Treatment Options for MZL: Second Line and Beyond

Tycel Jovelle Phillips, MD: This segues into some of the options we can use in the second-line setting, which in some ways still mirrors some of the things that we discussed before with patients with follicular lymphoma in a frontline setting. When patients do 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 line can be reused sometimes in the second line, especially if it’s in a single area, and again, something that’s amenable to radiation. Or if it is more diffuse disease, if it’s low burden, again, if they had a very durable response to rituximab, that’s something that we can also use again in a second-line setting without having significant concern about long-term toxicities.

Things are different obviously when we start talking about chemoimmunotherapy, but again, if these agents weren’t used in the frontline setting, options such as bendamustine and rituximab, bendamustine and obinutuzumab are things that we can use in a second-line setting with the anticipation of a very durable 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 reusing a bendamustine-based chemotherapy regimen. If you want to avoid use of an anthracycline, that will take us to CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], which is something we typically would defer to patients, unless we don’t have any other really viable chemoimmunotherapy options or there is a concern for transformation.

More recently, some novel agents have been approved in this setting, and we’ve had a lot in the last several years. Ibrutinib is the first-generation BTK [Bruton tyrosine kinase] inhibitor that has an indication in marginal zone lymphoma. Zanubrutinib is a second-generation BTK inhibitor that was recently FDA approved. The biggest takeaway from zanubrutinib versus ibrutinib is that zanubrutinib in some of these more recent studies appears to have a better safety profile compared to ibrutinib. It does have a different dosing in that it can be given either 160 mg BID [twice a day] or 320 mg daily, whereas ibrutinib is a daily dose. But the toxicity profile for zanubrutinib seems to indicate that this is a much better option at times when we want to use a BTK inhibitor in marginal zone lymphoma, especially based on the MAGNOLIA study, which was recently presented.

Lenalidomide and rituximab also has an indication in marginal zone lymphoma based on the AUGMENT study, albeit the responses in the patients with marginal zone lymphoma were not to the degree that we saw with the patients with follicular lymphoma with R² [lenalidomide and rituximab]. And then umbralisib, which is a PI3-kinase delta inhibitor we talked about earlier, has an indication in marginal zone lymphoma. Again, umbralisib compared to some of the other delta inhibitors does appear to have a better toxicity profile. But again, without a head-to-head comparison, it’s hard to say if there’s a true difference in these patient populations as we don’t like cross-study comparison of these agents.

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

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

In the CHRONOS-1 study, a phase 2 study, which included multiple patients with non-Hodgkin lymphoma, 23 of these patients had marginal zone lymphoma. Again, it is a rare disease, so it is a significant number of patients for this disease. In that 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 patients who received a median of 3 prior therapies, all of them were exposed to chemoimmunotherapy in some shape or form. Moreover, the progression-free survival was 2 years or 24 months, which is essentially double what we see in patients with follicular lymphoma with PI3K inhibitors. It seems that PI3K inhibitors, and in particular copanlisib, do have some impressive activity in marginal zone lymphoma.

Of course, again, this is intermittent administration of IV, intravenous, agent, and alpha inhibition comes with some specific toxicities. We see hypertension, we see hyperglycemia. Both typically tend to be transient. However, patients with uncontrolled diabetes may have more trouble with copanlisib than the general population of patients. And while there is some risk of neutropenia and thrombocytopenia, the risk of infections is low. And overall, in this whole study, the discontinuation rate was on the order of 25% due to adverse events, which is a very favorable number for the PI3K class. Copanlisib overall was well tolerated. There were very few delayed immune-mediated toxicities in the whole study. There was 1 case of colitis and 2 cases of pneumonitis, and no additional adverse events emerged over time. The PI3K inhibitors are a good option for patients with marginal zone lymphoma as well, which expands our armamentarium of drugs and improves outcomes of patients.

Tycel Jovelle Phillips, MD: The data were very impactful 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.

Transcript Edited for Clarity