Blood Podcast – April 10, 2025

Host: American Society of Hematology
Episode Theme:
A detailed exploration of recent breakthroughs in hematology from the journal Blood, focusing on:

• Interleukin-1 signaling in myelodysplastic syndromes (MDS)
• Targeting VISTA in graft-vs-host disease (GVHD)
• Epcoritamab plus chemotherapy in transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL)

1. The Role of Interleukin-1 Signaling in Myelodysplastic Syndromes

Article Discussed:
“IL1, R1 and IL18 signals regulate mesenchymal stromal cells in aged murine model of myelodysplastic syndromes” by Yuko Kawano et al.

Key Discussion Points & Insights

• Background on MDS

  • MDS is a group of hematopoietic stem cell disorders linked to bone marrow dysfunction, aging, and often progresses to leukemia.
  • Inflammation is implicated in MDS development, as patients show raised pro-inflammatory cytokines ([01:17]).

• Investigation of Cytokine Profiles

  • Researchers found elevated levels of IL1 pathway proteins (including soluble IL1 receptor and IL18) in MDS patient plasma compared to healthy controls, underscoring a link between inflammation and MDS ([02:05]).
  • No such differences appeared between young and old healthy donors, reinforcing the disease-specific inflammatory environment.

• Impact of Cytokines on Mesenchymal Stromal Cells (MSCs)

  • IL1β and IL18 were shown to significantly alter MSC function, directly impacting their ability to support hematopoietic stem cell growth and differentiation ([03:39]).
  • In co-cultures, these cytokines increased progenitor cell populations, but they did not have the same effect without MSCs involved—pointing to an indirect mechanism ([04:08]).

• Signaling Pathway Details

  • IL1β activated NF-κB signaling in immortalized mouse MSCs; both IL1β and IL18 triggered P38 MAPK and PI3K/AKT pathways, linked to inflammation and oncogenesis ([05:02]).

• Gene Expression Findings

  • Increased IRAK4 expression (for IL1 signaling) was found in MDS-model mouse MSCs; NLRP3 (inflammasome component) was upregulated in older mouse MSCs ([05:43]).

• Therapeutic Insights – Inhibition Studies

  • Applying IRAK4 and NLRP3 inhibitors reversed MSC proliferation and dysfunction and improved healthy cell counts in a mouse MDS transplant model ([06:30]).
  • IRAK4 inhibition selectively suppressed MDS cells while sparing non-MDS cells, leading to improved hematopoiesis.

Notable Quotes & Moments

• “These findings support the rationale for investigating anti-inflammatory agents as MDS therapies.” ([07:27])
• Commentary by Yan Liao and Chie Guo Kai:
  • “A significant advancement in our understanding of the inflammatory bone marrow niche in MDS… but considerable challenges remain before these findings can be translated into clinical practice.” ([07:42])

2. VISTA as a Target to Prevent Graft-vs-Host Disease

Article Discussed:
“Targeting cell surface VISTA expression on allospecific naive T cells promotes tolerance” by Brent Cohen et al.

Key Discussion Points & Insights

• GVHD Overview

  • Despite multidrug regimens, GVHD remains a critical obstacle for allogeneic transplant patients ([08:15]).
  • GVHD stems from donor T-cell responses against host tissues, regulated by immune checkpoints.

• Role of VISTA

  • VISTA acts as a negative immune checkpoint, maintaining T cell quiescence and self-tolerance.
  • Prior studies indicated a single anti-VISTA antibody dose could protect against GVHD.

• Research Findings

  • The study confirmed that a commercially available agonistic VISTA antibody (8G8) prevented acute GVHD across different mouse transplant models ([09:05]).
  • 8G8 specifically reduced alloreactive donor CD4 T cells during a critical 10-16 hour peri-transplant window ([10:09]).
  • Targeting VISTA on donor CD8+ T cells or host cells was ineffective for GVHD prevention.

• Mechanism of Action

  • Using tracking and inhibitor studies, the protective effect was shown to be due to antibody-dependent cellular phagocytosis of VISTA-bearing CD4 T cells (via macrophages), not intrinsic programmed cell death ([11:11]).
  • Importantly, the therapy preserved graft-vs-lymphoma activity—CD8+ effector cells have lower VISTA expression, thus remain functional.

• Compatibility with Standard Transplant Drugs

  • Calcineurin inhibitor (tacrolimus) during peri-transplant blocked GVHD protection, suggesting calcineurin signaling is necessary for VISTA action ([12:15]).
  • Rapamycin did not interfere, and tacrolimus could be administered later without loss of effect.

• Translation to Human Models

  • In a humanized mouse model, anti-human VISTA antibodies also prevented GVHD, suggesting clinical translatability ([13:11]).

Notable Quotes & Moments

• “Targeting VISTA co-inhibitory pathways on alloreactive donor T cells might be translatable to humans…while still preserving graft versus lymphoma activity…” ([13:51])
• Commentary by Takanori Teshima:
  • “Antivista therapy holds promise…though it would be technically difficult to recapitulate this work in humans, and we must confirm it doesn’t inhibit donor cell engraftment.” ([14:32])

3. Epcoritamab with Chemotherapy in Transplant-Ineligible Relapsed/Refractory DLBCL

Article Discussed:
“Epcoritamab Gemox in transplant ineligible relapsed refractory DLBCL: results from the EPCOR NHL 2 trial” by Joshua Brody et al.

Key Discussion Points & Insights

• Setting the Stage

  • Patients with relapsed/refractory DLBCL who can’t undergo autologous transplant have very poor outcomes—ORR ~26%, CR ~7%, median OS ~6 months ([15:09]).
  • Epcoritamab, a CD20/CD3 bispecific antibody, gained FDA approval in 2023 for these patients; offers an off-the-shelf alternative to CAR T therapy.

• About the EPCOR NHL 2 Trial (Arm 5)

  • Phase 1B/2 trial: 105 patients with CD20+ NHL, relapsed or refractory to ≥1 prior therapy, largely high-risk features ([16:00]).
  • Patients: 35% aged ≥75, 19% bulky disease, 61% stage IV, 10% double/triple hit, 52% primary refractory, and 28% had prior CAR T.

• Efficacy Results

  • At median 13.2 months follow-up:
    • ORR: 85%
    • CR: 61%
    • Median duration of response: 23.6 months ([17:09])
    • CR rate: 74% (1 prior line), 53% (≥2 prior lines)
    • Median PFS: 11.2 months (overall), 26.7 months (CR patients)
    • Median OS: 21.6 months overall; not reached in CR patients

• Safety Profile

  • Common adverse events:
    • Hematological: Thrombocytopenia (73%), neutropenia (65%), anemia (59%)—mainly grade 3 or above
    • Cytokine release syndrome (CRS): 52% (mostly grade 1/2, one grade 3); managed with tocilizumab (23%) and corticosteroids (17%) ([18:20])
    • Neurotoxicity: 3 patients (all resolved, one treatment discontinued)
    • Infections: 72% (COVID-19, pneumonia, UTI); 5 COVID-related deaths among 13 total deaths, reflecting pandemic context.
    • 57% discontinued treatment; main reasons: progressive disease (31%), adverse events/infections (19%).

• Clinical Implications

  • “Epcoritamab plus gemcitabine and oxaliplatin resulted in deep and durable responses…many of whom had high-risk disease.” ([19:48])
  • Commentary by Carmelo Carlos Della:
    • “This study establishes epcoritamab chemotherapy as a potential clinically meaningful option…[but] longer follow-up and minimal residual disease assessment needed to fully evaluate efficacy and safety.” ([20:15])

Key Segments & Timestamps

• MDS and IL-1 Signaling: [00:02]–[07:42]
• VISTA in GVHD Prevention: [08:15]–[14:32]
• Epcoritamab in rrDLBCL: [15:09]–[20:15]

Conclusion

This episode highlighted recent bench-to-bedside hematology research—showcasing new mechanistic insights into MDS, cutting-edge approaches to prevent GVHD, and promising therapy combos for tough-to-treat DLBCL. The host and expert commentaries emphasize the ongoing need for clinical validation while underscoring the excitement around translating these findings into real-world patient care.