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- [00:02]
A
Welcome to this week's bonus episode of Blood Podcast, your source for innovative ideas and cutting edge information. In this How I Treat series, Blood podcast editor Dr. Laura Michaels discusses the Wiscott Aldridge syndrome with author Dr. Sun Young Pai.
- [00:22]
B
I'm Laura Michaels. I'm at the Medical College of Wisconsin where I'm the Chief of Hematology Oncology and a clinical researcher in myeloid disorders. I'm here with Dr. Sunyoung Pai to talk about the How I Treat article on Wiscott Aldrich that's been recently published in blood. Dr. Pai this is not a disease that I'm seeing that often. I'm sure I'm like many individuals, many hematologists not seen it that often. One of my main questions when I started this was why is this the right time for blood to take another look at this relatively rare condition?
- [00:59]
C
Thank you very much. What's called Aldrich Syndrome is a disorder that has been described since the late 30s and it is indeed a very rare disorder. I think that it's a disease that I have often seen written about in blood because it has a combination of hematologic and immunological manifestations, particularly micro thrombocytopenia and multiple different immune defects. The reason why I and my co authors thought that this was a good time to update the Blood readership on the treatment of West Cut Aldridge Syndrome is because 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.
- [01:48]
B
Seems like what you're describing in the article is sort of a new risk benefit calculus as treatment treatments have gotten a little bit safer and as we've looked at longer term follow up for people with the theoretically less intense disease or less severe disease, that risk benefit calculus has to be redone compared to what we learned back in medical school from the textbooks.
- [02:11]
C
You are hitting right on the point of what I and my co authors wanted to get across. In the past it was a simpler decision whether to pursue conservative or supportive management versus curative int. And exactly as you said, 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, such that we can offer curative therapy to a wider range of people and that is indeed changing the risk of the treatment versus the benefits that they stand to gain.
- [03:00]
B
In your practice and the people that you've treated. What's the most difficult challenges facing both patients but also providers? What's the hardest part of treating the condition?
- [03:13]
C
That's a hard question to answer because I think there are many different difficult aspects. One is that when we encounter patients with this disease who are diagnosed late, then we already know we're a little bit behind the eight ball in terms of their likelihood of being safe through a curative intent therapy. Another is that patients who lack well matched donors we know are in a more difficult situation and we have a lot less information about how to perform those transplant safely. And I think right now the biggest challenge for me personally is that we have a growing amount of evidence of the safety and efficacy of gene therapy for this disease. And the general pattern in the field has been for academia to provide the proof of principle and for industry to state interest, but then to pull out. So. So we are left with information that autologous gene therapy could very well be the best option for somebody with poor donor choices. But we have limited and in the US no availability to offer that treatment.
- [04:36]
B
Just as an overview again for everyone. So it seems like treating this, the physician and what you address is sort of when to worry about thrombocytopenia. What is the usefulness of, for example, platelet stimulating thravopoietin agonists as well as immune deficiency issues that come up as well. And then of course finally the eczema. One thing that I hadn't recognized was the prevalence of renal insufficiency in these patients. Is that something that's been newly described?
- [05:09]
C
I would say it's not so much newly described as perhaps growing in recognition, particularly in the older patients with the Class 1 variants. It tends to be a later manifestation. I would say I've encountered very few babies or small children who have IgA nephropathy. It's more typical for me to be referred patients who are older than 10 teenagers. Young adults who have thrombocytopenia lifelong don't have much in the way of infections or eczema, but have IgA nephropathy. So that is probably where that is becoming more recognized.
- [05:51]
B
Understood. What's the right time for patient with Wiscott Aldrich to be referred to a center that sees a lot of these? Is that the first time it's diagnosed? When should patients be moved to someplace that's comfortable with these rare disorders?
- [06:12]
C
I would say there are two stages to that referral. I do agree that patients at the time of diagnosis should be referred to a center that has both Ideally an immunologist and a hematologist with familiarity with the disorder. I would say simultaneously that one of the things we wish to argue with updated information is that that many times patient will be referred for that WASS management expertise. But then there was hesitancy for certain types of patients to be referred to be considered for transplant. And we would like to argue that those should be going together. Those should be part and parcel of the diagnosis of a patient with wass. Because now that we recognize that those class one variant patients not nevertheless have a shortened lifespan and are at risk of progressing to very severe manifestations all of a sudden, it would be much better for those patients to have had a discussion about curative intent therapies, what's available, what does their donor situation look like so that at the time when they progress they can be re evaluated instead of it being a new conversation in extremis.
- [07:36]
B
Your clinical case in the How I treat gives you an opportunity to talk about gene therapy. What is your conversation with patients when you do talk and patients families when you do talk about curative therapy? On how to weigh the decision between transplant versus gene therapy or is transplant always first if a donor is available?
- [07:57]
C
Yes. So first let's presume that there is an available and open gene therapy trial. Of course there are going to be constraints about whether the person is eligible. So then the first thing off the bat is that up until now, patients who have a matched sibling donor have generally not been considered for a gene therapy trial. That's something that can change and that might be affected by other risk factors for poor outcomes such as age. But if we pretend that you're facing a person where there is a gene therapy trial available and they are on the surface eligible, then my usual approach to the conversation is to explain the differences and to explain the different risks on the side of allogeneic transplant. Of course, the major risk that distinguishes transplant from gene therapy is the risk of graft versus host disease. And simultaneously I usually tell them to recall that the treatment with allogeneic transplant is the tried and true. We have decades of experience, we know how to do it, we know which patients have higher risk factors than others to some degree. Gene therapy, on the other hand, of course avoids graft versus host disease. But there, I think what needs to be improved upon is whether the gene therapy leads to full correction in every cell. When you're doing a transplant using a healthy donor, every cell is going to express a normal level of WASP protein that's regulated in each cell type along the developmental path the way it's supposed to be. When we're doing gene therapy with the current vector, which has expression of the WAS CDNA driven by a fragment of the native WASP promoter, we know from looking at the patients that that promoter does not drive exactly normal expression in every cell. So that remains a disadvantage of gene therapy. This is why we hope to develop vectors that more faithfully recapitulate the endogenous pattern of expression. And then finally, what I usually talk to parents about is the fact that for now we still use generally the same agents for conditioning prior to transplant or for gene therapy. There are some subtle differences, but basically it's still the same risk and what we would really like in the future for both transplant and gene therapy to develop agents other than chemotherapy that are capable of clearing out the stem cell compartment.
- [10:49]
B
I was sort of thinking about what our fellows who are listening to this podcast should take away about Withcott Aldrich. Other than, you know, learning the constellation of features, what would you recommend that people take away?
- [11:03]
C
I would say that there's sort of a specific takeaway and a general takeaway. The specific takeaway, of course, is that you know about the disease itself, about the fact that the correction of the different compartments is not guaranteed and the degree to which the immune compartment is more easily correctable in the setting of mixed chimerism than the platelet compartment is directly related to the disease itself, to the biology of the disease, to the competition between a was sufficient and a was deficient cell. The more general principle I would say is for the fellows to recognize that transplant for non malignant disease has different considerations than transplant for malignancy, which of course is the vast majority of the patients who get transplanted as adults is for malignant disease. The same concept that the disease biology itself impacts the potential correction of its features is a theme for sickle cell, for other immunodeficiencies, for bone marrow failure, for storage disorders. So that is what I would want them to kind of think about when it comes to transplant for any non malignant disease.
- [12:22]
B
That's so elegantly stated. And when I was reading this, I thought about all the different kind of paths of learning. What is insertional mutagenesis means, how do we think about gene therapy and what are the idea of chimerism in the setting of gene therapy. All that was really interesting to me. So just want to thank you again for this, how I treat and for the time today.
- [12:44]
C
I and my co authors really appreciated the opportunity to write this article, as was enthusiasts we really want the public to be aware of the advances and to learn. So thank you.
- [12:58]
B
Absolutely. Thank you.
- [13:02]
A
Thank you for listening to this bonus episode of the Blood podcast. To read these articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.