Blood Podcast – March 13, 2025

Host: American Society of Hematology
Episode Theme:
Exploring innovative research from recent Blood journal articles, the episode delves into:

1. The efficacy and safety of azacitidine plus venetoclax in high-risk myelodysplastic syndromes (MDS)
2. A new risk scoring system for predicting post-CAR T-cell hematotoxicity in B-cell acute lymphoblastic leukemia (B-ALL)
3. A novel molecular mechanism behind inotuzumab ozogamicin resistance in B-ALL

1. Azacitidine Plus Venetoclax in High-Risk Myelodysplastic Syndromes

Segment Start: [00:02]

Main Discussion Points

• Background:
  High-risk MDS patients have limited treatment options, poor prognosis (median OS <2 years), high transformation risk to AML, and usually ineligible for stem cell transplant due to age/comorbidities. Standard care is hypomethylating agent monotherapy.

• Study Overview:

  • Article: “Efficacy and safety of Venetoclax plus azacitidine for patients with treatment naive high risk myelodysplastic syndromes”
    by Jacqueline Garcia et al.
  • Ongoing Phase 1b study evaluating azacitidine (AZA) plus venetoclax (VEN) in previously untreated high-risk MDS.
  • Initial daily VEN dosing (28 days/cycle) caused unacceptable fatal infections; regimen revised to 400 mg VEN on days 1-14 per cycle.

• Patient Demographics:

  • 107 participants; 86% with high/very high IPSS-R scores.
  • Median age: ~75 years; median follow-up: ~32 months.

• Efficacy Results:

  • CR (complete remission) rate: 29.9%.
  • Responses across all subgroups, including TP53-mutated and high-risk cytogenetic patients.
  • Median OS: 26.0 months (11.2 for TP53-mutant).
  • 40% of transfusion-dependent patients became independent.
  • 42% proceeded to stem cell transplantation.

• Safety:

  • 94% had ≥1 grade 3 or 4 treatment-emergent adverse event (mainly neutropenia, thrombocytopenia, febrile neutropenia, anemia).
  • GI AEs common but usually grade 1-2.
  • 40% had infections; notable SAEs: pneumonia, cellulitis, diverticulitis, sepsis.
  • 59 deaths (20% due to progressive disease); rare deaths possibly drug-related.

• Comparison to Standard of Care:
  “Their results compare favorably with historical outcomes for azacitine monotherapy, including higher overall survival and a longer median duration of CR.” — Host [06:35]

• Ongoing/Future Work:
  The AZA/VEN combo is being further studied in the Phase III VERONA trial.

• Expert Commentary:
  Sangeetha Venugopal & Mikhail Sekaris, University of Miami, highlighted the promising efficacy but cautioned about toxicity:

  “It might be worthwhile to explore whether venetoclax dosing might be reduced even further to improve safety without sacrificing efficacy, particularly for patients aged 80 years or older.” [07:40]

2. Post-CAR T-cell Hematotoxicity in B-ALL & the ALLHT Risk Score

Segment Start: [08:00]

Main Discussion Points

• Background:
  CAR T-cell therapies improve B-ALL outcomes but can cause severe, prolonged cytopenias (notably neutropenia), increasing infection risk.

  • Existing CAR-HT risk index (developed from lymphoma/myeloma) may not work for B-ALL.

• Study Overview:

  • Article: “Development of all Hematotox Predicting Post CAR T cell hematotoxicity in B Cell Acute lymphoblastic Leukemia”
    by Monica S. Nair et al.
  • Analyzed 156 pediatric relapsed/refractory B-ALL patients treated with CAR T (CD19 or CD22).
  • Median of 5 prior therapies; ~50% post-allo transplant at baseline; high disease burden common.

• Findings:

  • Median severe neutropenia lasted 13 days; 49% experienced prolonged severe neutropenia.
  • 62% had grade 3-4 neutropenia; 40% grade 3-4 thrombocytopenia.
  • Only 39% had both neutrophil and platelet recovery by 30 days.

• Assessment of Existing CARHT Score:

  • “Applying the CAR HT index to the full patient group identified 87% of patients as high risk, substantially higher than the 49% who experienced severe prolonged neutropenia... CAR HT did not discriminate well between patients who were more or less likely to experience severe hematotoxicity.” [11:15]

• Development of ALLHT Score:

  • Substituted bone marrow disease burden for ferritin level as a risk factor (since B-ALL patients have higher ferritin, and more frequent marrow involvement).
  • ALLHT identified 47% as high-risk: median neutropenia 26 days (high-risk) vs 4 days (low-risk); OS 9.8 vs 24 months.

• Validation:

  • Score applied in two independent cohorts (Memorial Sloan Kettering, Seattle Children’s). Confirmed discrimination between high- and low-risk.

• Expert Commentary:
  Regina M. Myers (Penn) & Michael A. Pulsifer (Utah) praised the methodology as “an important first step in understanding post CAR T cell cytopenia in patients with relapsed refractory B ALL.” [15:56] However, they noted the need for longer-term studies to understand late cytopenias.

3. DNTT-Mediated Inotuzumab Ozogamicin Resistance in B-ALL

Segment Start: [17:20]

Main Discussion Points

• Background:
  Inotuzumab ozogamicin (INO): CD22 antibody-drug conjugate for relapsed/refractory CD22+ B-ALL. High CR rates (60-80%), but variable duration and resistance common.

  • Known resistance mechanisms: loss of CD22, alterations in BCL2/apoptosis, TP53 mutations.

• Study Overview:

  • Article: “DNTT Mediated DNA Damage response drives Inotuzumab Ozogamycin Resistance in B Cell Acute Lymphoblastic Leukemia”
    by Carolyn S. Escherich et al.
  • Used genome-wide CRISPR knockout in CD22+ B-ALL to identify resistance genes.
  • Top hits: CD22, BAC1, and the novel DNTT gene.

• Role of DNTT:

  • DNTT (DNA nucleotidyxotransferase): a DNA polymerase for repairing double-strand breaks via non-homologous end joining.
  • Knockout of DNTT led to profound INO resistance, including to calicheamicin (drug payload), mitoxantrone, etoposide (other double-strand breakers).
  • No resistance to single-strand break drugs or nucleobase analogs.
  • DNTT knockout blunted DNA damage gene response and associated signaling/protein expression (e.g., H2AX, CDKN1A), reduced apoptosis.

• In Patient-Derived and In Vivo Models:

  • Lower DNTT expression in newly diagnosed patient-derived B-ALL cells correlated with less INO-induced apoptosis in cell cultures.
  • In xenograft mouse models, DNTT-negative blasts were selected and expanded under INO treatment.
  • In phase II pediatric trial, 21/26 patients showed DNTT downregulation after INO (vs 4/26 who lost CD22).

• Implications:

  "DNTT is an important mediator of inoresistance in B ALL that warrants further investigation. This protein might also eventually serve as a biomarker for inoresistance in patients." [23:26]

• Expert Commentary:
  Philippe Rousselot (Universite Versailles Paris Sacle) called DNTT downregulation “a new and important form of INO resistance” and pointed to ongoing INO combination efforts as potential mitigators of resistance risk.

Memorable Quotes & Moments

• On AZA/VEN efficacy:
  “Their results compare favorably with historical outcomes for azacitine monotherapy, including higher overall survival and a longer median duration of CR.” — Host [06:35]

• On toxicity in older adults:
  “It might be worthwhile to explore whether venetoclax dosing might be reduced even further to improve safety without sacrificing efficacy...” — Sangeetha Venugopal & Mikhail Sekaris [07:40]

• On the ALLHT risk score:
  “This new risk score was able to identify high-risk groups who were more likely to have had severe prolonged neutropenia... and who had reduced overall survival.” — Host [14:49]

• On the DNTT resistance mechanism:
  “DNTT is an important mediator of inoresistance in B ALL that warrants further investigation.” — Host [23:26]

• On clinical implications and future research:
  “This study only looked at the first 30 days post treatment. It does not shed light on late developing cytopenias, which are also clinically important.” — Regina M. Myers & Michael A. Pulsifer [16:34]

Useful Timestamps for Key Segments

• [00:02] – Episode introduction and overview of topics.
• [00:48] – AZA/VEN in high-risk MDS: study background, design, and patient data.
• [04:01] – Efficacy and safety results for AZA/VEN.
• [06:27] – Comparative analysis and expert commentary.
• [08:00] – CAR T-related hematotoxicity and the CARHT risk scoring system.
• [11:15] – ALLHT risk score development and validation.
• [15:56] – Expert commentary on ALLHT and implications for future studies.
• [17:20] – Inotuzumab ozogamicin resistance and the DNTT mechanism.
• [19:50] – DNTT knockout and functional resistance findings.
• [22:20] – Patient-derived model results, clinical data, and expert commentary.

Conclusion

This episode provides a comprehensive look at emerging research in hematology, addressing key clinical challenges in MDS and B-ALL through novel treatment regimens, predictive risk tools, and mechanistic insights into drug resistance. The expert commentary highlighted not only the promise of these advances but also the importance of continued safety monitoring, risk stratification, and mechanistic study to inform future therapeutic strategies.