Review Series on Marginal Zone Lymphoma

Summary

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Blood Podcast: Review Series on Marginal Zone Lymphoma

Podcast Host: American Society of Hematology
Published: January 8, 2026
Episode Theme: In-depth review and discussion of the latest advances and challenges in the understanding and treatment of marginal zone lymphoma (MZL), led by Associate Editor Dr. Philippe Armand with authors Dr. Ariela Noy and Dr. Juan Pablo Alderuccio.

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Episode Overview

This bonus episode centers on the recently published review series on marginal zone lymphoma (MZL) in Blood, the leading peer-reviewed journal in hematology. Dr. Philippe Armand moderates a discussion with Dr. Ariela Noy and Dr. Juan Pablo Alderuccio, both contributing authors, focusing on the distinct nature of MZL, nuances across its subtypes, current treatment paradigms, the complexity of clinical trials in this population, and the pressing need for tailored research and drug development.

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Key Discussion Points & Insights

1. Marginal Zone Lymphoma: A Distinct and Underappreciated Entity

• Not as rare as perceived:
  • MZL is the third most common non-CLL B-cell non-Hodgkin lymphoma ([00:52]).
• Distinct from other indolent lymphomas:
  • "People assume it's a rare lymphoma and we don't need to know much about it because we can just treat it like other indolent lymphomas, particularly like follicular lymphoma. And I think those statements are both incorrect." – Dr. Philippe Armand [00:52].
• Diversity within MZL:
  • The disease encompasses three biologically and clinically distinct subtypes:
    • Extranodal MZL (EMZL)
    • Splenic MZL (SMZL)
    • Nodal MZL (NMZL)

2. Clinical Approach to MZL Subtypes

Subtype Differentiation & Influence on Treatment

• Extranodal MZL:
  • Usually localized at diagnosis (stage I)
  • Rare bone marrow involvement
  • Frequently managed with localized radiation, often achieving durable remission ([03:00]).
• Splenic MZL:
  • Usually disseminated, with bone marrow and blood involvement.
  • Systemic agents (e.g., rituximab monotherapy) preferred, especially for patients requiring therapy ([03:00]).
• Nodal MZL:
  • Primarily involves lymph nodes.
  • Treatment paradigms often extrapolated from follicular lymphoma ([03:00]).

Relapsed/Refractory Setting

• The disease's biology and site of relapse inform decisions:
  • Ocular EMZL typically relapses only on the contralateral side.
  • SMZL can evolve into nodal patterns; "it becomes more fluid as the disease progresses."
  • Nodal relapses may mimic follicular lymphoma management, but splenectomy can remain an option in SMZL ([04:30]).
  • "It's a marathon, not a sprint... we're not treating an aggressive lymphoma for cure. We only have palliative therapy." – Dr. Ariela Noy [06:35].

3. Systemic Therapy Preferences and Sequences

Frontline Systemic Therapy

• Bendamustine-Rituximab (BR):
  • Preferred for NMZL and disseminated EMZL.
  • In SMZL, higher risk of infections/treatment-related mortality; thus, rituximab monotherapy is often favored ([08:41]).

Second-Line and Beyond

• Lenalidomide-Rituximab (R2):
  • Reasonable across subtypes if not previously used.
  • Not all tolerate it well; some data limitations noted ([09:43], [11:05]).
• Bruton Tyrosine Kinase Inhibitors (BTKi) [e.g., Zanubrutinib]:
  • Strong option in relapsed settings with favorable toxicity (especially Zanubrutinib for cardiac safety in elderly).
  • "It is very reasonable. It is NCCN and FDA approved. Patients can enjoy very prolonged disease control and progression-free survival on a BTKi." – Dr. Ariela Noy [10:28].
• Insurance approval and lack of FDA label for some agents (e.g., acalabrutinib, pirtobrutinib) create access challenges ([12:32]).
• Lack of standardized sequencing:
  • "Even we're just in second line... already there is a small difference of opinion between two experts, which reflects how little definitive standard of care exists." – Dr. Philippe Armand [13:04].

Beyond Second Line:

• Bispecific Antibodies (e.g., Mosunetuzumab):
  • Early results are promising, particularly in relapsed EMZL.
  • Caution advised in SMZL with circulating disease due to CRS risk.
  • Pre-phase therapy (e.g., dexamethasone) may reduce disease burden and lower CRS risk ([13:56]).
• Logistical considerations regarding antigen competition and selection of bispecifics highlighted ([15:10]).

CAR T-Cell Therapy

• Still in its infancy for MZL.
• Emerging data could mark a paradigm shift if curability is proven, but significant commitment and immunosuppression risks must be considered.
• Real-world use is rare; most patients opt for other therapies or trials ([15:55]).

4. Key Differences from Follicular Lymphoma

• Toxicity profiles and unique clinical features:
  • Higher infection risk in particular settings (e.g., SMZL with BR).
• Challenges in clinical trial accrual:
  • Current Lugano criteria can exclude typical MZL presentations (small lesions, extranodal sites, moderate splenomegaly without lymphadenopathy).
  • Need for disease measurement criteria adaptation ([18:21], [19:27]).
  • "By Lugano criteria, that patient has no disease. That is absurd." – Dr. Ariela Noy [19:27].

5. Challenges in Clinical Trial Design and Research for MZL

• Barriers:

  • Lack of suitable measurement criteria for disease burden limits eligibility ([19:27]).
  • Overall survival is impractical as a primary endpoint; many patients require lengthy follow-up.
  • Surrogate endpoints like CR24 and CR30 (complete remission at 24/30 months) are not yet FDA-accepted for approval ([23:00]).
  • Economic disincentives for industry to invest in drug development ([24:31]).
  • Difficulty in establishing "standard of care" due to lack of RCTs and variable eligibility.

• Quotes Highlighting Issues:

  • "You can't run a clinical trial for 10 years." – Dr. Juan Pablo Alderuccio [24:13]
  • "Not having a uniform way to evaluate 100 patients on a trial is not a way to move drug development." – Dr. Ariela Noy [20:43]
  • "Any one of us here could come up with a great trial design... [but] our company is not aligned with this, we can't prioritize that." – Dr. Ariela Noy [24:31]

• Suggested Solutions:

  • Modify trial eligibility criteria for MZL.
  • Push for regulatory acceptance of surrogate endpoints.
  • Increase advocacy for research prioritization and better industry incentives.

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Notable Quotes & Memorable Moments

• "People assume it's a rare lymphoma...I think those statements are both incorrect."
  – Dr. Philippe Armand [00:52]

• "It's a marathon, not a sprint... we're not treating an aggressive lymphoma for cure. We only have... palliative therapy."
  – Dr. Ariela Noy [06:35]

• "Even we're just in second line and already there is a...small difference of opinion between two experts, which reflects how little...definitive standard of care exists."
  – Dr. Philippe Armand [13:04]

• "By Lugano criteria, that patient has no disease. That is absurd."
  – Dr. Ariela Noy [19:27]

• "You can't run a clinical trial for 10 years."
  – Dr. Juan Pablo Alderuccio [24:13]

• "Any one of us here could come up with a great trial design... but our company is not aligned with this, we can't prioritize that."
  – Dr. Ariela Noy [24:31]

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Key Timestamps

• 00:52: Introduction of MZL as distinct and underestimated in frequency and complexity.
• 03:00: Overview of MZL subtypes and how they influence diagnosis and initial treatment.
• 04:30: Clinical approach and changing patterns at relapse.
• 06:35: Philosophy behind therapy selection—tailoring to palliative goals.
• 08:41: Current treatment sequences for frontline and beyond.
• 10:28: BTK inhibitors' role and their tolerability.
• 13:04: Discussion of off-label and investigational therapies, highlighting research gaps.
• 15:55: Reflections on CAR T-cell therapy and real-world considerations.
• 18:21–24:31: Challenges in trial design, measurement criteria, surrogate endpoints, and industry engagement.

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Conclusion

This episode provides a comprehensive and candid assessment of marginal zone lymphoma as a unique, diverse, and under-recognized set of diseases. The experts emphasize the need for nuanced, subtype-specific approaches, highlight the lack of robust evidence guiding therapy sequencing, underscore the challenges faced in clinical research and drug development, and advocate for urgent systemic changes in how MZL research is prioritized and conducted.

For further details or to read the full review articles, listeners are encouraged to visit bloodjournal.org.

Transcript

[A]

Welcome to this week's bonus episode of the Blood podcast, your source for innovative ideas and cutting edge information. In this episode, Associate Editor Dr. Philippe Armand discusses the review series on marginal zone lymphoma. Two of the contributing authors, Dr. Juan Pablo Alvarochio and Dr. Ariel Noye, discuss a variety of treatment considerations for marginal zone lymphomas on this episode.

[B]

Hello, everyone. My name is Philippe Armand. I'm one of the associate editors at Blood, and I had the pleasure of putting together this review series on marginal zone lymphoma. And we have with us today two of the authors, Dr. Ariela Noy and Dr. Juan Aldorucho. Thank you very much for joining.

[A]

Thank you very much for having us.

[C]

Thank you, Dr. Orman.

[B]

Marginal zone lymphoma, I think, has always struck many of us as being in some way the forgotten stepchild of lymphoma, where people assume it's a rare lymphoma and we don't need to know much about it because we can just treat it like other indolent lymphomas, particularly like follicular lymphoma. And I think those statements are both incorrect. It has its own biology, it has its own treatment vulnerabilities, it should have its own treatment pathways, it should have its own clinical trials. And it's actually not that rare. It is the third most common non CLL form of B cell non Hodgkin lymphoma. So we thought that would be an opportunity to ask several marginal zone lymphoma experts to. To write about different aspects of this disease. In the review series, there are three articles, there's one authored by Dr. Laurent and Dr. Bertoni on the biology of marginals on lymphoma, and also specifically on the biology of the different subtypes, because MZL has three different subtypes and we now recognize more and more that they're biologically different and that that knowledge probably should inform how we approach them clinically. So that's a great article which I invite you all to read. We have a very clinical article on the treatment of marginal zone lymphoma, which was authored by our two guests today, Dr. Noid, Dr. Aldrucho. So we'll talk about that a lot. And then the Last article by Dr. Thibelmont, Dr. Bomier, Dr. Karas, is about how do we develop drugs, how do we develop clinical trials in the space of marginal zone lymphoma? Because that poses unique challenges that are not present when we address other diseases like large cell lymphoma or follicular lymphoma, we're which don't quite have the same issues. And that requires potentially a specific rethink of how we conduct marginal zone lymphoma research. So we'll see if we have time to talk about that on today's podcast. But I'm gonna start maybe with you, Dr. Aldrucho, and start from this point of view that there are these different NZL subtypes. So practically in your clinical world, how do you use this difference? How do you approach a patient? First determine what subtype they might have and how, if at all, does that inform your treatment decisions? I know it's a broad, so take it however you wish.

[C]

Thank you, Dr. Alman. I think it's an important question because although margins and lymphoma are grouped together, they are very clinically, biologically and treatment should be approached differently. Regarding the most common subtype, extranodal marginal cell lymphoma, usually it's localized at the time of diagnosis. So usually patients present with stage one disease, the incidence of bone marrow involvement is very low, contrary to what happened with splenic margins on lymphoma that usually is a disseminated disease at the time of diagnosis with bone marrow and peripheral blood involvement. And so these give us a different approach as extranal Martian lymphoma. Usually most of the patients the diagnosis are to receive radiation therapy that can be approached associated with long term progression of survival. Splenic margins and lymphoma is a disease that in those that require therapy, treatments like systemic agents like rituximab may be needed in that population. Then nodal Martian cell lymphoma follows a little more type of follicular lymphoma, type of biology that mainly involves lymph nodes. And the data has been extrapolated mainly from follicular lymphoma clinical trials.

[B]

Thank you so much. And Dr. Noye, if I may turn to you, how does this apply in the relapse refractory setting? Does it change anything once a patient has relapsed, whether they're emzl, smcl, nodal MZL or not?

[A]

I think it makes a lot of difference. First of all, I think part of the confusion generally is that people just get maybe nervous or scared when they realize it's not just one disease, which is what Dr. Aldurruchio was explaining, and that the approach even within the subtypes differs. Right. So it makes a difference whether you have an extranodal marginal zone lymphoma of Your conjunctiva versus your stomach versus subcutaneous. And then that complexity is compounded in the relapse setting. Most of the patients that have just the ocular tend not to relapse or they relapse on the contralateral side, which is a mystery biologically. How did it get there? Or is it a new primary? But they tend not to develop, for example, gastric or nodal. Whereas patients that have splenic marginal zone lymphoma for a long time will often go into a phase of a nodal subtype in addition. Right. So I think it becomes more fluid as the disease progresses. Of those, probably the most complicated is the nodal because that can now go anywhere. And that mimics exactly what Dr. Alderuccio said, is that at that phase the approach is really similar to one of follicular lymphoma at diagnosis. I think the approach is very different. You would never say to a patient with follicular lymphoma, oh, if A and B therapy don't work, you know, we could always do a splenectomy. And your progression free survival after splenectomy is going to be 10 years. That's not an approach that's appropriate to follicular lymphoma, but it's entirely appropriate to splenic marginal zone.

[B]

And when you're choosing systemic therapy, Dr. Noy, for again, a patient with relapse refractory disease, do you think about where they started biologically, do you think about where their disease is now or does it not matter anymore? Again, just for systemic therapy, I think.

[A]

It matters a lot. You need to recognize that I like to say it's a marathon, not a sprint. Right. We're not treating an aggressive lymphoma for cure. We only have at this point, palliative therapy. The data on CAR T and marginal zone lymphoma is really in its infancy. So I caution anyone who uses the word cure. And we just have to say, all right, what is the goal of the therapy right now? And will that therapy give us a reasonable progression free survival? So if I have a patient in front of me and I know that they have systemic disease, but most of it is clinically occult, I'm more concerned on what is their current problem. And if I can get them knowing the biology, if they've been in my practice for 10 years and they have minimal disease, but they have one spot right now that is clinically problematic, I'm not going to go to a systemic therapy. But if I see somebody that has a relapsing pattern over shorter periods of time. It's telling us about the biology of the disease. And that's a patient where I would be perfectly comfortable saying, hey, let's look at this clinical trial for you because the conventional approach isn't necessarily working. And do you want to be on a bispecific trial? Do you want to be on a car t trial? I think their disease has declared itself to be biologically different.

[B]

Thank you. And Dr. Aldruccio, maybe could you walk us through a typical sequence of therapies? So maybe the patient, as you said in frontline, had radiation for localized disease and maybe now they relapse or maybe they start with nodal disease to begin with and you need to deploy systemic therapy. What's a typical sequence today for you? And what are, let's say the major branch points where you think, okay, for certain patients this is definitely not an appropriate sequence.

[C]

Yeah, that's a great question and thank you. For patients, when they require systemic therapy, I think Bendamastin rituximab is one of the preferred agent regimens. However, I think the caveat will be in patient with a splenic margins on lymphoma where European study showing around 50 patients that were enrolled that the incidence of infections and the incidence of treatment related mortality occur in patients with splenic martian cell lymphoma. So I usually reserve pendomastom rituximab for patients with extranodal martianza lymphoma that present disseminated disease or nodal martian cell lymphoma. However, in those with splenic martian lymphoma in need for systemic therapy, singulation rituximab based on retrospective data has been proved to be an effective and safe measure approach.

[B]

And what about the next step? So after you've used let's say rituxan, Bendamustine or Rituxan and then maybe rituxan and chemo. What's your second line or your third line?

[C]

Go to the second line. Outside clinical trials is lenalinomide in combination with rituximab. Something I think relevant that we discussed with Dr. Noy in our manuscript is about other anti CD20, especially obinituzumab and also in the clinical trials that show higher incidence of infections, adverse events and potential treatment related mortality when we use in this population. So My preferred anti CD20 is rituximab in patients with margins on lymphoma. So yeah, second line therapy if the patient was not previously exposed Lenalinomide rituximab. I think across the three subtypes is a reasonable line effect.

[A]

And if I could add to that, I think my personal approach actually would be a btki. And I recognize the word indefinite on indefinite. Therapy is not something that people like from many perspectives including financial toxicity, but it is very reasonable. It is NCC and an FDA approved approach. Patients can enjoy very prolonged disease control and progression free survival on a btki.

[B]

And so your approach is to use those typically as second line or third line.

[A]

Again, I think the data on Lenalidomide is fraught. It was a subset of a prospective trial where unfortunately the confidence intervals due to the small number of patients on the trial are very broad. And not everyone tolerates lenolidomide, especially in an older population with pre diabetic or diabetic tendencies, people can just really suffer. So every single drug that we use has an AE profile and we have to tailor it to the patient. I don't think there's a wrong or right answer really. It's very reasonable to say let's try this and then if it doesn't work we're going to switch to something else. But I do want to put the BTKIs on there, you know, and I think what we've learned from this, we're always borrowing from other subtypes, which is good. So borrowing from CLL and Alpine and other studies, it's increasingly clear that of the three covalently bound Bhutan tyrosine kinase inhibitors, Sanibrutinib is the best tolerated. It has the lowest toxicity profile with regard to cardiac and I feel comfortable in an elderly population especially that I'm not putting them at an overt risk of a cardiac event.

[B]

And if I'm not mistaken, acalbridinib does not have FDA approval in marginal zone lymphoma as well.

[C]

Right.

[B]

Which makes it easy.

[A]

I would have to look, but I can tell you that you usually have. It ends up being insurance. You know, even Pirdobrutinib, the non covalently bound, in the right setting you can get that approved by an insurance. So there is data for Piritobrutinib, it's just not on the compendium yet. Which brings us to the problems of studying, doing clinical trials on these patients. Diseases, right?

[B]

Most definitely. And we'll get to that. Before you do, first I'd like to point out that it's impressive that even we're just in second line basically and already there is a, let's say a small difference of opinion between two experts Which I think reflects so well how little there has been in this disease and to enshrine definitive standard of care, how few randomized controlled trials and the ones that we have, as you allude to it, haven't been, many of them have not been particularly useful to clinical practice. I think that speaks to the need, as you do too Dr. Noye, for new or reinvigorated marginal zone lymphoma specific research. Having said that, Dr. Aldurucho. So okay, so now we're past, let's say we're past chemo, we're past BTK inhibitors, we're past lenalidomide, we're in the land of off label therapy. What's there other than clinical trials of course. What do you go to? What do you look for?

[C]

I think the data of mosenutuzumab that was recently presented at EHA in untreated extranadal marginal cell lymphoma is highly encouraging. Definitely something that I will consider if that will be an option in patients that are outside clinical trials. I think the bispecifics have a role. My only concern about the bispecifics is the in splenic margins of lymphoma when the patient has more circulating cells and that may trigger a higher incidence of crs. So I will be a little bit cautious in that specific scenario, acknowledging that there's no FDA approval of this agent yet in this setting. But this is a type of patients that I would like to give a pre phase of dexamethasone for a couple of days, decrease the disease burden and then start the by specific in this case Massonatuza. But I think definitely these agents will have a role in the treatment of.

[A]

Marginal lymphoma and you could reduce the disease burden even if you know that a monoclonal antibody, either Oban or Ritux will not have long term efficacy. Before you give a bispecific you could bring down the white count by using like a pre phase.

[B]

Although there maybe with mosanutuzumab you might worry about competition, nepotope competition I think which is less of an issue with the other two. But I don't know if that would be a concern.

[A]

Right. That would be a problem. You're right. With the mosanutuzumab it would not be a problem with any of the other bispecifics. And I think some of the clinical trials that the three of us are all involved in actually will address that.

[B]

Thank you. And then Dr. Noor, you alluded earlier to CAR T being in its infancy. So do you use it in this disease? And I think we're expecting a potential FDA approval for CAR specific for marginal zone lymphoma, maybe in the next few weeks or months. So what's the role of CAR T in your practice for this disease?

[A]

I'm not sure that my practice is emblematic of this, but it might be because I think probably all three of us see more patients with this disease than most, you know, community oncologists, for sure, and even hematologists. I have yet, to be honest, to offer, well, execute a CAR T program for a patient with marginal zone lymphoma. I have offered it to one patient and I do think her disease pattern and treatment pattern over, dare I say, 22 years, has actually reflected the evolution of the disease in terms of our understanding of the disease and the biology of the disease. I think somebody has to be of a certain mindset to be willing to do CAR T. Certainly it's not as drastic as what we've offered in the past to patients with multiple refractory disease, which is an allogeneic transplant. But I think we should never discount that it does require a commitment of at least one year of significant immunosuppression. We tend to overlook that. And there are significant risks with that. And many of these patients, I fear, will come to this already immunocompromised. You know, they didn't have a chance for B cell recovery, for example, so they're coming into it at risk for dying of COVID And there are patients that don't want to take that risk. You know, they'll play out or they'll go to another clinical trial and the next step and the next step. And I think that is understandable. At the same time, although the data is limited and then follow is limited, there is the hope that CAR T cell, which seems to maybe have a plateau on the curve for follicular, as that data matures, will also demonstrate a curability for marginal zone lymphoma. And that would be a real paradigm shift that will be very, very exciting.

[B]

Thank you. And Dr. Aldruchu, in thinking about marginal lymphoma as not being follicular lymphoma. And I think you. You guys alluded to the fact that many people many times approach it like FL for lack of specific data, really, in MCL across many drug classes. But what would you say is fundamentally different between approaching a patient with FL and approaching a patient with mcl?

[C]

If anything, I think in some Specific cases, as we discussed, is the toxicity profile can be slightly different in comparing merchants on lymphoma with other subtypes. And also the caveat is one of the challenge for enrollment in clinical trials is the presentation that we currently our eligibility in clinical trials is based on the 2014 Luano classification that requires measure of disease. And in many patients with marginal zone lymphoma, they have small lesions. For example, a patient with a conscientiva conscientiba electronal margins on lymphoma or a gastric margins on lymphoma that didn't respond to antibiotics or the patient refused, doesn't want radiation therapy for other regions. Reasons I think that patients are not elision. So that's the challenge that we have about conducting clinical trials and producing prospective therapeutic data in this disease. So that's why many of us are advocating for some modifications in the current Lugano classification for this disease in order to increase the enrollment of these patients.

[A]

And I think that's really, really important. If you took a patient that had 25 subcutaneous lesions and we see these patients, they don't have a single lymph node Greater than 1.5, the SUV max of these lesions is 2.4. And so technically speaking, by Lugano criteria, that patient has no disease. That is absurd. And I think Dr. Alteruccio and his colleagues at Miami have very carefully outlined an idea that you would look at the surrounding tissue. If the surrounding tissue has an SUV of just say one. Right. It's zero, basically. Right. Then you're looking at the relative glucose uptake. You don't need to be above the liver to know that that's lymphoma. You have biopsy proven disease. And changing the criteria in that setting would be invaluable because right now all of those patients cannot go on a study.

[C]

Yeah, the same as example for a patient with a splenic Martian lymphoma with only splenomegaly and without lymph nopathies. By the definition, splenomegal is not measure of disease.

[A]

Well, actually in the revised Lugano, so the craniocaudal dimension greater than I think it's. It's 13 allows it. But you're not going to put a patient with a spleen of 14 centimeters on a study. But it does get complicated because the way that you measure complete remission, there's no way to do partial. What is partial? Is 24 to 22 a partial remission. And then because of the conventions that we have for those criteria, it Becomes fraught and you actually end up in these discussions with the radiologist saying, no, no, I need you to write down this is a partial remission, but that's not how it's supposed to happen. Right. So now you have a form that says stable disease and then it says principal investigator comment patients responding to disease. And we don't want that. Not having a uniform way to evaluate 100 patients on a trial is not a way to move drug development and certainly not a way to get either an NCCN compendium or an FDA approval.

[B]

Those are all great points. And so because we're on this topic, which is so important here, and I think with a dedicated subject of one of the reviews, what are the other barriers to MZL research and how do we overcome them? So what do we do now? Maybe I'll start with you, Dr. Aldoruccio.

[C]

I think one of the efforts that Dr. Thievermont carried out about the CR24 in patients with extranodal Martian lymphoma, a surrogate endpoint that's important. Potential primary endpoints in clinical trials. Martinson lymphoma is an indolent disease where overall survival is not a feasible primary endpoint for clinical. Accelerate approval of these agents and progression free survival may be another challenge as well because patients will need several years of follow up. So trying to generate data on this type of surrogate endpoints can help to expedite the drug development as long as they are correctly validated. And of course capturing the toxicity of this agent may produce, you know, Dr. Armond.

[A]

The CR30 use as a surrogate endpoint for follicular lymphoma was published by Shih et al in 2017. And here we are eight years later and the FDA does not recognize CR30 as a, as a regulatory endpoint for approval that hampers our ability to move the needle. And I agree totally, Dr. Alteruccio. Now we've validated it again. Okay. But it's really the same concept. Whether one looks at CR30 or CR24 is frankly clinically irrelevant. But it really speaks to the issue of having the FDA recognize that we have no problem also collecting progression free survival. But if we are going to make an impact, and we understand that complete remission then serves as the surrogate for the PFS endpoint, we will be able to move things much faster. We can't sit and wait for, like you were saying, a median. You know, you can't run a clinical trial for 10 years.

[C]

Right.

[B]

And as we get better and try to move some of our more active agents in frontline. These problems will only be magnified because right now, if you're in third line, for example, many treatments don't have this kind of very prolonged pfs, but they will as we move them up the treatment chain or as we develop better treatment. So.

[A]

And I think we also face an economic problem which is probably beyond the three of us, is that if you're in drug development from a pharmaceutical company perspective, any one of us here could come up with a great trial design in five minutes or less that says, okay, I want to do X in marginal zone lymphoma. And we've all been in these meeting rooms where people say, you know, that's a great idea, but our company is not aligned with this. We can't prioritize that. And I'm not demonizing them in any way. I understand why that would be. I understand that perspective. And yet I also understand the patient and the researcher perspective saying, okay, now what do we do? And so we have a lot to learn from other orphan diseases. How to recruit patients better. There are patients, right? How do we get drug companies interested? How do we leverage? Well, if it ever comes back, government funding. And these are really the difficult questions, right?

[B]

That's such a great point. And in this article from Dr. Thibaulmore and her colleagues, they do talk a little bit about this and what might be broader solutions that are not, as you say, not really within the purview of academic institutions to change things like patents, etc. That might re incentivize industry to pursue this as a market. So it's very important. But this has been terrific, and I urge our listeners, if they're interested, to read the review articles, which I hope they will find as informative as I have. And in the meantime, I'd like to thank both of you for taking your time today and for sharing your insights.

[A]

Well, thank you for inviting us, and it's really been a wonderful collaboration and a great pleasure to work with all of you.

[C]

Thank you.

[A]

Thank you for listening to this bonus episode of the Blood podcast.

[B]

To read these articles, visit bloodjournal.org this.

[A]

Episode is copyrighted by the American Society of Hematology.