Blood Podcast – Episode Summary

Episode Title: New Research: Mitochondrial DNA in TRALI and Venetoclax-Obinutuzumab in CLL Trials
Date: November 13, 2025
Host: Dr. James (Jim) Griffin
Featured Authors: Dr. John Semple, Dr. Othman (Rothman) Alsawaf

Overview

This episode of the Blood Podcast features two deep-dive interviews on recent studies published in Blood:

1. Dr. John Semple discusses new insights into the pathophysiology of Transfusion-Related Acute Lung Injury (TRALI), especially the role of mitochondrial DNA as a "first hit" through recipient toll-like receptor 9 (TLR9) activation.
2. Dr. Othman Alsawaf presents pooled clinical trial data assessing how patient fitness and dose intensity affect clinical outcomes of Venetoclax-Obinutuzumab in chronic lymphocytic leukemia (CLL), challenging the current dogma on fitness-based treatment selection.

1. Mitochondrial DNA & TLR9: A New First Hit in TRALI

Guest: Dr. John Semple (Lund University, Sweden)
Segment: [00:33 – 07:51]

Key Discussion Points & Insights

• TRALI Overview & Traditional Model

  • TRALI is a leading cause of transfusion-related death; characterized by non-cardiogenic pulmonary edema, fever, and respiratory distress within six hours of transfusion.
  • Traditionally modeled as a "two-hit" process:
    • First hit: Patient’s clinical condition.
    • Second hit: Transfusion components (e.g., antibodies).

• Aging Blood and Mitochondrial Debris

  • As blood products age, especially platelets (stored 5–7 days), they accrue mitochondrial debris.
  • Prior studies link increased mitochondrial particles to adverse transfusion reactions.

• Study Design & Findings

  • Mouse model: Replaced standard first hit (LPS) with purified mitochondria (from mouse liver) intravenously, followed by pathogenic antibody.
    • Mice exhibited severe lung injury within 30 minutes — increased wet/dry lung ratios, cytokine activation, and pulmonary neutrophilia.
  • Pinpointed mitochondrial DNA (mtDNA), characterized by unmethylated CpG motifs, as the key pro-inflammatory actor.
  • Synthetic DNA agonist (ODN2395) also induced lung injury, whereas antagonist (48F) blocked it.
  • Isolated mtDNA replicated the effect; again blocked by DNA antagonists.
  • Other mitochondrial DAMPS (e.g., formyl peptides) caused only mild effects and their inhibition did not block TRALI.

"It seems that mitochondrial DNA in fact can cause a first hit in TRALI."
— Dr. John Semple [04:28]

• TLR9 Dependency
  • TLR9 blockade (with F448 inhibitor) completely negated mitochondrial DNA’s first-hit effect, supporting a direct mechanistic link.

"When we blocked toll like receptor 9, we could completely block the TRALI response."
— Dr. John Semple [05:08]

• Clinical Implications
  • Suggests accumulating DAMPs in stored blood may trigger TRALI in susceptible patients (first evidence in mouse models).
  • Plans to extend to in vitro and eventually clinical studies are underway, recognizing the challenge of direct human studies.

Notable Moments & Quotes

• Therapeutic Possibilities:
  Interleukin-10 (IL-10) has shown promise in dampening TRALI in mice and “alleviating symptoms” in opportunistic human studies ([06:30]).
• Predictive Biomarkers:
  High-risk TRALI groups include ICU and septic patients, but single-patient risk prediction remains elusive ([07:19]).

2. Fitness, Dose Intensity & Clinical Outcomes in CLL Treated with Venetoclax-Obinutuzumab

Guest: Dr. Othman Alsawaf
Segment: [07:52 – 18:13]

Key Discussion Points & Insights

• Background

  • CLL patients are highly heterogeneous in age and comorbidities.
  • Traditional chemotherapy regimens relied heavily on fitness assessments (e.g., Cumulative Illness Rating Scale), reflected in major clinical guidelines.

• Targeted Therapy Era: Rethinking Fitness

  • Recent years have seen a shift to targeted therapies, particularly fixed-duration regimens.
  • Uncertainty whether conventional fitness definitions still predict outcomes with modern agents.

• Study Details

  • Pooled patient-level data from two randomized clinical trials (CLL13, CLL14), focusing on those receiving fixed-duration venetoclax-obinutuzumab (n > 400).
  • About 50% of patients were “fit,” and 50% “unfit” (CIRS >6 and/or GFR <70 ml/min).

• Major Findings

  • Efficacy:
    Both fit (median age 58) and unfit (median age 72) patients had similar response rates and undetectable MRD rates (~80–85%).
    • Progression-Free Survival (PFS): 3-year PFS >80% in both groups.

"The fitness does not really have any prognostic role in terms of how good the response to therapy will be."
— Dr. Othman Alsawaf [11:27]

• Safety:
  Unfit patients had more cytopenias (especially neutropenia), but serious complications (e.g., febrile neutropenia, TLS, infusion reactions) were comparable between groups.
  • Intriguingly, younger/fit patients had more infusion reactions.

"We saw slightly more infusion related reactions in the young and fit patients—which was a contrast to what you would expect."
— Dr. Othman Alsawaf [13:50]

• Discontinuations:
  Unfit patients discontinued treatment more frequently (16% vs. 5%); most had completed at least half of the planned course, possibly explaining maintained efficacy.

• Dose Intensity Insights

  • Reductions in venetoclax dose intensity down to 70% did not affect MRD or PFS.
  • Drops below 70% correlated with suboptimal responses and shorter PFS.

"It’s not necessary to in all patients complete every day with 400 milligrams of venetoclax... we can actually confidently also do dose reductions to manage side effects and tolerability and still gain good efficacy outcomes."
— Dr. Othman Alsawaf [16:08]

Notable Moments & Quotes

• Future of Fitness Assessment:
  Traditional comorbidity-based scores are inadequate for modern CLL therapy. Dr. Alsawaf advocates incorporating “functional parameters” (e.g., grip strength, walking distance), with several ongoing studies exploring comprehensive geriatric assessments ([17:12]).

"We probably need to have a little bit more sophisticated data, things like grip strength or walking distance... These are probably much more relevant tools to capture fitness in CLL."
— Dr. Othman Alsawaf [17:21]

Key Segments & Timestamps

| Topic | Speaker | Timestamp | |-------------------------------------------------------------------|---------------------|---------------------| | TRALI Two-Hit Model & Mouse Studies | Dr. John Semple | 01:02 – 05:39 | | Mitochondrial DNA Mechanism & TLR9 Blockade | Dr. John Semple | 03:51 – 05:39 | | Therapy Implications for TRALI (IL-10, TLR blockers) | Dr. John Semple | 06:23 – 07:09 | | CLL Regimens and Fitness Definitions | Dr. Othman Alsawaf | 08:11 – 10:10 | | Efficacy and Safety Outcomes of Venetoclax-Obinutuzumab | Dr. Othman Alsawaf | 10:11 – 15:00 | | Dose Intensity & Implications for Practice | Dr. Othman Alsawaf | 15:00 – 16:48 | | Rethinking Patient Fitness for Modern CLL Treatment | Dr. Othman Alsawaf | 17:12 – 18:07 |

Tone & Style

• Technical, yet accessible: Both experts explain complex immunological and clinical trial concepts with clarity, referencing real-world relevance for both investigators and clinicians.
• Forward-looking: The discussion emphasizes translational potential, future research priorities, and the need to refine clinical tools for personalized medicine.

Summary

This episode highlights two pivotal advances in hematology:

• The recognition of mitochondrial DNA’s pro-inflammatory role in TRALI pathogenesis could reshape both blood banking practices and future TRALI therapeutics.
• In CLL, venetoclax-obinutuzumab shows robust efficacy and tolerability in both fit and unfit patients, supporting more flexible, individualized dosing and heralding a shift away from traditional, comorbidity-driven fitness algorithms.

For further reading, visit bloodjournal.org.