Advancing Blood Disorder Treatments Through Precision Therapeutics

Summary

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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

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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.

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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.

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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)

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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.

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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

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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.

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For further reading, visit bloodjournal.org.

Transcript

[A]

Welcome to the American Society of Hematology Conversations with Blood authors. This blood podcast episode is hosted by Dr. Laura Michaels. She discusses isatuximab for relapsed and or refractory al amyloidosis, results of a prospective phase 2 trial, SWOG S1702 and a bispecific nanobody for the treatment of von Willebrand disease type 1, with authors Dr. Terry Parker and Dr. Peter Lenting.

[B]

Hi, and welcome to the Blood Podcast. Today I have the happiness of speaking to Dr. Terry Parker and Dr. Peter Lenting. I'm going to start first with Dr. Terry Parker, who's going to talk a little bit about the Southwest oncology Group trial S1702 isatuximab in relapsed and or refractory al amyloidosis results of a prospective phase two trial. Welcome, Dr. Parker.

[C]

Thank you for having me.

[B]

I wonder if you might talk a little bit about the environment of amyloidosis treatment at the time that this study was designed and then a little bit of the background about why something like isatuximab might be helpful in amyloidosis.

[C]

That's a great question. So at the time this trial was designed, CD38 monoclonal antibodies were really just starting to come into their own in both multiple myeloma and both frontline and in relapsed refractory al amyloid. So when this trial started enrolling patients back in 2019, we didn't have the first line approval of daratumumab that we do today, which gained approval based on the Andromeda clinical trial in combination with cyclophosphamide, bortezumab and dexamethasone. When we had relapsed or refractory ill amyloid patients, they were really cd38 naive at the time of this clinical trial.

[B]

And at that time, what was the typical first line for al amyloid?

[C]

So the majority of patients ended up getting the cyclophosphamide bortezomib, dexamethasone or cyber D or VCD backbone. However, large majority still would relapse or have refractory disease. Those patients then received a variety of treatments, but there's not a standard of care in that second line setting someone onto autologous stem cell transplants. Others use different proteasome inhibitors or immunomodulatory agents.

[B]

Can you tell me a little bit about your study? I understand about 43 patients were registered and about 35 patients dosed. What makes it hard to run a trial in amyloid. And did you run into difficulties with getting people through the treatments?

[C]

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 such as what can be done through a cooperative group, which was great that this was able to be conducted through swog. The patient population being a clinical trial was relatively fit. I would say the majority of our patients here were ECOCHG performance status 0 or 1 and the majority were revised or European modification of the Mayo classification, Mayo stage one or two. So that may have contributed to the majority of patients tolerating the therapy very well. When looking at the safety profile and and their ability to receive the majority of treatments.

[B]

Tell me a little bit about the choice of overall hematologic response rate as the endpoint for this trial is that typical enameloid protocols so you really want.

[C]

To try to suppress or eliminate the light chain production as that is what's getting deposited into the tissue. The thought process is that if you can achieve a hematological very good partial response or complete response that that would hopefully translate into organ respons down the road.

[B]

Great. So the overall results seemed pretty good. I'm not a myeloma doctor, so I wasn't exactly know what to expect from a single arm study. What are the main take homes of the study results?

[C]

The primary endpoint here was the overall hematological response which was 77%. But I think what we need to look at is really those achieving a very good partial response or cr because again you really want to eliminate that light chain production. And the VGPR or better rate here was 57% and that did translate into organ responses. Again this is a phase two study, so the numbers are relatively small when you look at it. But the cardiac response for patients who are valuable was 57% and the renal responses were 50%. So I think that really is the take home message that if we can achieve a good hematological response, it did translate into organ responses for these patients.

[B]

Now I know folks who'd received prior daratumumab were allowed on this study. What can we know, if anything about the fact that the patients with the prior daratumumab didn't respond to isatuximab?

[C]

That's a very good point. So there were only two patients in the current clinical trial that had prior daratumumab exposure. Patients were allowed on as long as they were not considered refractory and they had to have been at least 56 days since their last exposure. So the one patient had a relatively recent exposure of just over two months, while the other one was a little bit longer at 6 months. But given the cell size of N of 2, I think it's really hard to kind of draw conclusions from that. And additional trials would be needed to really examine what is the role of isatuximab, especially now as the majority of patients in al amyloid are receiving daratumumab as first line therapy.

[B]

What do you speculate will be the next kind of study to understand the role of isatuximab in these?

[C]

I think you really have to look at those who have had DARA not being refractory, but currently there's no standard maintenance. If you look at the Andromeda clinical trial, they continued single agent daratumumab up to 24 cycles and then typically it's discontinued and those patients go on observation. So for patients who potentially progress off of CD38 monoclonal antibody, could ezatuximab be used in that setting or potentially could you use it in combination? So. So adding it to additional agents and whether or not there would be improvement in that VGPR and CR rates.

[B]

Fabulous. Is there anything else that I've missed that you want to bring up to the audience?

[C]

No, I think we've hit the highlight. So thank you so much.

[B]

Thank you so much for participating. I'm here with Dr. Peter Lanting who's going to discuss with this the study that he's the one of the authors, Anna, about a bispecific nanobody for the treatment of von Willebrand's disease, type 1. Dr. Lenting, I found this a fascinating article. I wonder if you might first talk about how you approach the question of how we could increase the half life of endogenous von Willebrands and why this sort of. You came up with the idea of exploiting this particular pathway.

[D]

Thank you for having me on your podcast. It's an honor to be there. How did we come to this type of study? I'm working in bleeding disorders now for 30 something years and there's been a lot of developments, especially with hemophilia. And there is actually one big group that is a bit underserved in all this and that are patients with the mild bleeding disorders, whether it's hemophilia A or whether it's with disease. And actually we wanted to develop something that could serve this, this group of patients. By thinking about that. We thought of tools that nature already had given to us. And that is some proteins that have a very long half life, like albumin or IgG, that are being recycled via the FCRN pathway. The second tool is that in these patients, the protein, the target protein, in this case will Braun factor, is already present in the patient or there is just not enough of it. And 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? And if we can make that bridge, that link between the two proteins, then we can increase the half life of this protein and increase the levels of the protein of which there is not enough in the patients. That was a bit the background of why we started to do this study.

[B]

And what kind of comparability is there between von Willebrand's in a murine model and von Willebrand's in a human patient?

[D]

Actually, there is a difference because normally human VWF does not react with murine platelets. And to make it as much as possible close to the human situation, 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 the clinical trial without having to change the antibody or using a surrogate antibody for the testing in the preclinical situation.

[B]

That's fascinating. Were there any other big hurdles to developing something in this particular model that you want it to be as translational as possible? At the end, there are two things.

[D]

The first one is that you have to find the right antibodies, the right nanobodies in this case, because not all nanobodies will do what the antibody that we have found is actually doing. And the second is that you of course have these nanobodies. They are not of human origin, so you have to humanize them. Well, the good thing is that nanobodies, they are very homologous to the VH3 sequence of human IgG, so they are very easy to humanize. You only need a few amino acids to change in order to become compatible with the human situation. So it is a bit of a hurdle, but finally it's not a big hurdle to overcome.

[B]

That's great. What are some of the differences, if any, in the function of von Willebrand's as it ages? If we're leaving something in the circulation for 10 additional days, does it work the same as when it was just produced or does it degrade?

[D]

That's a very good question. And that's something we have been looking into. We know from other studies that one of the reasons that VWF is going to be cleared over time is that sometimes the sialic acids that are covering the glycans on VWF that they can be removed and that will accelerate the clearance of vwf. What we see in the mice is that if we give a single injection of the nanobody, we can actually double the level of VWF between 10 and 14 days. So that's much longer than the three hour half life that we normally see in the mouse. So there were two things that were very important to check. The first one is VWF is a multimeric protein, Willebrand factor. So the first question was can we actually recycle all the multimers, even the high molecular weight multimers? And actually we can. We don't see any change in the multimeric pattern over time and all that. And the second thing that we needed to check is whether the molecule stays functional over time. And also that seems to be the case in test for GP1B binding or collagen binding with this VWF. Of course, another important aspect of VWF is that it keeps factor VIII in the circulation. What we see is that if there is an increase in vwf, the factor VIII levels also go up over time and they stay also increased over the same period as VWF is being increased.

[B]

That's fascinating. Are there other diseases where this type of approach that you're aware of, that this type of approach is being used?

[D]

I know that a company, hemap, is trying to do the same for vwd. So that's sure. I'm not sure whether people use the same approach for other disorders, but in our lab we're actually trying to develop this approach also for some other bleeding disorders. We are currently developing nanobodies against different type of proteins and actually this approach can be used for any plasma protein of which there is not enough. So it can have a very broad applicability.

[B]

What are the steps that it needs to take before we can think about using this in humans? And then another question is early. Like von Willebrand's factor, type 1 is not necessarily associated with life threatening events. In which cases of like, in which human clinical situations would you think that this kind of treatment would be judicious?

[D]

There is a big misconception that type 1 VWD is not a severe bleeding disorder. Indeed it's not severe in that the bleeds are not life threatening. But what we see from all the quality of life studies that have been done. And that's particularly true for women and girls, that the quality of life of these patients is very much reduced. They have very frequent minor bleeds. So I know examples of patients who do not want to go to the restaurant anymore because they are afraid of having spontaneous nose bleeds. Amenorrhagia is very is actually frequently found in patients with type 1 filibront disease. I know a girl who doesn't want to go to the beach because she has bruises all over her legs, et cetera. So the disease has a lot of impact on these patients. And what we think is that if you can provide a EC type of treatment that means subcutaneous injection once or twice a month, that you increase the levels of the protein and that will reduce the bleeding tendency in these patients. Well, where are we with our molecule? We have advanced a lot in the pre clinical development. We have a humanized variant that has been tested all over the place. There has been a production has been put in place. We are now looking for partners to do the next step because we are just a small research lab and we cannot do that by ourselves.

[B]

That's very exciting. Thank you so much. It's been really interesting to walk through this study with you and I really appreciate your time.

[D]

Thank you very much. It was a pleasure to discuss it with you. Thank you very much again for having invited me.

[B]

Absolutely.

[A]

Thank you for listening to this blood podcast of conversations with blood authors. To read these articles, please visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.