Blood Podcast — September 18, 2025

Host: American Society of Hematology
Episode Theme:
Summarizing recent advances in hematology, this episode covers:

• The emerging role of azacitidine in VEXAS syndrome
• A leap forward in high-throughput, precision blood matching for transfusions
• The identification of a novel therapeutic vulnerability in TP53-mutated AML

1. Azacitidine in VEXAS Syndrome: Promising Therapy Amidst Challenges

[00:30 – 09:55]

Main Points & Study Summary

• Study Referenced: Large-scale, retrospective multicenter study by Vincent Jacquier (Hospital Saint Antoine, Paris) and the Frenvex group

• About VEXAS:

  • Severe, complex monogenic disorder with hematologic, autoimmune, and inflammatory presentations
  • Caused by somatic mutation in UBA1 gene
  • Primarily seen in men over 50, rare in women
  • Features overlapping cytopenias, bone marrow vacuoles, and sometimes MDS

• Treatment Landscape:

  • Corticosteroids as mainstay standard
  • Steroid-sparing agents (JAK, IL6, IL1 inhibitors) have limited efficacy
  • Azacitidine—a hypomethylating agent traditionally used for MDS—shows promise

• Frenvex Study Highlights:

  • Patients: 88 with VEXAS syndrome, all had received azacitidine (study period included retrospective DNA sequencing to establish UBA1 mutations)
  • Response Definitions:
    • Inflammatory Response: Clinical improvement, inflammatory markers, steroid reduction
    • Hematological Response: Standard MDS response criteria
  • Key Results:
    • Inflammatory Response: 41% at 6 months, 54% at 12 months; 61% of patients overall
    • Relapse-Free Survival: 90% at 1 year, 85% at 5 years
    • Relapse after Discontinuation: High, but robust response upon retreatment in most cases
    • Hematologic Responses:
      • 65% achieved red blood cell transfusion independence
      • 69% improved erythroid lineage
      • 77% improved platelet lineage
      • 65% had molecular response (notably, nearly half reduced UBA1 VAF to <2%)
    • Adverse Events: 34% experienced infections—significant concern due to either disease or immunosuppression

Expert Commentary Highlights

• David P. Steensma (Ajax Therapeutics) & Rinal M. Patnaik (Mayo Clinic) Comment:
  • "The high rate of response and durability of improvements seen with azacitidine is encouraging." [09:18]
  • Stressed the need for standardized response criteria and clarity on using azacitidine as a bridge to allogeneic transplant
  • Clinical trials ongoing, but majority of treatments remain outside trials, making real-world data like this essential

Memorable Moment

• Quote: "These new data will help inform clinicians on azacitidine, which represents an attractive approach to treating this syndrome." [09:41]

2. Precision Blood Matching: High-Throughput Array Genotyping

[10:10 – 18:18]

Main Points & Study Summary

• Study Referenced: Nicholas S. Gleadal et al. (University of Cambridge)

• Problem Addressed:
  Frequent transfusion leads to alloimmunization—formation of antibodies against donor antigens, leading to complications and challenging long-term care.

• Current State:
  Traditional serological and limited DNA-based typing insufficient for full antigen matching; particularly problematic for regularly transfused patients (e.g., sickle cell disease, transplant candidates).

• Innovation:

  • Blood Transfusion Genomics Consortium developed a high-throughput array for simultaneous genotyping of erythroid, platelet, leukocyte, neutrophil antigens, and markers of ancestry and donor health.
  • Study Sample: 6,946 donors (diverse ancestries)

• Key Outcomes:

  • Genotype Reproducibility: >99% for 17,244 variants
  • Concordance: 99.98% (HEA), 99.90% (HPA), 99.93% (HLA)
  • Detected: rare RHD alleles, GYPB deletion (EU phenotype), 14 high-frequency antigen negatives, 276 hemochromatosis-associated HFE variants

Expert Commentary Highlights

• Aline Flock (Paris East Créteil Univ.) & Thierry Peyrard (Université Paris Cité & Univ. of the Antilles) Comment:
  • "The future of blood group typing may indeed be 'all in one place.'" [17:52]
  • Platform's value: cost-effectiveness, scalability, improved likelihood of finding compatible donor matches
  • Sets groundwork for correlating genetic markers with transfusion outcomes

Memorable Moment

• Quote: "Automated high throughput genotyping array... could alleviate cost and scalability factors that have limited donor typing strategies in the past." [17:45]

3. TP53-Mutated AML: Exploiting a New Vulnerability via BAP1 Loss

[18:24 – 27:03]

Main Points & Study Summary

• Study Referenced: Jacqueline Andrikovich, Cohen Lapp, Alexandros Tatsos (George Washington University)

• Background:
  TP53 mutations confer resistance and poor prognosis in AML, but additional molecular events ("second hits") are assumed necessary for full transformation, as suggested by Li-Fraumeni Syndrome cases.

• Discoveries:

  • BAP1 loss found in ~1/3 of TP53-mutated AMLs—defines a poor-prognosis, erythroid-primed AML subtype.
  • Compound loss of BAP1 and TP53 cooperatively transforms multipotent progenitors to erythroleukemia (validated in transgenic mouse models)
  • Disease shows pro-inflammatory gene expressions, aggressive nature

• Key Therapeutic Insight:

  • Leukemias with BAP1/TP53 deficiency are dependent on BCL-XL, an anti-apoptotic protein. Targeting BCL-XL (via selective inhibitors) reduced leukemic burden and partially restored normal blood cell production in preclinical models.
  • Specificity: BCL-XL inhibition affects leukemic, not non-leukemic, cell lines; pan-BCL inhibitors effective where standard drugs failed

Expert Commentary Highlights

• Tsu Chi Ho & Reuben Kapoor (Indiana University) Comment:
  • "This selective dependency on BCL-XL reinforces the translational relevance of the findings." [26:28]
  • Acknowledged need for further validation in human trials and long-term studies; the preclinical work opens significant therapeutic avenues

Memorable Moment

• Quote: "Andrikovich et al have... identified a new therapeutic vulnerability, opening new avenues for clinical intervention that could improve outcomes in these patients." [26:47]

Notable Quotes & Timeline Overview

| Timestamp | Speaker/Section | Quote/Highlight | |---------------|---------------------|------------------| | 09:18 | Steensma & Patnaik | "The high rate of response and durability of improvements seen with azacitidine is encouraging." | | 09:41 | Commentary Summary | "These new data will help inform clinicians on azacitidine, which represents an attractive approach to treating this syndrome." | | 17:45 | Flock & Peyrard | "Automated high throughput genotyping array... could alleviate cost and scalability factors that have limited donor typing strategies in the past." | | 17:52 | Flock & Peyrard | "The future of blood group typing may indeed be 'all in one place.'" | | 26:28 | Ho & Kapoor | "This selective dependency on BCL-XL reinforces the translational relevance of the findings." | | 26:47 | Ho & Kapoor | "Andrikovich et al have... identified a new therapeutic vulnerability, opening new avenues for clinical intervention that could improve outcomes in these patients." |

Recap & Impact

• Azacitidine offers new hope for VEXAS but requires long-term follow-up and optimal management of infection risk.
• Next-generation high-throughput genotyping for blood antigens could revolutionize transfusion safety, especially for chronically transfused or ethnically diverse patients.
• Discovery of BAP1 loss and its link to BCL-XL dependency in TP53-mutated AML suggests a promising, targeted therapy path for a patient group with few options.

For further reading, access featured articles from this episode at bloodjournal.org.