Analysis of IELSG37 Trial Results and PF4 in Stem Cell Aging

Summary

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)

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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.

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Key Discussion Points and Insights

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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.”

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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.”

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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.”

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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

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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.

Transcript

[Podcast Host]

Welcome to the American Society of Hematology Conversations with Blood Authors. This blood podcast episode is hosted by Dr. James Griffin from the Dana Farber Cancer Institute in Boston. He discusses impact of immuno chemotherapy regimens on outcomes of patients Tregs in target tissues, ameliorating GVHD Post HSCT with Dr. Emmanuel Zuka and platelet factor 4 regulates hematopoietic stem cell aging Dr. Sen Zeng.

[Dr. James Griffin]

Hello everyone, I'm Jim Griffin. I'm an associate Editor for the podcast presentations for Blood journal. We have two very interesting articles to discuss today. The first will be discussed by Dr. Emmanuel Zuka from the Oncology Institute of Southern Switzerland in Bellinzona, Switzerland and the topic of this article his impact of immunochemotherapy regimens on outcomes of patients with primary mediastinal B cell lymphoma in the IELSG 37 trial. Dr. Zuka thank you.

[Dr. Emmanuel Zuka]

Primary mediastinal B cell lymphoma is a quite rare subtype of non Hodgkin lymphoma. It comprises about 5% of non Hodgkin lymphomas and is particularly overrepresented in younger white women. The disease shows a peak incidence in the third fourth decade of life. This lymphoma is considered a specific entity in both the current lymphoma classifications because it has peculiar gene expression profile different from the rest of large cell lymphomas and very close to the one of the classical Hodgkin lymphoma. It is constituted by large B cells with clear cytoplasm, prominent sclerosis and very often you can see residual thymic cystic structures in the biopsy consistent with the origin from the thymus B cells. It is characterized by by a very aggressive behavior with a rapidly progressive mediastinal mass, often with local invasions and compressive symptoms. The response to combination chemotherapy and nowadays the combination immuno chemotherapy is usually very good and outcomes are bester than in the other DLBCL types, mainly because of patient younger age, but not just for that. Nevertheless, if initial treatment fails, standard salvage chemotherapy has often poor results. A residual mediastinal mass is commonly observed at the end of induction immunochemotherapy. A full for this reason there has been a very long debate on whether or not consolidation related therapy should be given to this entity and we built and launched as International Externodal Lymphoma Study Group a randomized trial ILG37 to see whether we can omit radiation therapy in patients responding to immunochemotherapy and the study was allowing any kind of induction treatment, provided that the regimen would include rituximab and an anthracycline regimen at the end. 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. A byproduct of this study is the focus of the present article and is the role of different regimens. Unfortunately, the study did not randomize the choice of chemotherapy which was anyway taken by each participating institution before entering in the study for all their patients. What we have seen is that patients receiving induction with R chop given every three weeks, the so called R chop 21 regiment had a much higher rate of post immuno chemotherapy residual disease with the duval score of 5. They were usually responding lesions compared to the baseline PET scan, but still with a pretty high metabolic uptake which is considered a treatment failure nowadays according to the Lugano classification and which is leading people to give them additional systemic therapy or in a few cases just radiotherapy. But nearly all patients with the risk of 5 had additional treatment. Overall the study provide very good outcomes with an overall survival close to 90%. Therefore it's difficult to see a survival benefit in spite of a large population enrollment over 400 cases. But we have seen that this association of inferior metabolic responses with CHOP21 was statistically significant and confirmed by multivariable analysis. Controlling for other risk factors. The patient with chop 21 had 2.6 higher risk of the risk of 5 compared to those receiving chop 14 any two weeks and even more than 5 times higher compared to those receiving DA EPOCR which is the most widely used regimen with this disease. This is what we got and there are other clues supporting this evidence. Patient treated with chop 21 had higher residual uptakes, had higher residual metabolic tumors, not just the metabolic uptakes and therefore in spite of the impossibility to show a survival difference, we think that chop 21 should not be recommended even if at the end we can anyway give additional therapy and get a cure for everybody or nearly everybody. It is better to avoid additional treatment and risk of late sequela and therefore if you are a believer in dossogastic hippocamp, this would be your choice. But also if you are a believer of R chop, then give it every two weeks which is much better. And in patients that are usually young. This is not adding a significant additional toxicity comparing to the three weeks regimen which in our opinion is no longer to be recommended.

[Dr. James Griffin]

A couple of quick questions for you. Thank you for that nice presentation. How good of a marker is of response after initial treatment is a PET scan? Should other tests potentially in the future be used to make that a better marker of complete response or minimal response?

[Dr. Emmanuel Zuka]

That's an important question. Thank you. In fact, in spite of having an association with the Vscore 5, we see that at least half of patients with the risk 5 can anyway be cured with additional therapy and also all patients with the risk of 4, which is another treatment failure at the end of induction had a very good outcome. We will plan to address this topic in future study using CTDNA analysis. The idea is that a liquid biopsy can be complementary to PET scans and allow to understand what who are the true failures and who are the false positive that do not need additional treatment. But this is a matter for the future.

[Dr. James Griffin]

Thank you very much for that discussion. The second topic is entitled Platelet Factor 4 regulates hematopoietic stem Cell Aging. It will be presented by Dr. Sen Jiang from the Department of Pharmacology and Regenerative Medicine at University of Illinois in Chicago.

[Dr. Sen Zeng]

Dr. Shang thanks Dr. Griffin. It's my pleasure to share our recently published work on how platelet factor 4 or PF4 can rejuvenate aged hematopoietic stem cells. Our goal was to address a fundamental question in hematopoietic biology and aging research. What drives stem cell aging? Is it actually reversible? While stem cell aging has often been viewed as an intrinsic decline, our investigation of the aging bone marrow microenvironment revealed an unexpected change in the makaryaestatic niche, a marked decrease in PFO production. This immediately connected to our earlier work from MY Manta showing that mekaryocytes use PFO to selectively restrain the proliferation of myloid based hsc. And importantly, this is exactly the subset that expands with aging. This led us to investigate whether PFO might play a regulatory role in the aging of hematopoietic stem cells. Building on that insight, we found that PFO is a key determinant of stem cell youthfulness. PFO deficient mass display classic features of celebrated hematopoietic aging and include reduced lymphoid output, increased myeloid B, and also the DNA damage. Remarkably, prolonged continuous treatment of old mice with the recombinant PFO restored young characteristics to their stem cells, improved the polarity, reduced DNA damage enhanced their transplantation performance and also very interestingly, this also helps to make a balanced lineage output. Mechanistically, PFO acts through the LDR and CXCR3 receptors and the loss of both receptors produce aging phenotypes that closely mirror PF4 deficiency. Combined with recent reports that PF4 can also reduce neuroinflammation and enhance cognitive function function, it's becoming clear that PFO could have broad applications spanning hematopoiesis, immunity and potentially the aging brain. Importantly, this biology extends to humans. Recent studies have also reported that human mekariocytes undergo similar alterations. Human hematopoietic stem cells from donors across different age groups also respond robustly to PF4, showing improved function properties and the features associated with cellular youngs. This suggests that PF4 signaling represents a conserved mechanism essential for maintaining hematopoietic health through an individual's left spine. This has real clinical implications. In bone marrow transplantation we simply cannot use all the donor cells because they engraft poorly, they are always myeloid, screwed and have limited regenerative capacity. PFO might offer a way to rejuvenate those aging stem cells before transplantation or even improve immune recovery afterward. Taken together, our newly published findings are position PFO as a K regulator and a promising therapeutic target for reversing age related decline in the hematopoietic system and maybe the aging brain. We believe this work opens new avenues for enhancing immune function, improving regenerative capacity and potentially alter the course of age associated disease. So while it's far away from the clinic yet, the therapeutic blueprint is very promising. Now.

[Dr. James Griffin]

Thank you very much. Couple of questions. You mentioned in your article that PF4 levels fall as humans age. Can you describe that a little bit more? And does a fall in PF4 levels in the serum correlate with any functional consequences of the bone marrow?

[Dr. Sen Zeng]

Yes. Studies have been explored that across different species, PFR levels in the serum drops a lot during aging. We know PFR is mainly produced by both mercaryocyte and activated platelet. So that's why what we found is during aging the macaryocyte niche really changes. They become smaller and immature so they produce less pfo. That's why we think, oh, this is a big rhythm. The niche really drives the stem cell aging.

[Dr. James Griffin]

Interest in aging of the stem cell has increased a lot recently with the discovery of clonal hematopoiesis of indeterminate potential or chip. What does PF4 do to chip cells? If you had a chance to look at that.

[Dr. Sen Zeng]

Yeah, that's exactly what we are doing right now. Our work already suggested that the aging makaryaesthetic niche contributes to the environment that favors clonal hematopoiesis. As mekaryocytes age they produce much less PF4 which normally keeps the maloid bare stage in check. When PF4 levels decline, this maloid bear st can expand bond more freely creating a set that may facilitate the emergence of or growth of the clonal hamatopoiesis. So PFO loss might cause clonal hematopoiesis directly but it's like create a permissive niche. And also interestingly our lab is also investigating whether this PFO would drive leukemogenesis. So it's really exciting direction because this platelet acetokine or niche driven mechanism may finally cause the malignant transformation.

[Dr. James Griffin]

Good luck with those studies and thank you very much for your discussion. Thanks to both of you.

[Podcast Host]

Thank you for listening to this blood podcast of conversations with blood authors. To read the articles visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.