The Fellow on Call: The Heme/Onc Podcast

Episode 139: Follicular Lymphoma Series, Pt 4 – Relapsed/Refractory Management (Cellular therapy options)
Date: September 17, 2025
Hosts: Ronak (A) and Vivek (B)
Guest: None (Dan is on vacation)

Episode Overview

This episode concludes the follicular lymphoma series by diving into the management of relapsed/refractory disease, focusing on cutting-edge cellular therapies: CAR T-cell therapy and bispecific antibody therapies (often referred to as “CAR T vs. Bispecifics”). The hosts break down the mechanisms of action, compare efficacy and toxicity profiles, review pivotal clinical trial data, and provide pragmatic guidance on patient selection and side-effect management. Throughout, the conversation is accessible to fellows and clinicians at all levels.

Key Discussion Points & Insights

1. Clinical Case Introduction: Setting the Stage

[01:40]

• 70-year-old woman with relapsed follicular lymphoma, extensive prior therapy, now presenting with B symptoms and disease progression.
• Emphasis on always repeating a biopsy to rule out transformation, ideally excisional if accessible.
  • “It's always important to repeat the biopsy, especially of that most avid lesion... to ensure that this isn't a transformation to a large B cell lymph.” – Ronak [02:39]

2. Foundations of Cellular Therapies

[04:22]

• Brief immunology recap: B cells make antibodies, T cells (CD4/CD8) orchestrate immune attack, but tumors evade immune surveillance through “self” antigens.
• “Tumor cells will definitely have self antigens. As a result, T cells have a difficult time finding and binding to the tumor cells.” – Ronak [05:35]
• Cellular therapies are designed to circumvent these limitations and force an immune attack on tumor cells.

3. Mechanisms of Action: CAR T vs. Bispecifics

CAR T-cell Therapy

[06:18]

• Patient’s own T cells are collected, genetically modified to target CD19 (found on all B cells), and reinfused after lymphodepleting chemotherapy.
• “We modify these T cell receptors to search for a very specific target… All B cells universally express CD19… It's basically searching for CD19. We'll hit it and we'll kill it.” – Vivek [07:04]
• A lengthy, multi-step process: insurance approval, apheresis, off-site engineering, reinfusion, and observation.
• “One and done” therapy with the possibility of durable remission/cure.

Bispecific Antibody Therapy

[09:00]

• Off-the-shelf agents with two binding arms:
  • One binds CD3 on T cells, other binds CD20 on B cells (“molecular matchmaker”).
  • Forces immune engagement at the tumor site.
  • Step-up dosing to mitigate toxicity, then fixed or continuous administration.
• “It's like a molecular matchmaker... This will trigger the cytotoxic T cell activity, resulting in cell death of the CD20 expressing B cell.” – Ronak [09:15]
• More accessible and quicker to administer than CAR T.

4. Toxicity Profiles: CRS and ICANS

[10:27]

• Cytokine Release Syndrome (CRS):

  • More frequent/severe with CAR T (life-threatening SIRS-like illness).
  • Bispecifics: CRS typically mild, manageable at home/outpatient.
  • “In general, when we think about CAR T cell therapy, there's more inflammation, it's a sprint... whereas in bispecific antibody therapy, it's a slower churn.” – Vivek [10:41]

• Neurotoxicity (ICANS):

  • Can occur with both, but is rare and generally mild with bispecifics.
  • Monitored with ICE score (akin to mental status exams); managed with steroids for both.
  • “ICANS can occur at higher rates in severity with CAR T therapy... It's extremely uncommon with bispecific antibody therapy.” – Ronak [13:14]

• Immune Suppression:

  • Both deplete B cells → risk of infections and hypogammaglobulinemia.
  • IVIG supplementation and revaccination (especially after CAR T).

5. Patient Selection and Practical Considerations

[15:47, 18:52]

• Bispecifics:

  • “Off-the-shelf,” outpatient, broad eligibility (including frail/older patients), lower side-effect burden.
  • “We encourage everybody… to understand this can be safely done in the community – not just at specialized centers.” – Vivek [16:08]

• CAR T:

  • Requires specialized center, rigorous evaluation, considerable time lag (insurance, manufacturing), higher risk toxicities, but possibly more durable remission/cure.
  • “There's a big time gap because of the insurance approval, the apheresis, the manufacturing, all the things we talked about... For patients who are chemo refractory, that becomes quite a challenge.” – Vivek [17:26]

6. Clinical Trial Data Review

Bispecifics

• Mosunetuzumab (IV, fixed duration):

  • Phase 2, 3-year follow-up: ORR 80%, CR 60%.
  • PFS at 3 years: 50% (72% in those reaching CR remain in CR at 3 years).
  • CRS (mostly mild) in 40%, ICANS rare and reversible.
  • “60% of them, over half of them are achieving a remission, which is crazy.” – Vivek [21:48]

• Epcoritamab (SQ, until progression):

  • ORR 82%, CR 63%.
  • CRS in 60% (reduced with dose optimization), ICANS 6% (all reversible).
  • More convenience with subcutaneous dosing, but indefinite therapy.
  • “Epcoritamab is a subcutaneous injection… Patient comes in… I’m going to give you a shot and you’re good to go. So easy peasy, right?” – Ronak [24:18]

• Odranextamab (IV, Europe):

  • Complex dosing and hospitalization requirements.
  • Efficacy similar to above; less appealing due to logistical/timing burden.

CAR T-cell Therapies

[31:00]

• Axi-cel (ZUMA-5, CD19-directed):

  • Third-line and beyond, high-risk cohort.
  • CR ~80%; 5-year follow-up: 50% of those in CR remain event-free.

• Liso-cel (TRANSCEND FL):

  • Some patients in 2nd-line; CR 94% (awaiting long-term durability data).

• “The CR rate in that (ZUMA-5) study was about 80%. The five year follow up... showed that 50% of patients who achieved a CR remained in CR.” – Vivek [31:27]

7. How to Choose Between CAR T and Bispecifics?

[34:17]

• No clear winner; selection highly patient- and disease-specific.

  • Rapidly progressing/aggressive disease → consider CAR T (more intensive, possibly curative).
  • Older/frail, indolent cases → bispecific antibody (less toxic, outpatient).
  • If large cell transformation suspected, epcoritamab may be preferred due to efficacy overlap in aggressive histologies.

• “For a lot of us who treat this frequently, it's hard not to recommend one of these less toxic bispecific antibody products, particularly because many of our follicular lymphoma patients are older.” – Vivek [33:48]

8. The Evolving Landscape

[26:44, 29:06]

• Newer combinatorial regimens (e.g., epcoritamab + lenalidomide + rituximab) likely to move bispecifics into earlier lines.
• Improvements in formulations (e.g., subcutaneous mosunetuzumab) for improved patient convenience.
• Anticipation of bispecifics becoming standard-of-care in 2nd line.

Notable Quotes & Memorable Moments

• “Super fascinating. Although some of you may be getting flashbacks to immunology, maybe from college, but really, really, really fascinating stuff.” – Ronak [06:00]
• “Bispecific antibody therapies are very manageable. At Rouleaux, I've treated a patient who's 90 years old with a bispecific… and is playing bridge in their bridge group now. That’s how amazing these products are.” – Vivek [35:20]
• “It's an amazing time to be in hematologic malignancies and just really excited to see where the field goes.” – Vivek [35:41]
• “If things work really effectively in later lines, why not try to really push the bar there and bring it higher up in our treatment algorithm?” – Ronak [29:06]

Timestamps for Important Segments

• Introduction to Cellular Therapies and Case: [01:04] – [02:39]
• Mechanistic Immunology Refresher: [04:22] – [06:18]
• CAR T-cell Process Breakdown: [06:18] – [09:00]
• Bispecific Antibody Explanation: [09:00] – [10:27]
• CRS and Neurotoxicity Comparison: [10:27] – [13:15]
• Immune Suppression Considerations: [13:15] – [15:47]
• Pragmatics of Therapy Selection: [15:47] – [18:52]
• Mosunetuzumab (Trial Data & Side Effects): [18:52] – [24:36]
• Epcoritamab (Trial Data & Comparison): [24:36] – [26:44]
• Odranextamab & Trial Design: [29:30] – [30:31]
• CAR T in Follicular Lymphoma; Data Review: [31:00] – [34:17]
• Summary, Pearls, and Closing Thoughts: [34:17] – [35:59]

Conclusion

This episode provides a comprehensive, practical, and evidence-based overview of the modern approach to relapsed/refractory follicular lymphoma, spotlighting the rise of CAR T-cell and bispecific antibody therapies. The hosts emphasize individualized decision-making, understanding of mechanisms and toxicity, and the exciting evolution of the field. Essential listening for anyone managing lymphoma in 2025 and beyond.