can be used. Copanlisib, duvelisib and idelalisib are the 3 PI3K inhibitors that can also be used in the treatment of marginal zone lymphoma. Copanlisib recently received a breakthrough designation from the FDA for this disease, based on the CHRONOS-1 study. Copanlisib is a pan-PI3K inhibitor with a predilection for the alpha and delta isoforms of PI3K.

In the CHRONOS-1 study, a phase 2 study, which included several patients with non-Hodgkin lymphoma, 23 of these patients had marginal zone lymphoma. Again, this is a rare disease, so there is a significant number of patients for this disease. In this disease, when copanlisib was administered at 60 mg per dose on days 1, 8, 15 of a 28-day cycle, the overall response rate was 78%. And that was in the patients who received a median of 3 previous treatments, all of them were exposed to chemoimmunotherapy in one form or another. Additionally, progression-free survival was 2 years or 24 months, which is essentially double what we see in follicular lymphoma patients with PI3K inhibitors. PI3K inhibitors, and in particular copanlisib, appear to have impressive activity in marginal zone lymphoma.

Of course, again, this is intermittent administration of agents IV, intravenously, and alpha inhibition is accompanied by some specific toxicities. We see hypertension, we see hyperglycemia. Both generally tend to be transient. However, patients with uncontrolled diabetes may have more problems with copanlisib than the general patient population. And although there is some risk of neutropenia and thrombocytopenia, the risk of infections is low. And overall, throughout this study, the discontinuation rate was in the order of 25% due to adverse events, which is a very favorable number for the PI3K class. Copanlisib was generally well tolerated. There were very few delayed immune toxicities throughout the study. There was 1 case of colitis and 2 cases of pneumonitis, and no additional adverse events occurred over time. PI3K inhibitors are also a good option for patients with marginal zone lymphoma, which expands our drug arsenal and improves patient outcomes.

Tycel Jovelle Phillips, MD: The data was very powerful and led to the more recent study, CHRONOS-3, which was presented by Matthew Matasar, MD, at AACR [the American Association for Cancer Research annual meeting] in 2021.

Transcription edited for clarity

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