Review Series on Follicular Lymphoma

Summary

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Blood Podcast: Review Series on Follicular Lymphoma

Host: Dr. Philippe Armand, American Society of Hematology
Guests: Dr. Carla Casullo, Dr. Sarah Rutherford, Dr. Aaron Perry
Date: October 30, 2025

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Overview of the Episode

This bonus episode centers on the state-of-the-art in follicular lymphoma (FL), with a focus on relapsed/refractory disease, the future treatment landscape, and the critical issue of transformation. Dr. Philippe Armand moderates a vibrant discussion with three authors of the recent Blood review series: Dr. Carla Casullo (relapse/refractory treatment), Dr. Sarah Rutherford (future directions), and Dr. Aaron Perry (biology and transformation). The panel shares insights into current therapies, evolving advances (notably bispecific antibodies and CAR T-cell therapy), the promise of molecular monitoring, and the hope for functional cure.

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Key Discussion Points & Insights

1. Treatment of Relapsed/Refractory Follicular Lymphoma

With Dr. Carla Casullo

• Bispecific Antibodies and CAR T-cell Therapy (01:48)

  • Major excitement surrounds bispecific antibodies, in use alone or with other drugs, and CAR T-cell therapy.
  • These targeted agents, previously reserved for patients post–second-line therapy, are advancing into earlier lines.
  • "To me, I think those represent probably one of the most important potentially practice-changing advances in this space." (Dr. Casullo, 02:33)

• Personalizing Therapy Selections (03:08)

  • Therapy selection in FL is inherently individualized, considering patient specifics, prior treatments, comorbidities, and duration of response.
  • Indolent lymphoma allows strategic, thoughtful decision-making. Patient quality of life and preference are integral to treatment choices.

• Role of Tumor Biology (04:08)

  • While genetic markers like EZH2 mutations may guide choices, overall molecular biology is not yet driving precise therapy due to limited actionable predictors.
  • "Biology...has even taken a bit of a backseat...I would love to be in that space very soon." (Dr. Casullo, 04:15)

2. Evolving Treatment Landscape & Future Directions

With Dr. Sarah Rutherford

• Frontline Bispecifics and New Combinations (05:00)

  • Multiple ongoing trials are evaluating bispecific antibodies, often with drugs like lenalidomide; these options likely to shift into frontline treatment soon.
  • Intent is to move away from more toxic chemotherapy (e.g., bendamustine) toward better-tolerated, effective options.

• CT-DNA Monitoring and Adaptive Treatment (05:50)

  • The field is moving toward using circulating tumor DNA (ctDNA) for guiding management and surveillance.
  • Potential for ctDNA-based de-escalation or re-initiation of therapy could personalize duration and timing, improving safety and flexibility.

• Therapy Sequencing and Multiple Lines (07:24)

  • As with rituximab, bispecifics may be reused in later lines for some, but for others, new strategies (e.g., tri-specific antibodies, NK cell targeting) are emerging.
  • CAR T-cell therapy holds potential for durable remission—and possibly cure—in select patients, though toxicity and aggressiveness remain considerations.
  • "In the last five years there’s just been an explosion." (Dr. Rutherford, 08:29)

3. Biology and Clinical Management of Transformation

With Dr. Aaron Perry

• Mechanisms of Transformation (09:10)

  • Transformation shares a clonal origin with FL but acquires additional genetic and microenvironment changes.
  • Advanced tools for studying patient-derived samples are deepening biological understanding, but much remains to learn.

• Strategies for Prevention and Intervention (10:17)

  • Key future challenge: predicting which patients will transform to enable proactive intervention.
  • Need to assess risk before first-line therapy and develop strategies for interception or prevention.

• Therapeutic Approaches for Transformed FL (11:57)

  • There is heterogeneity in transformed FL, and some will resemble large cell lymphoma subtypes. Current practice applies DLBCL (large cell) regimens, but future may bring divergence.
  • Aspirational vision: developing therapies that target the common progenitor cell to prevent transformation and relapse—a “holy grail” for achieving cure.

4. The Prospect and Concept of Cure in Follicular Lymphoma

Panel Discussion—Drs. Rutherford and Casullo

• Functional Cure vs. True Eradication (13:40)

  • Many patients achieve a “functional cure,” living long and well post-therapy, even if relapse status is not actively monitored.
  • Surveillance strategies emphasizing patient quality of life, with less aggressive testing in selected cases.

• Aggressive Disease & Curative Intent (14:40)

  • For young patients with high-risk or early-relapsing disease (e.g., POD24), more aggressive interventions—including trials with CAR T-cell therapy—are considered in pursuit of permanent remission.

• Transplantation in the Era of Novel Agents (15:46)

  • Autologous stem cell transplant is becoming rare in well-resourced settings, largely replaced by novel therapies.
  • Allogeneic transplant remains uncommon but may be appropriate in refractory, young patients; caution required due to high toxicity.
  • "Within the United States, I'm very infrequently recommending autologous transplant…very few and far between." (Dr. Casullo, 16:00)

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Notable Quotes & Memorable Moments

• "I view indolent lymphoma as really a very strategic and thoughtful process because…we can be very thoughtful and selective…"
  — Dr. Carla Casullo, (03:11)

• "What I keep telling my patients that I’m so excited about, it’s been such a wonderful time to be in this field."
  — Dr. Sarah Rutherford, (08:23)

• "The holy grail, I think, of therapy as we think towards a possibility of cure."
  — Dr. Aaron Perry, (13:18)

• "[On transplant]...those treatments can come with the possibility of cure, but at a significant toxicity. So we have to weigh the balance very carefully so that we don't hinder someone's progress."
  — Dr. Carla Casullo, (16:17)

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Important Segment Timestamps

• Overview and Series Introduction: 00:24–01:48
• Relapsed/Refractory FL Treatment & Personalization: 01:48–04:37
• Future Directions (Bispecifics, CT-DNA, CAR T): 04:37–08:42
• Transformation: Biology, Management, and Prevention: 08:42–13:26
• Cure & Advanced Therapies (CAR T, Transplant): 13:26–16:50

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Tone and Takeaway

The conversation is collegial, optimistic, and deeply patient-centered, reflecting hope and excitement for rapidly expanding treatment options and the personal nature of care in FL. There is a clear sense of progress—“an explosion” of new approaches—and an undercurrent of anticipation for the next set of advances, especially regarding prevention of transformation and movement toward a true cure.

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For Further Reading

Interested listeners are encouraged to explore the full review series published in Blood, as referenced throughout this discussion.

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Transcript

[Dr. Philippe Armand]

Welcome to this week's bonus episode of Blood Podcast, your source for innovative ideas and cutting edge information. In this episode, Associate Editor Dr. Philippe Armand discusses the review series on follicular lymphoma with authors Dr. Aaron Perry, Dr. Sarah Rutherford and Dr. Carla Cosullo.

I'm delighted to be present at this podcast and to have with me three of the authors today that contributed to recent review series in follicular lymphoma in blood. The review series was aimed to give the readers a glimpse of where this rapidly evolving field is now, both clinically and scientifically, and also a sense of what the future, at least the near future, might bring in terms of treatment landscape changes. And today I'm accompanied by Dr. Perry, Dr. Rutherford and Dr. Kosulo, who authored and co authored three of the reviews in this series. I will note that there are two reviews for which the authors are not here today, today. One on the biology of follicular lymphoma, which is a great review by Dr. Begelin and colleagues, and one on the treatment of frontline follicular lymphoma, which is also a field that is going to undergo some significant changes likely in the near future. Another great review by Dr. Bashti and colleagues. But today we're going to focus a little bit on relapse follicular lymphoma, on the future of treatment, and on the always important issue of transformation. Dr. Casullo, if I may, I'd like to start with you. You wrote this great review on the treatment of relapse refractory follicular lymphoma. Can you tell us broadly where you think the field is in terms of what the most exciting, what the most powerful treatments are for the treatments for the treatment of relapsed patients today?

[Dr. Carla Cosullo]

Hi, it's great to be here and thanks for the opportunity to discuss the paper. So I think that the field of relapsed follicul lymphoma is expanding really broadly. And one of the things that I find most interesting is bispecific antibodies that are being used either alone or in combination with other drugs, as well as CAR T cell therapy. And what we had been seeing are these targeted agents being available for patients after two or more lines of treatment. And what we're seeing now is that they're moving earlier into second line treatment as well as first line treatment. And based on some recent data that hasn't yet been published, but we'll hopefully hear about @ash, I think that we're going to hear about another option for bispecific with revlimid and ret rituximab in relapse follicular lymphoma in addition to now tafecitumab with revlimid and rituximab in relapse follicular lymphoma. So to me, I think those represent probably one of the most important potentially practice changing advances in this space. And it'll likely change our approach to sequencing treatments since a lot of them are also being used in first line.

[Dr. Philippe Armand]

Great. Given the multiplicity and growing number of options now, how do you think when you're dealing with an individual patient, how do you think about what therapy is best for this particular patient at a given time in their treatment journey?

[Dr. Carla Cosullo]

I think it depends on the individual. And I view indolent lymphoma as really a very strategic and thoughtful process because unlike for aggressive lymphoma, where we know that there's such an urgency to treat, we sometimes have a little bit of a luxury of time in indolent disease where we can be very thoughtful and selective about what the patient has had before for who they are in terms of their medical conditions, their time from last treatment, did they. Was observation a strategy in the first line? Was it bendamustine based treatment? Was it something else? Was it a clinical trial? And I use duration of response to first line therapy as an important metric of understanding the aggressiveness of their disease. So I think it's hard to answer in general terms because I really view it as a very precision approach to the individual. But those are some of the things that I use to help me make those decisions. And then obviously patient preference and their quality of life concerns as well.

[Dr. Philippe Armand]

And do you use anything about the biology of the tumor itself, any kind of molecular characterization to guide your choices at present?

[Dr. Carla Cosullo]

Yeah, I think if they have an ETHG mutation, that really is very helpful. But you know, unfortunately we're not in an era yet, hopefully soon, but we're not yet in an era where we can use predictors of response to guide us. Or the biology has even taken a bit of a backseat in terms of grading and its importance in the WHO classification. So I think it's harder in my view, to use biology as a measure of predicting what to do next. But I would love to be in that space very soon.

[Dr. Philippe Armand]

Great. And so, Dr. Rutherford, looking a bit further afield, you co authored this review on where the treatment of FL might be going, and Dr. Gasullo already gave us some teasers about what's around the corner, how do you think this field is going to evolve in the next few years? What do we have to look forward to in terms of new agents or new combinations or new positions of those agents?

I agree with all of what Dr. Kutzulo said about the bispecific antibodies in particular. And there are many trials going on right now with bispecific antibodies in the frontline setting, some as single agents, but most in combination with drugs like Lenalidomide. We have one at Cornell with tazemetostat and BTK inhibitors. And it's been such a a gratifying experience to be able to offer patients this type of treatment that we think is likely to be more effective and better tolerated than chemotherapy based approaches such as Bendamustine, which we know has some toxicities that we like to try to avoid if possible. So I think that eventually, and probably not too far in the future we'll see bispecific antibodies being used in the frontline setting. I do want to note that I still think there will be many patients who can be observed without treatment and so some of our principles will remain the same. And I agree completely with what Dr. Koussoli said from the standpoint of the need to individualize the approach. Certainly some, particularly older patients may be monitored and never even need treatment. The other aspect of this disease is monitoring. That I think is going to change a lot. And I think we can talk about this more as we move forward. But I'm really excited about the concept of being able to use circulating tumor DNA to guide management and surveillance for all lymphomas. But I think in particular follicular lymphoma. So one place I could foresee that being helpful is with bispecific antibodies. Some of the currently available agents have a fixed duration approach, while as others are given continuously. And we know there's some downsides of continuing bispecific antibodies, in particular infection risk. So I look forward to being able to use a CTD DNA type test, be able to tell when a patient could potentially stop treatment, and then maybe later could restart that same treatment, which would give us more options over time.

Thank you. Those are great thoughts. I'm curious because so many clinical trials now are based on bispecific antibodies, some of which you summarize in combination with pretty much everything in sight. So, okay, maybe there's a winner, maybe there isn't. How many times are we going to use these drugs and then what else are we going to do now? Because patients are Going to receive it probably in second line based on what's coming, probably in frontline. But do you think they'll use it like Rituxan at every line of therapy or do we need something else? And what's that going to be?

Right. I think it's a great point. I could see it being used depending on the patient. I have some patients, and I'm sure you do too, who have received rituximab as a single agent multiple times. And so that might still be an option for some older patients, for example. But I do think there are a number of other novel strategies, particularly in this immune therapy type space. So different targets or tri specific antibodies that are also targeting NK cells in addition to the B and T. I think the CAR T cell space is really interesting and will evolve as well. Certainly some patients, though this is a more aggressive approach in some ways in terms of toxicities. It may even potentially cure some patients. I know that's not a term that we typically use. We did get into that concept a bit in our article. So I think what I keep telling my patients that I'm so excited about, it's been such a wonderful time to be in this field. I've been in attending for about 10 to 11 years now. In the first five years or so, we just use the same drugs over and over again. And then the last five years there's just been an explosion. And I think that we're going to continue to have more and more options for patients and hopefully that will go along with better efficacy, improved profile of safety, and then also the quality of life aspect that I do want to get into later as well.

Thank you. Let's switch gears for a moment and talk about transformation, which you will likely agree with me, remains one of the most difficult aspects of treating follicular lymphoma. And so, Dr. Perry, you wrote this great review on the biology and the clinical management of transformation, and tell us with the biological understanding today, how it helps you approach this question for your patients and for research in the near future.

[Dr. Carla Cosullo]

Thanks.

[Dr. Aaron Perry]

So I think that we've really benefited from recent scientific work that's provided new insights into biology. But I think we still have a long way to go in terms of understanding. What we do know is that transformation sort of emerges from a common precursor cell as the follicular lymphoma. So they share a genetic history and then it occurs through acquisition of additional genetic alterations. And we're just beginning to also understand some of the core features of the microenvironment and disease biology that evolve in parallel. And a lot of this has really been shaped by some of our different tools that we have for sort of deep study of primary patient derived samples.

[Dr. Philippe Armand]

And do you think, if you were going to speculate on how we will be successful in terms of, let's call it broadly managing transformation, where is the point of maximal impact? Is it the detection and early interception? Is it early diagnosis? Is it prevention? Is it better treatment? Where do we attack the problem from?

[Dr. Aaron Perry]

I think a really critical question is, is there a way that we could identify which patients are likely to develop transformation? And that would provide certainly a way to think of novel strategies to intercept or prevent transformation in parallel. I think our treatment strategies, as they've evolved and we've gained new therapies for large cell lymphoma, those have certainly made an impact on our ability to clinically manage and treat transformation when it does occur. But I think the question of whether we could get to a point where we can actually assess that individual patient's risk before we choose their initial follicular limb therapy, lymphoma therapy is actually a really intriguing question.

[Dr. Philippe Armand]

If you could detect with very high probability the future transformation event, so if you could, say, 90% chance that a given patient is going to transform within a year, what do you think that would lead to? What clinical trial would you do to test the ability to actually make a difference?

[Dr. Aaron Perry]

So, from thinking from a scientific perspective, if we knew that that clonal evolution hadn't yet happened, but it was something that we could potentially interven, we would want to select a therapy that would uniquely sort of intercept or treat that evolving clone before it gets to the point of transformation. And as to what is the best therapy to treat that evolving clone at this time, I don't know. I think that our studies will hopefully provide additional insight into what are those properties of the evolving clones and whether they're uniquely susceptible to some of the novel therapies that we've just heard about, such as bispecifics or immune targeting, as compared to a traditional chemotherapy.

[Dr. Philippe Armand]

Great, because I'm on a roll with asking impossible to answer questions in terms of the treatment of transformed follicular lymphoma. Do you think it's likely that we will have a fundamentally different approach than we do for large cell lymphoma, or will it continue to be, I think, as it has been, where the treatment just benefits from the advances in drbcl and we tend to apply them more or less unchanged?

[Dr. Aaron Perry]

I think that is another really good Question. There's a lot of heterogeneity in just looking at the available data that we have in transformation. And some might share a lot of genetic and immune microenvironment similarities with certain genetic subtypes of large cell lymphoma. And so from that sort of perspective or background, it might be that these large cell lymphoma therapies are the way to go. But I think as we assemble these data sets, it will be also important to contrast how things might be different. There's key properties to the immune microenvironment or to the tumor biology that might be interesting to target differently. I think the other interesting thing to speculate about, since we're talking about things that are not currently possible, that we want to become possible, is if we could have therapies that could target more of a cell of origin or common progenitor, which would sort of prevent evolution to transformation and also potentially prevent future follicular relapses. That's sort of the holy grail, I think, of therapy as we think towards a possibility of cure.

[Dr. Philippe Armand]

Thank you very much. That's a great answer. And since now you guys have said the C word twice, I'm going to go Back to you, Dr. Rutherford, tell us, how do you think about curing this disease? Is it possible? Is it necessary? Is it curious, useful?

I think one of the keys, again, is looking at the individual patient. So we all know many patients over the years who may have had six cycles of bendamosin and rituximab at age 70, and then they live another 15 years or so, and then they die of some other cause. And we would consider that like a functional cure. And so I think that will still be maintained as a concept for us. I think, as you know, I'm someone who advocates for less surveillance type testing, for example, bone marrow biopsies and imaging. We typically at Cornell, have followed patients really closely clinically, but not do a lot of imaging tests. So I think that's actually helpful for people's quality of life. Getting back at that question. So sometimes we don't know if someone has relapsed, but if they're not having any symptoms and they're feeling well and living their life normally, then it's sort of irrelevant whether we consider that to be sort of a cure in some form. On the flip side, we do have some young patients who may have a pod 24 status relapse within a short period of time. I'm dealing with a situation like this right now in that Case we want to be very aggressive, for example, try to enroll them on a clinical trial with CAR T cell therapy for the second line setting and hope that maybe in that type of patient we could potentially achieve a cure. I know there are some patients who've had very long responses to CAR T cell therapy. So I think that again, just like we keep saying, and I think it's one of the challenges that probably the biggest challenge of follicular lymphoma is how heterogeneous it is. But I do think that we may be able to achieve cure for some patients in the future with some of these novel approaches.

Thank you. Historically, we have thought about stem cell transplant as being the main, or perhaps until CAR T came along, the only vehicle to cure. Whether that's true or not. Dr. Kasula, I wonder how you think about the evolving role of both autologous and allogeneic approaches in FL now.

[Dr. Carla Cosullo]

I think that autologous transplant is probably not something that we'll be using very frequently outside, outside of a resource limited setting, recognizing that not all parts of the world have access to some of these novel treatments or even have the ability to deliver to have a stem cell allergenic stem cell transplant. So I don't know that I'd rule it out as a global option. But within the United States, I'm very infrequently recommending autologous transplant and even allogeneic transplant. Probably in my career of similar to Dr. Rutherford and other probably like 12 years or so. I've probably sent three patients for an aloe transplant. So very few and far between. But I think that there is a role for that for the right person. If they're a young person with really refractory disease that really truly nothing has helped. And that's there's absolutely a role for allogeneic transplant. And so those treatments can come with the possibility of cure, but at at a significant toxicity. So we have to weigh the balance very carefully so that we don't hinder someone's progress.

[Dr. Philippe Armand]

Well, this will conclude our podcast. I'm very grateful to the three of you for the reviews that you authored and for your insights today and for everything that you've contributed to the field. As I said in our introduction, the field of follic lymphoma is changing rapidly and that is in such large part thanks to the work that you're doing. I also want to thank our listeners for tuning into this podcast and hope that you will go and read the articles in this series and hope that you enjoy them. Thank you very much.

Thank you for listening to this bonus episode of the Blood podcast. To read these articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.