Blood Podcast: Advancing Blood Disorder Treatments Through Precision Therapeutics

Host: Dr. Laura Michaels
Guests: Dr. Terry Parker & Dr. Peter Lenting
Release Date: November 20, 2025

Overview

This episode of the Blood Podcast, hosted by Dr. Laura Michaels of the American Society of Hematology, features two major discussions:

• The results of the SWOG S1702 phase 2 trial evaluating isatuximab for relapsed and/or refractory AL amyloidosis (with Dr. Terry Parker).
• The development of a bispecific nanobody to enhance therapy for von Willebrand Disease Type 1 (with Dr. Peter Lenting).

The theme centers on how precision therapeutics and tailored molecular innovations are advancing treatment options for hematologic disorders.

Segment 1: Isatuximab in Relapsed/Refractory AL Amyloidosis (Dr. Terry Parker)

1. Background, Rationale, and Study Design

• AL Amyloidosis Treatment Landscape (01:02–02:31):
  • At the time of trial design (2019), CD38 monoclonal antibodies were just emerging as promising agents.
  • Daratumumab, a CD38 antibody, was not yet the first-line standard; most relapsed/refractory patients were CD38-naive.
  • First-line therapy typically included the "CYBOR-D" backbone (cyclophosphamide, bortezomib, dexamethasone).
  • No standardized second-line care; options varied widely.

Notable Quote:

“When this trial started enrolling patients back in 2019, we didn’t have the first-line approval of daratumumab that we do today... When we had relapsed or refractory al amyloid patients, they were really cd38 naive at the time of this clinical trial.”
— Dr. Terry Parker (01:18)

• Trial Structure (02:31–03:32):
  • 43 patients registered; 35 dosed.
  • Rare disease required multicenter cooperation.
  • Patients were generally fit (ECOG 0–1); majority in Mayo stage I or II.
  • Most patients tolerated treatment well, likely due to favorable baseline status.

Notable Quote:

“I think one of the challenges is that it is a rare disease so it’s really hard to do a single center study and you really do need a multi center study...”
— Dr. Terry Parker (02:47)

2. Study Endpoints and Efficacy

• Primary Endpoint: Overall Hematologic Response Rate (03:32–04:14):

  • Endpoint focused on suppressing/eliminating amyloidogenic light chains.
  • Achieving very good partial response (VGPR) or complete response (CR) hoped to translate into organ responses.

• Results Summary (04:14–04:57):

  • Overall hematologic response: 77%
  • VGPR or better: 57%
  • Cardiac response: 57% (evaluable patients)
  • Renal response: 50%
  • Key takeaway: Strong hematologic responses translate into organ improvements.

Notable Quote:

“The VGPR or better rate here was 57% and that did translate into organ responses... That really is the take home message.”
— Dr. Terry Parker (04:14)

3. Impact of Prior Daratumumab Exposure (04:57–05:52)

• Two patients had prior daratumumab; neither responded to isatuximab.
• Small sample size (n=2) limits meaningful interpretation—more research needed.

4. Future Directions (05:52–06:36)

• Future studies may evaluate isatuximab for patients progressing off CD38 therapy or in combination with other agents.
• Exploring maintenance settings and strategies to improve deep response rates.

Segment 2: Bispecific Nanobody for Type 1 von Willebrand Disease (Dr. Peter Lenting)

1. Rationale Behind the Approach (06:45–08:42)

• Inspired by advances in hemophilia, Dr. Lenting sought similar precision therapeutics for mild bleeding disorders.
• Hypothesis: Bridge a plasma protein with long half-life (e.g., albumin) and underrepresented endogenous protein (VWF) to increase its lifespan and circulating levels using a bispecific nanobody.

Notable Quote:

“Our idea was, can we not make a bridge between the protein with the long half life albumin and the protein where we do not have enough of it?... If we can make that bridge... then we can increase the half life of this protein and increase the levels...”
— Dr. Peter Lenting (07:20)

2. Preclinical Model and Technical Hurdles (08:42–10:18)

• Developed a murine model expressing human VWF and GP1b for better clinical translation.
• Main technical hurdles: finding the right (humanized) nanobody, but nanobodies are easily humanized due to sequence homology.

Notable Quotes:

“We actually created mice that are expressing human VWF and also human gp1b... so the molecule that we develop can be tested in these mice and can then directly go into clinical trial...”
— Dr. Peter Lenting (08:51)

3. Functional Longevity of Modified von Willebrand Factor (10:18–12:02)

• Key questions: Does prolonged circulation affect VWF’s multimeric structure or function?
• Findings:
  • Nanobody doubles VWF levels for up to 14 days in mice (vs. 3-hour half-life normally).
  • Multimeric pattern preserved; no functional loss in factor VIII or binding ability.

Notable Quote:

“We can actually double the level of VWF between 10 and 14 days... we don’t see any change in the multimeric pattern over time...”
— Dr. Peter Lenting (10:36)

4. Broader Applications and Next Steps (12:02–14:35)

• The technology could be adapted for any plasma protein deficiency.
• Dr. Lenting’s team is exploring similar nanobodies for other bleeding disorders.
• Translation to human trials will require industry partnership.
• Acknowledges that Type 1 VWD is underestimated in its impact on quality of life: recurrent minor bleeds, menorrhagia, psychosocial limitations.

Notable Quote:

“There is a big misconception that type 1 VWD is not a severe bleeding disorder... what we see from all the quality of life studies... the quality of life of these patients is very much reduced...”
— Dr. Peter Lenting (13:08)

Key Takeaways & Memorable Moments

• The SWOG S1702 study shows promising efficacy for isatuximab in a rare, challenging patient population, with high rates of hematologic and organ response.
• Future studies are needed, especially as prior CD38 exposure becomes common due to changing first-line standards.
• Dr. Lenting’s bispecific nanobody program could represent a major leap for patients with mild, chronic bleeding disorders—moving beyond crisis management to long-term quality-of-life improvements.

Timestamps for Important Segments

• [01:02] — Trial background and therapeutic landscape for AL amyloidosis
• [02:47] — Challenges of amyloidosis clinical trials
• [03:32] — Study endpoints and rationale
• [04:14] — Study results and implications
• [05:12] — Impact of prior daratumumab on trial outcomes
• [06:45] — Introduction to Dr. Lenting and rationale for nanobody therapy
• [08:51] — Advantages of the humanized murine model for translational research
• [10:36] — Functional assessment of long-lived VWF
• [13:08] — Real-world impact of Type 1 VWD on patients’ lives
• [14:35] — Next developmental milestones for nanobody therapy

Tone and Style

Both experts conveyed optimism about the direction of targeted, molecularly precise therapies. Dr. Parker was pragmatic about study limitations but enthusiastic about the translation of response rates into real-world benefit. Dr. Lenting combined technical rigor with a patient-centered perspective, highlighting both molecular innovation and the lived experiences of individuals with bleeding disorders.

For further reading, visit bloodjournal.org.