Blood Podcast Episode Summary

Podcast: Blood Podcast
Host: Dr. Laurie Sen, American Society of Hematology
Date: November 27, 2025
Episode Title: Fixed-Duration Epcoritamab Combination Therapy for Relapsed or Refractory Follicular Lymphoma and Pre-Transplant Strategies for GVHD post-HSCT

Episode Overview

This episode highlights two recent Blood journal articles through in-depth interviews with lead and senior authors:

1. Dr. Lorenzo Falci (Memorial Sloan Kettering): Discusses results from a phase II trial of fixed-duration epcoritamab, lenalidomide, and rituximab (R2) for relapsed or refractory follicular lymphoma.
2. Dr. Robert B. Levy (University of Miami): Explores a novel pre-transplant strategy targeting TNFRSF25 and CD25 to stimulate regulatory T cells (Tregs), ameliorating GVHD post-hematopoietic stem cell transplant (HSCT).

I. Fixed-Duration Epcoritamab R2 in Relapsed/Refractory Follicular Lymphoma

[00:39 – 11:00]
Guests: Dr. Laurie Sen (Host), Dr. Lorenzo Falci (Lead Author)

Key Themes

• Transformation in bispecific antibody therapy for B-cell malignancies
• Rationale and results of the epcoritamab/lenalidomide/rituximab combination
• Efficacy, safety, and infection management
• Potential for shorter-duration regimens

1. Role of Bispecific Antibodies in Follicular Lymphoma

[01:02 – 02:56]

• Background: Bispecific antibodies mark a transformative advance for B-cell non-Hodgkin lymphoma, demonstrating powerful T cell–mediated killing of lymphoma cells.

• Clinical Impact:

  “We are starting to shift the old paradigm of lower chance of response and shorter duration of response with each subsequent therapy. … Now seeing higher response rates and perhaps longer durations, even in patients in their third, fourth or fifth line.”
  — Dr. Lorenzo Falci [02:39]

• Combination Potential: Easy to combine with other standards, with ongoing trials exploring various regimens.

2. Rationale for Epcoritamab + Lenalidomide + Rituximab

[03:05 – 04:30]

• Design Logic: Building on lenalidomide’s ability to restore the immune synapse and reinvigorate T-cell function, combined with the established efficacy of rituximab/lenalidomide in relapsed FL.
• Preclinical Insights: Rituximab shown not to interfere with epcoritamab’s cytotoxic effect.

  “Lenalidomide … can reinvigorate T cell efficacy, and then engaging those T cells with a bispecific antibody is certainly very enticing.”
  — Dr. Lorenzo Falci [03:19]

3. Study Design and Key Results

[04:30 – 07:18]

• Design: Mirrored previous trials, with rituximab/lenalidomide as per the AUGMENT protocol and epcoritamab dosed weekly, then monthly, over two years.

• Patient Cohort: 108 patients enrolled.

• Efficacy Data:

  • Overall Response Rate: 96%
  • Complete Metabolic Response Rate: 88%
  • Follow-up: Median of 28.2 months
  • Duration of Response: Median duration 82%, nearly 80% progression-free survival

• Notable for High-risk Patients:

  “These figures were really recapitulated in select patient subsets, including those with POD24, primary refractory, or double refractory disease.”
  — Dr. Lorenzo Falci [05:48]

4. Safety Profile and Infections

[07:18 – 09:45]

• Expected Adverse Events: Cytokine release syndrome (CRS), injection site reactions (epcoritamab); neutropenia, diarrhea, skin rash (R2).

• No Unexpected Toxicities:

  “We didn’t see a particularly worrisome signal really anywhere. … The results justify the safety profile as well.”
  — Dr. Lorenzo Falci [06:59]

• Infection Risks: High rates of infection (esp. respiratory, COVID-19, pneumonia); strong emphasis on prophylactic strategies (VZV, PJP, IVIG as needed).

  “More than half of our patients have infections… I think this is a profoundly immunosuppressive therapy. … We really need to pay attention to how we can mitigate, prevent, and promptly treat these infections.”
  — Dr. Lorenzo Falci [08:00, 08:33]

• COVID-19 Specifics: The study ran during the pandemic; Dr. Falci anticipates lower impact now due to herd immunity and vaccination.

5. Questioning Duration: Could Shorter Therapy Be Equally Effective?

[09:45 – 11:00]

• Commentary Spark: Community is questioning whether such high efficacy warrants shorter treatment, potentially lowering infection risk.

• Real-world Insight:

  “We looked at patients who had to discontinue therapy while in remission – those patients did remain in remission for the most part, in-trial proof of concept that shortening treatment was not detrimental.”
  — Dr. Lorenzo Falci [10:11]

• Next Steps: Phase III trial underway to test one year versus two years; anticipation for future data.

II. Pre-Transplant Treg Expansion for GVHD Prevention in HSCT

[11:00 – 21:04]
Guests: Dr. Laurie Sen (Host), Dr. Robert B. Levy (Senior Author)

Key Themes

• Mechanistic basis of GVHD and Treg biology
• Strategy and results of pre-transplant expansion of host Tregs
• Clinical translation potential

1. GVHD Pathophysiology & Treg Role

[11:57 – 13:05]

• GVHD Trigger: Initiated by pre-transplant conditioning hurting the GI tract, activating antigen-presenting cells and donor T cells.
• Target Organs: Liver, skin, GI tract, thymus, bone marrow.

2. Rationale for Targeting TNFRSF25 and IL2

[13:13 – 14:56]

• Molecular Rationale: TNFRSF25 highly expressed on Tregs but not conventional T cells; can expand Treg compartment 5–6 fold using a TL1A-based fusion protein.

• IL-2 Synergy:

  “T regulatory cells require IL2 to survive. … if we expanded the Treg compartment… they would quickly run out of IL2 and perish. So we introduced IL2 alongside.”
  — Dr. Robert B. Levy [13:50]

• Clinically Appealing: Can manipulate Treg levels at specific, planned times prior to transplant.

3. Study Methodology and Results

[15:02 – 17:27]

• Pre-Transplant Expansion: Mice pretreated 3–4 days pre-transplant with TNFRSF25 fusion protein + IL2; achieved robust Treg expansion in situ, including GVHD target tissues (GI, skin, liver).
• Functionality: Enhanced Treg proliferation and suppressive function in target tissues.
• Clinical Outcomes:
  • Reduced GVHD Severity: Improved survival, lower clinical GVHD scores.
  • Maintained Graft-versus-Leukemia (GvL):

    “The animals were able to mediate anti-tumor responses.”
    — Dr. Robert B. Levy [17:18]

4. Clinical Implications and Translation

[17:27 – 19:20]

• Current Landscape: Most clinical efforts focus on in vitro Treg expansion and adoptive transfer—costly and challenging.

• In Vivo Manipulation:

  “We’ve really always focused on the notion of manipulating [Tregs] in vivo. … What we thought was a good way … was to treat the patient before transplant. … There are human reagents for stimulating both TNFRSF25 and the IL2 receptor.”
  — Dr. Robert B. Levy [18:03]

• Potential Impact: Ready for clinical translation, with human trials feasible targeting the peri-transplant window.

5. Could This Strategy Also Heal Established GVHD?

[19:04 – 21:04]

• Commentary Note: Harun Shaikh (U. Würzburg) wonders about application post-onset of GVHD.

• Expert Opinion:

  “Early after transplant … it’s really not possible to effectively expand Tregs.”
  — Dr. Robert B. Levy [19:59]

• Combinatorial Potential: Combining pre- and post-transplant strategies, plus integration with other GVHD interventions holds promise.

Memorable Quotes

• “The idea of reinvigorating T cell efficacy, and then engaging those reinvigorated T cells with a bispecific antibody, is certainly very enticing.”
  — Dr. Lorenzo Falci [03:19]

• “More than half of our patients have infections… I used [infection prophylaxis] in the clinical trial, and anticipate using it if this becomes an accepted and approved therapy.”
  — Dr. Lorenzo Falci [08:15]

• “We thought we could start out with a pretreatment and get the regs in place before the transplant, with the potential then to utilize this strategy later on after a transplant if GVHD does emerge.”
  — Dr. Robert B. Levy [20:53]

Key Timestamps

| Segment | Timestamp | |-------------------------------------------------|------------| | Bispecific antibody background | 01:11–02:56| | Rationale for combination regimen | 03:05–04:30| | Study design and outcomes summary | 04:35–07:18| | Infection risk and management | 07:18–09:45| | Shortening therapy debate | 09:45–11:00| | GVHD basics and Treg rationale | 11:57–14:56| | Study methodology and findings (GVHD) | 15:02–17:27| | Clinical translation potential (GVHD) | 17:27–19:20| | Post-GVHD application discussion | 19:20–21:04|

Summary

This episode provides an in-depth look at transformative developments in hematology—first, epcoritamab-based fixed-duration combination yielding high, durable remissions for relapsed/refractory follicular lymphoma with a manageable safety profile, and second, a ground-breaking, translational approach to pre-emptively expanding host Tregs for GVHD prevention in allogeneic HSCT with preserved graft-versus-leukemia activity. Both studies highlight innovation, pragmatic trial design, and close attention to patient safety, with promising implications for future clinical practice.