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Apr 1, 2021

In today’s episode, Dr. Daniel Weisdorf, hematologist/oncologist and bone marrow transplant physician at the University of Minnesota, discusses advances in allogeneic transplantation amid the expansion of donor registries globally and approaches to limit the morbidity of graft-versus-host-disease after allo HCT.



ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Daniel Weisdorf, a hematologist and oncologist, and bone marrow transplant physician at the University of Minnesota.

Dr. Weisdorf joins me to discuss the recent expansion in potential stem cell sources to treat hematologic malignancies. We'll also discuss approaches to optimize donor choice and limit the morbidity of graft-versus-host disease after allogeneic HCT. Dr. Weisdorf reports no conflicts of interest relating to our discussion today. Full disclosures relating to all episodes of the podcast are available at Dr. Weisdorf, welcome to the ASCO Daily News podcast.

Dr. Daniel Weisdorf: Thank you very much. Happy to be here.

ASCO Daily News: Dr. Weisdorf, your review article in the Journal of Clinical Oncology outlines the design and development of approaches to select the best donor and limit the morbidity of graft-versus-host disease after allogeneic HCT (DOI: 10.1200/JCO.20.01771). The field has grappled with the toxicity and morbidity of GVH for many years. Can you tell us about these challenges?

Dr. Daniel Weisdorf: Well, graft-versus-host disease, it's been the dominant non-relapse mortality and morbidity problem that follows allogeneic hematopoietic stem cell transplantation for its entire 60, 70 years of existence. It's less of a problem than it used to be. But in terms of the morbidity and mortality associated directly with the complication of the therapy, this is the one that is dominant. And because it's a disease that sadly we create in our recipient patients, there's always been an enormous interest in learning how to prevent it or even better, perhaps, modulate it, because there are some associated antineoplastic benefits that come with the development of at least limited severity GVH.

ASCO Daily News: Well, your article highlights the significance of expanding donor options to prevent toxic and morbid graft-versus-host disease. Can you tell us about this and other key takeaways from your review?

Dr. Daniel Weisdorf: Well, all GVH isn't bad, but there is toxic and morbid GVH that we try very hard to prevent because GVH, as I alluded to a moment ago, carries with it the genetic anti-tumor effect, the nickname graft-versus-leukemia effect, but it doesn't have to be leukemia only. So the allogeneic response of the donor cells against the recipient residual tumor can limit the risk of relapse and increase the number of people who are cured.

So the goal was to highlight the issues that are associated with limiting the toxic morbidity and mortality of GVH. And they come from choosing the best donor and preventing the clinical syndrome as best as possible. And it was also clear, and we tried to emphasize through this paper, that the approaches for different donor types may vary because the best approach for HLA match sibling donor may not be the best approach for those who receive a partially matched unrelated donor or a partially matched family donor for that matter.

ASCO Daily News: Dr. Weisdorf, can you give us a sense of the progress that has been made in expanding donor registries globally?

Dr. Daniel Weisdorf: Well, there's almost a donor for everyone nowadays. It's not quite true because there are people with no first degree relatives, siblings, parents, or children who are either available or have the right constitution themselves, meaning they have to be healthy enough to become a haploid identical donor, but about 90% people have a potentially partially matched and suitable donor in their family. People from Northern and Western Europe have about a 70% to 80% chance of finding a very well-matched, allele-matched, if you will, donor in the international registries in the U.S., the National Marrow Donor Program, the Be the Match Registry, but linked to international searching for donors all over the world. But that's for people from Northern and Western European heritage.

People from mixed ethnic or mixed racial backgrounds, or from minorities that are not well-represented in the international registries around the world have a much smaller chance, in the ballpark of 20% for the average African-American who has mixed ethnic backgrounds because they have genetic elements from ancestors from Africa and many genetic elements from ancestors from Europe that create less common tissue types. And therefore, they're less well-represented in the international registries. And the third option - the third non-family option - is umbilical cord blood units, which have many millions to seek out. We know now that matching is not essential at the HLA level, it's beneficial. There are better outcomes with better match cord blood units. And the limitation there is cell dose.

And so bigger people with smaller grafts that are in cord blood banks may have an unsatisfactory outcome. So sometimes double cords, two units at once are used. And there's a variety of promising cord blood expansion approaches, none of which are simple, but there are a number that are very promising and have been used in a variety of platforms to overcome that cell dose limitation.

And then finally we come back to where it all started was with matched brothers and sisters. One in four siblings who have the same parents, will have the same HLA types. But as family size has gotten smaller over the last 100 years, in many parts of the world, the chances of having a well-matched and available family sibling donor are a little less, particularly as transplantation has moved into older ages, whereas now we in most big centers regularly offer transplantation to people in their 50s, and 60s, and with caution to people in their 70s, the ages where most hematologic malignancies exist. Many times, even if they have a matched sibling, the sibling is not medically suitable to proceed with being a donor, because the sibling has their own medical issues of one sort or another that preclude the sibling from being available. 

But we do have all these options. And therefore, it's become more relevant to understand how to create a hierarchy of donor choice that is what is best for the patient, suitable for the experience and protocols that are given transplant center, and adapt the GVH HCT prophylaxis and supportive care measures to make that donor choice as suitable and safe as possible.

ASCO Daily News: Well, I'd like to address donor options for patients from underrepresented minority groups, many of whom have not had acceptable donor options until recently. So surely the recent expansion in donor options is an excellent development for this patient population.

Dr. Daniel Weisdorf: It's made a very big difference in availability of transplantation when it was limited by the availability of donor. So patients from underrepresented minorities or from mixed ethnic and racial backgrounds can look to cord blood units where mismatching is really the norm, or they can look to haploid identical or half-matched relatives within their own family - that can be parents, or siblings, or adult children. And that has produced availability of a donor for patients in minority groups with much greater frequency.

It is important to emphasize that donor availability is not the only thing that has kept people from minority populations from having access to transplantation. They first have to have easy and affordable access to high quality hematology care if it's for hematologic malignancy. And they have to have the insurance support, family support, and proximity to a sophisticated and experienced transplant center, where they can take advantage of that better chance of finding a good donor.

ASCO Daily News: Absolutely. Was there anything in the data, in your review, that surprised you or your colleagues?

Dr. Daniel Weisdorf: I think the surprise is that even though--and this wasn't necessarily emphasized in this particular paper--even though donor options are much more broadly available, we still don't have clear internationally recognized standards of how to balance all the other factors that are important beyond simple HLA compatible or suitable donors because the other issues of the age of the donor, the health of the donor, ABL compatibility, issues of CMV serology, and previous exposure to that virus, family predisposition to certain malignancies in some disease settings, particularly important for non-malignant disorders where transplantation is the right treatment, like inherited hemoglobin disorders, thalassemia or sickle disease, the carrier states may or may not be suitable for transplantation as a donor.

And there are also genetic predispositions to germline mutations and we don't know whether those impair the judgment about suitability for a donor, what is now called CHIP or genetic abnormalities of indeterminate potential, Clonal Hematopoiesis of Indeterminate Potential is what the word CHIP stands for. There's a couple of others; the other acronym is ARCH, but those are people or families who acquire mutations in some of the genetic elements that have been associated with the malignancies or leukemias. They've to-date been recognized as more likely to have cardiovascular disease rather than a predisposition to leukemia, but we don't really have very strong data about whether people with CHIP are suitable and if there's any difference in outcome when they're used for transplantation. We couldn't really explore that, because that's a field that has not been fully developed because the recognition of this as a cardiovascular disease risk is 3 to 5 years old only and hasn't been explored in the depth that we would like.

ASCO Daily News: Indeed, there are a lot of other complex factors at play here, but do you think these advances and improvements in donor options can potentially help accelerate progress across the oncology field?

Dr. Daniel Weisdorf: Absolutely. Now the oncology field still focuses on--when we're talking about allogeneic transplantation, we're still looking at non-malignant disorders that are based in the bone marrow. So metabolic diseases, hemoglobin disorders, anaplastic anemia, and a whole broad array of hematologic malignancies, which is where the vast majority of all the transplants are performed, there has been limited expansion of allografting into the solid tumor arena, because many solid tumors, first, don't express HLA target molecules that make them amenable to the immunologic graft-versus-tumor approach. And the understanding of how to regulate immune responses against solid tumors with checkpoint inhibitor therapy has been much more exciting, still has plenty of limitations, but has been much more exciting in recent years.

What we are learning is that as many more people, particularly older people up until the 60s and at least the early 70s, are suitable candidates for transplantation, because an allograft is first more available and way safer than it used to be even 10 years ago. There's substantially less transplant associated morbidity and mortality than even the last decade. We can figure out when and how to approach those older patients, which is where the majority of people with hematologic malignancies are. We can approach them with allo transplant as a potentially curative therapy. And we really couldn't until or at least people were extremely reluctant to do so until 5 to 10 years ago.

ASCO Daily News: So looking ahead, Dr. Weisdorf, how do you see the field evolving with respect to allogeneic transplantation?

Dr. Daniel Weisdorf: Well, we used to think that allo transplant was primarily a T cell mediated attack on host tissue leading to GVH and host tumor leading to graft-versus-leukemia, but we know that the host environment is much more complex and interesting. So genetic predispositions to things that are related to tissue repair, the microbiome, and its metabolic crosstalk with epithelial targets that can be the targets of GVH or crosstalk with the immune system that is so important for the immunologic reason we do allo transplant in the first place. All of those elements are starting to become first much more important, but also of greater fascination in figuring out how we can make patients better.

It's not just improving the suppression. It might be stimulation of tissue repair. It might be alteration of the microbiome to make it more facilitative of a good allo-response. There's lots more that we need to learn, but it makes the biology much broader then--I don't want to use the word simple immunologic attack of GVH versus GVL--but it's much more intriguing and therefore much more amenable to bringing the new tools of research into the field.

ASCO Daily News: Excellent. Well, thank you, Dr. Weisdorf, for sharing your valuable insight with us today on the ASCO Daily News podcast.

Dr. Daniel Weisdorf: Thank you very much.

ASCO Daily News: And thank you to our listeners for your time today. Dr. Weisdorf's article is available in the transcript of this episode. And if you're enjoying the content on the podcast, please take a moment to rate and review us wherever you get your podcasts.


Disclosures: Dr. Daniel Weisdorf

Consulting or Advisory Role: Incyte, Fate Therapeutics

Research Funding: Incyte

Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.