Blood Podcast – "How I Treat Wiskott-Aldrich Syndrome"

Host: Dr. Laura Michaels, Chief of Hematology/Oncology, Medical College of Wisconsin
Guest: Dr. Sunyoung Pai, Lead Author of "How I Treat Wiskott-Aldrich Syndrome" (Blood, 2025)
Date: October 2, 2025

Episode Overview

In this special "How I Treat" bonus episode, Dr. Laura Michaels interviews Dr. Sunyoung Pai about updated approaches to managing Wiskott-Aldrich Syndrome (WAS), a rare X-linked immunodeficiency with both hematologic and immunologic manifestations. The discussion covers advances in curative therapies, including transplant and gene therapy, updated risk–benefit considerations as disease understanding and treatments evolve, and practical treatment recommendations for clinicians.

Key Topics & Insights

1. Why Revisit Wiskott-Aldrich Syndrome Now?

Timestamps: 00:21–01:47

• Historical Context: WAS has been recognized since the late 1930s, with both hematologic (notably microthrombocytopenia) and immune defects.
• Rationale for Update:
  • New insights into the disease's natural history and long-term outcomes.
  • Advancements in curative therapies (transplant and gene therapy).
  • Evolving risk–benefit profiles for both mild and severe cases.

Quote:

“We have learned things recently both about the course of the natural history of the disease and the factors that impact the outcome after treatment as well as new treatments.”
— Dr. Sunyoung Pai, 00:58

2. A Changing Risk–Benefit Calculation

Timestamps: 01:47–03:00

• Historically, conservative care was more common, especially for milder cases due to risks of treatment.
• New data reveal that even "mild" phenotypes face significant long-term risks.
• Curative therapies (transplant/gene therapy) are now safer and more widely applicable.
• Thus, the criteria for recommending curative intent therapy have broadened.

Quote:

“We have both grown to understand more about how patients thought to have milder disease nevertheless are at risk for severe morbidity and mortality. And we have learned how to make the treatments less intense in terms of their complications...”
— Dr. Sunyoung Pai, 02:10

3. Major Challenges in Treating WAS

Timestamps: 03:00–04:35

• Late Diagnosis: Delayed recognition reduces safe windows for curative therapies.
• Donor Availability: Lack of well-matched donors complicates transplant options.
• Gene Therapy Limitations: Despite potential, gene therapy is often unavailable in the US due to lack of industry support.

Quote:

“The biggest challenge for me personally is that we have a growing amount of evidence of the safety and efficacy of gene therapy...but we have limited and in the US no availability to offer that treatment.”
— Dr. Sunyoung Pai, 03:36

4. Clinical Features and New Manifestations

Timestamps: 04:35–05:50

• Traditional features: thrombocytopenia, immune deficiency, eczema.
• Increasing recognition of renal insufficiency (IgA nephropathy), especially in older patients with Class 1 variants; rare in young children.
• Stressed need for clinicians to be aware of organ-specific late manifestations.

5. Referral and Specialized Care

Timestamps: 05:50–07:35

• Early Referral Essential: Newly diagnosed patients benefit from immediate involvement of immunologists and hematologists experienced in WAS.
• Simultaneous Evaluation for Transplant: The old model delayed transplant evaluation for "less severe" cases; the updated approach calls for early and comprehensive evaluation for all.
• Timely transplant discussions enable preparedness for disease progression.

Quote:

“We would like to argue that ... those should be going together. Those should be part and parcel of the diagnosis of a patient with WAS.”
— Dr. Sunyoung Pai, 06:33

6. Curative Options: Transplant vs. Gene Therapy

Timestamps: 07:35–10:49

• Transplant (Allogeneic): Remains the standard where well-matched donors are available. Rich clinical experience, but risk of graft-versus-host disease (GVHD).
• Gene Therapy: Attractive due to no GVHD risk. Current limitations:
  • Inconsistent WASP protein expression at the single-cell level.
  • Gene therapy eligibility often excludes patients with matched sibling donors.
  • Both approaches currently use similar myeloablative conditioning.
  • Future hope: non-chemotherapy agents for conditioning.

Quote:

“The major risk that distinguishes transplant from gene therapy is the risk of graft versus host disease...gene therapy, on the other hand, of course avoids graft versus host disease. But ... what needs to be improved upon is whether the gene therapy leads to full correction in every cell.”
— Dr. Sunyoung Pai, 08:20

7. Key Takeaways for Clinicians and Trainees

Timestamps: 10:49–12:21

• Disease-Specific Insight: Correction of immune and platelet compartments may differ post-curative therapy; mixed chimerism is less effective for platelets.
• General Principle: Transplant for nonmalignant diseases is fundamentally different from malignant contexts—biology dictates which features are correctable.

Quote:

“Transplant for nonmalignant disease has different considerations than transplant for malignancy...the disease biology itself impacts the potential correction of its features...”
— Dr. Sunyoung Pai, 11:33

Memorable Moments & Final Thoughts

• Laura Michaels’s Reflection:

  “When I was reading this, I thought about all the different kinds of paths of learning...insertional mutagenesis, gene therapy, chimerism...all that was really interesting to me.” (12:21)

• Dr. Pai’s Closing Note: Their goal was to raise awareness within hematology about advances in WAS and to stimulate ongoing learning (“...as WAS enthusiasts we really want the public to be aware of the advances and to learn.” – 12:44)

Summary Table: Important Segments

| Timestamp | Section | Key Points | | --------- | ----------------------------------------------------- | ------------------------------- | | 00:21 | Why revisit WAS? | New data & therapies | | 03:00 | Treatment challenges | Late dx, donor limits, GT access| | 04:35 | Renal disease recognition | IgA nephropathy in older pts | | 05:50 | Early referral and simultaneous transplant evaluation | New standard of care | | 07:35 | Transplant vs. gene therapy discussion | Pros/cons, eligibility | | 10:49 | Fellow/clinician takeaways | Principles, chimerism |

Conclusion

This episode delivers a comprehensive, practice-oriented update on Wiskott-Aldrich Syndrome. Key messages emphasize evolving indications for curative therapy, greater awareness of disease heterogeneity, early and integrated referral patterns, and the promise and challenges of gene therapy. Dr. Pai’s insights specifically encourage practitioners to revisit their preconceived boundaries between supportive and curative therapies for rare nonmalignant disorders like WAS.