Blood Podcast – April 3, 2025

Host: American Society of Hematology
Episode Theme:
This episode features summaries of three recent research articles from Blood, focusing on:

• How aging shifts platelet function from hemostatic to proinflammatory roles
• The efficacy of odronextamab, a CD20/CD3 bispecific antibody, after CAR T failure in DLBCL
• The safety and efficacy of Prizlon-cel, a dual-target CAR T therapy, in relapsed/refractory B-NHL

1. Aging Platelets Shift from Hemostatic to Proinflammatory Function

• Article: "Aging platelets shift their hemostatic properties to inflammatory functions" (Afra Anjem, University Hospital LMU Munich & German Center for Cardiovascular Research)

Discussion & Insights

• Platelet Function Beyond Hemostasis:

  • Platelets not only mediate clotting but also regulate immune responses and host defense mechanisms.
  • They arrive early at inflammation sites, facilitate immune cell adhesion, immunosurveillance, and leukocyte extravasation.

• Key Research Question:

  • Do all platelets equally possess hemostatic and immune abilities, or do these roles change with platelet age?

• Innovative Pulse Labeling in Mice:

  • Researchers tracked platelets at different ages, using single-cell functional assays, genetic mouse models, and transfusion experiments.

• Findings:

  • Young (reticulated) platelets are optimized for clot formation and have high thrombotic potential.
  • As platelets age, they lose hemostatic abilities and gain immunomodulatory functions:
    • Greater formation of platelet-leukocyte aggregates.
    • Increased adhesion to neutrophils and enhanced ability to kill bacteria.
    • Upregulation of immune pathway-associated proteins and receptors.
    • Enhanced participation in pulmonary inflammation in acute injury models.
  • Human relevance: Stored human platelet concentrates lost hemostatic function and gained immunomodulatory potential over time.

• Clinical Implications:

  • Transfusing fresher, less proinflammatory platelets might benefit patients vulnerable to inflammation.
  • These discoveries could impact management where platelet life cycles are altered or antiplatelet therapy is applied.

Memorable Quotes

• Host ([02:40]):

  “Young platelets are essentially optimized for clot formation, but as they get older, platelets become more predisposed to carrying out immune-related functions.”

• Laura Gutierrez, Carlos III Health Institute, Madrid ([06:10]):

  “These findings elegantly show how aging platelets shift their functional profile from hemostatic to inflammatory, a finding which might translate to changes in the management of conditions where the platelet life cycle is altered or where antiplatelet treatment is required.”

Notable Segment

• [01:15-08:10]: In-depth walk-through of research design, in vitro/in vivo findings, and potential implications for transfusion strategies and disease state management.

2. Odronextamab Bispecific Antibody Therapy After CAR T Failure in DLBCL

• Article: "Odranextamab Monotherapy after Progression with CAR T Cell Therapy: Primary Analysis of ELM1 Study" (Max S. Topp, University Hospital Würzburg, Germany)

Key Points & Insights

• Background:

  • CAR T therapies (Axi-cel, Tisa-cel, Liso-cel) are transformative in DLBCL but almost half of patients don’t achieve durable responses; median OS post-relapse is ~5 months.

• Bispecifics as a Solution:

  • Bispecific antibodies (targeting CD3 on T cells and CD20 on B cells) can activate T cells to kill lymphoma cells.
  • Odronextamab is one such novel, FC-silenced bispecific antibody. Previous studies in CAR T-naive patients showed 53% response rates.

• ELM1 Study – Post CAR T Cohort:

  • 60 heavily pretreated DLBCL patients (median 3 prior therapies, ~70% CAR T refractory) received odronextamab.
  • Outcomes:
    • Overall response rate: 48.3%
    • Complete response: 31.7%
    • Median response duration: 14.8 months
    • Median PFS: 4.8 months
    • Median OS: 10.2 months
    • At 12 months, 26.5% progression-free; 77% of CRs maintained
  • Safety:
    • 48.3% cytokine release syndrome (all ≤ Grade 2)
    • 20% grade ≥3 infections (most needing IV antibiotics)
    • No grade ≥3 neurotoxicity or CRS

• Exploratory Findings:

  • CD20 expression did not predict response; no negative impact on T cell fitness.
  • Suggests bispecifics can succeed even where CAR T fails.

Memorable Quotes

• Host ([13:45]):

  “The median duration of response to odronextamab was 14.8 months, and the median duration of complete response was not reached.”

• Jason Weston, MD Anderson ([15:20]):

  “…a promising option for a population with limited alternatives. This study begins to address the question of whether bispecific antibodies and CAR T cells have different resistance mechanisms.”

Notable Segment

• [08:30-16:00]: Results and clinical implications, expert commentary on the significance of bispecific antibodies post-CAR T failure.

3. Prizlon-cel: A Novel Bispecific CAR T in Relapsed/Refractory B-NHL

• Article: "Phase 1 Trial of Prisoln captigene autoleucel: a CD19/20 CAR T for Relapsed/Refractory B cell Non-Hodgkin Lymphoma" (Wen Xianyu, Zhejiang University School of Medicine, China)

Key Points & Insights

• Background:

  • Resistance to CAR T, especially due to loss or downregulation of CD19, remains a major hurdle in B-NHL.

• Bispecific Dual Targeting Strategy:

  • Prizlon-cel targets both CD19 and CD20 to circumvent antigen escape.

• Phase 1 Study Highlights:

  • 48 patients with relapsed/refractory B-NHL (mostly large B cell); single-dose after lymphodepletion.

  • Safety:

    • No dose-limiting toxicity observed
    • Most common grade ≥3 events: neutropenia (83%), leukopenia (50%)
    • CRS seen in nearly all, but severe cases rare (only 1 grade 3); neurotoxicity mild

  • Efficacy:

    • Overall response rate (LBCL): 95.1%
    • Complete response (LBCL): 85.1%
    • Median follow-up 30 months
    • Estimated 2-year duration of remission: 66%, PFS: 62.6%, OS: 76.5%

• Expert Commentary:

  • Alberto Musetti & Anna Sereda (Catalan Institute of Oncology) note the “promising clinical results,” emphasizing dual targeting’s value in overcoming antigen-loss resistance and describing the 2-year durability as “especially compelling.”
  • Mentioned are “shortcomings in manufacturing processes” and the need for ongoing trials to optimize and validate this approach.

Memorable Quotes

• Host ([22:20]):

  “Prizloncel had a favorable safety profile and deep, durable responses in this phase one study and could become a promising treatment option for patients with relapsed or refractory B cell NHL.”

• Musetti & Sereda ([24:10]):

  “Prizlon-cel directly addresses antigen heterogeneity and loss, which are key drivers of resistance in single antigen CAR T cell therapies.”
  “The durability of responses at two years was especially compelling.”

Notable Segment

• [16:20-25:00]: Safety/efficacy analysis, expert appraisal, and discussion of future directions for dual-target CAR T.

Conclusion

This episode highlights major advances in understanding the dynamic roles of platelets and in the treatment landscape for aggressive B-cell lymphomas.

• Aging platelets’ drift towards immune functions may require updates to transfusion practices.
• Odronextamab offers hope for DLBCL after CAR T failure, with manageable toxicity and meaningful response rates.
• Prizlon-cel and other bispecific CAR Ts show high promise in surmounting conventional resistance, with durable safety and efficacy seen in early reports.

For more detail, refer to the full articles in Blood (linked in show notes).