Blood Podcast Episode Summary

Podcast: Blood Podcast (American Society of Hematology)
Episode: Analysis of IELSG37 Trial Results and PF4 in Stem Cell Aging
Date: December 4, 2025
Host: Dr. James Griffin (Dana-Farber Cancer Institute)
Guests: Dr. Emmanuel Zuka (Oncology Institute of Southern Switzerland), Dr. Sen Zeng (University of Illinois at Chicago)

Main Theme

This episode presents in-depth discussions of two recent studies published in Blood:

1. The impact of immunochemotherapy regimens in primary mediastinal B-cell lymphoma, focusing on the International Extranodal Lymphoma Study Group (IELSG37) trial.
2. The role of Platelet Factor 4 (PF4) in regulating hematopoietic stem cell (HSC) aging and its potential therapeutic applications.

Key Discussion Points and Insights

1. IELSG37 Trial: Immunochemotherapy in Primary Mediastinal B-cell Lymphoma

Overview of Disease

• Description:
  • Primary mediastinal B-cell lymphoma (PMBL) is a rare, aggressive subtype of non-Hodgkin lymphoma, representing about 5% of cases.
  • Overrepresented in young white women, peaking in incidence in the 30s and 40s.
  • Unique gene expression—closely related to classical Hodgkin lymphoma.
  • Clinical features: large B cells, clear cytoplasm, prominent sclerosis, with residual thymic cystic structures (origin: thymic B cells).
  • Rapid progression, mediastinal masses, frequent local invasion and compressive symptoms.
• Standard Treatment & Challenges:
  • Immunochemotherapy is highly effective, resulting in better outcomes than other diffuse large B-cell lymphoma (DLBCL) subtypes.
  • If initial therapy fails, salvage options are limited and less effective.
  • Persistent residual mediastinal masses on imaging have led to longstanding debates about post-therapy radiation.

IELSG37 Trial Design and Main Findings

• Study Aim:
  • Determine if radiation therapy can be omitted in patients achieving complete metabolic response (CMR) by PET scan after immunochemotherapy.
• Regimens Studied:
  • Any regimen with rituximab and anthracycline was allowed; specific regimen choice was determined per institution.
• PET Response as a Key Marker:
  • CMR (Duval Score <5) on PET post-induction meant patients could skip radiation, lowering late side effects for young survivors.
  • Key Quote ([03:01], Dr. Emmanuel Zuka):

    “The study has proven that in patients achieving a complete metabolic response on PET scans at the end of the induction in monochromatic radiation therapy is no longer needed and this is reducing the risk of late side effects in a population of young people with a high chance of cures.”

• Chemotherapy Regimen Impact:
  • Regimen selection affected metabolic responses:
    • R-CHOP21 (every 3-week administration) had significantly higher rates of PET-positive residual disease (Duval Score 5) than R-CHOP14 (every 2 weeks) or DA-EPOCH-R.
    • Multivariable analysis confirmed inferior outcomes for R-CHOP21 (2.6x higher risk of poor metabolic response than R-CHOP14; >5x higher than DA-EPOCH-R).
    • Despite high rates of cure after further therapy, needing additional treatment increases potential late toxicity.
    • Recommendation: R-CHOP21 should not be preferred; R-CHOP14 or DA-EPOCH-R regimens are safer choices for this patient population.
  • Key Quote ([06:34], Dr. Emmanuel Zuka):

    “In spite of the impossibility to show a survival difference, we think that CHOP21 should not be recommended...if you are a believer of R‑CHOP, then give it every two weeks which is much better...this is not adding a significant additional toxicity comparing to the three‑week regimen which in our opinion is no longer to be recommended.”

Role of PET and Future Directions

• Current Limitation: PET scans do not perfectly identify treatment failures; many with residual PET activity can be cured with further therapy.
• Next Step: Incorporating circulating tumor DNA (ctDNA, "liquid biopsy") to discriminate true failures from false positives and guide therapy less invasively.
• Key Quote ([08:17], Dr. Emmanuel Zuka):

  “We plan to address this topic in future study using ctDNA analysis. The idea is a liquid biopsy can be complementary to PET scans and allow to understand who are the true failures and who are the false positives that do not need additional treatment.”

2. Platelet Factor 4 (PF4) and Hematopoietic Stem Cell (HSC) Aging

Background and Study Rationale

• Question: What drives HSC aging, and is it reversible?
• Previous Insight: The bone marrow niche, especially megakaryocytes, change with age and produce less PF4, a factor previously shown to restrict expansion of myeloid-biased HSCs.

Study Findings

• Role of PF4 in Aging and Rejuvenation:
  • PF4-deficient mice display accelerated stem cell aging (lower lymphoid output, increased myeloid bias, more DNA damage).
  • Administering recombinant PF4 to old mice rejuvenates stem cell function—restoring youthful polarity, reducing DNA damage, yielding more balanced blood cell production, and improving transplant capability.
  • PF4 acts via LDR and CXCR3 receptors; knocking out these mimics the aging phenotype.
• Human Relevance:
  • Human megakaryocytes also produce less PF4 with age; human HSCs respond to PF4 with improved function.
  • Suggests PF4 signaling is a conserved mechanism for healthy hematopoiesis throughout life.
  • Key Quote ([11:48], Dr. Sen Zeng):

    “PF4 signaling represents a conserved mechanism essential for maintaining hematopoietic health through an individual’s lifespan. This has real clinical implications.”

Clinical Implications

• Potential Applications:
  • Rejuvenate aging donor cells prior to bone marrow transplantation—overcoming poor engraftment and myeloid bias of older donors, and boosting immune recovery.
  • May have roles in neuroinflammation and cognitive function, as PF4 also acts in the brain.
• Outlook:
  • PF4 is a promising therapeutic target for age-related hematopoietic decline and possibly neurodegeneration.
  • “Still far from the clinic,” but a “therapeutic blueprint” is emerging.
  • Key Quote ([12:48], Dr. Sen Zeng):

    “PF4 as a key regulator and a promising therapeutic target for reversing age‑related decline in the hematopoietic system and maybe the aging brain...this work opens new avenues for enhancing immune function, improving regenerative capacity, and potentially alter the course of age associated disease.”

PF4, Serum Levels, and Clonal Hematopoiesis (CHIP)

• PF4 and Aging:
  • PF4 levels in serum drop consistently with age in both animals and humans.
  • Age-related changes in the megakaryocyte niche reduce PF4 production, which may drive stem cell aging.
  • Quote ([13:58], Dr. Sen Zeng):

    “During aging the macaryocyte niche really changes. They become smaller and immature so they produce less PF4.”

• CHIP and Leukemia Risk:
  • Lower PF4 creates a permissive environment for clonal hematopoiesis and potentially leukemogenesis.
  • Lab is currently studying PF4 effects on CHIP and leukemia development.
  • Quote ([14:49], Dr. Sen Zeng):

    “Our work already suggested that the aging megakaryocytic niche contributes to the environment that favors clonal hematopoiesis...PF4 loss might cause clonal hematopoiesis directly but it’s like creating a permissive niche.”

Notable Quotes & Memorable Moments (with Timestamps)

• On the IELSG37 trial’s impact:

  • [03:01], Dr. Emmanuel Zuka:

    “The study has proven that in patients achieving a complete metabolic response on PET scans...radiation therapy is no longer needed and this is reducing the risk of late side effects in a population of young people with a high chance of cures.”

• On selecting chemotherapy regimens in PMBL:

  • [06:34], Dr. Emmanuel Zuka:

    “CHOP21 should not be recommended...if you are a believer in R‑CHOP, then give it every two weeks which is much better...which in our opinion is no longer to be recommended.”

• On refining response assessment:

  • [08:17], Dr. Emmanuel Zuka:

    “...liquid biopsy can be complementary to PET scans and allow to understand who are the true failures and who are the false positives.”

• On PF4 as a therapeutic target:

  • [12:48], Dr. Sen Zeng:

    “PF4 as a key regulator and a promising therapeutic target for reversing age‑related decline in the hematopoietic system and maybe the aging brain.”

Timestamps for Key Segments

• 00:34 – Host introduces episode & guests
• 01:10 – Dr. Zuka explains PMBL and rationale for IELSG37 trial
• 03:01 – Results of omitting radiation therapy based on PET
• 04:00–07:50 – Summary of chemotherapy regimen findings and clinical recommendations
• 07:57–09:08 – PET as a response marker, ideas for future improvement
• 09:24 – Dr. Zeng introduces PF4 and HSC aging
• 10:00–12:48 – Key lab findings, clinical implications, and therapeutic potential of PF4
• 13:36 – Discussion on PF4 levels and consequences for stem cells and CHIP
• 14:49 – PF4’s impact on clonal hematopoiesis and future research directions

Conclusion

This episode highlights:

• Optimized treatment strategies and regimens for young patients with PMBL, suggesting a move away from R-CHOP21.
• Promising new biology around PF4 as a critical factor in HSC aging with broad potential for therapy in hematology and possibly neurology.

Listeners come away with actionable insights for both clinical management and the future of basic and translational research.