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Life-Changing Gene Therapy for Beta-Thalassemia Patients with Jennifer Schneiderman, MD

A novel gene therapy promoted transfusion independence in more than 90 percent of adult and pediatric patients with transfusion-dependent beta-thalassemia. Study co-author Jennifer Schneiderman, MD, discusses results, published in the New England Journal of Medicine.


 Jennifer Schneiderman, MD

“It's been actually really inspiring to see these patients…because they were just so hopeful and so brave for embarking on this journey, seeing how their lives have been changed and not really being chained to their medical home as much as they had been. Seeing them be able to get away from their thalassemia has really been amazing.” 

— Jennifer Schneiderman, MD

Episode Notes 

For patients with beta-thalassemia major, the only curative treatment so far has been allogeneic hematopoietic stem cell transplant, which requires finding a compatible donor and runs the risk of graft versus host disease. Jennifer Schneiderman, MD, co-author of the new study, discusses her involvement in a phase 3 clinical trial, recently published in the New England Journal of Medicine, in which patients underwent a novel gene therapy with remarkable results, eliminating the need for an allogeneic hematopoietic stem cell transplant.

  • Schneiderman specializes in pediatric stem cell transplantation at Feinberg, and in particular, finding innovative and less toxic ways of performing stem cell transplants in children with various types of cancers and hemoglobin disorders, including those with thalassemia and sickle cell disease.
  • Beta-thalassemia is a disorder of red blood cells in which mutations occur in beta-globin genes that either reduce or prevent the production of beta-globin. This leads to an imbalance in hemoglobin molecules that shortens the lifespan of red cells.
  • There are over 300 known mutations in beta-globin, making beta-thalassemia a disorder of great clinical variation.
  • Largely diagnosed in infancy, beta-thalassemia typically shows up in most newborn screening programs for infants born in the United States. 
  • Beta-thalassemia occurs in about 60,000 births per year worldwide, most frequently in people from Mediterranean countries, North Africa, the Middle East, India, Central Asia, and Southeast Asia. 
  • Patients with beta-thalassemia minor make a reduced amount of beta-globin, but don't need red cell transfusions. Patients with beta-thalassemia major make virtually no beta-globin and have zero normal red blood cells, making them transfusion-dependent.
  • Life-long blood transfusions lead to poor quality of life for many including shortened lifespan, living only into their 40s, as well as complications from transfusions like iron overload. 
  • For patients with beta-thalassemia major, the only curative treatment so far has been allogeneic hematopoietic stem cell transplant, which requires finding a compatible donor such as a sibling and runs the risk of graft versus host disease. The treatment also requires chemotherapy.
  • In the novel gene therapy, phase 3 clinical trial conducted at the Ann & Robert H. Lurie Children’s Hospital of Chicago, patients have instead undergone autologous hematopoietic stem cell transplantation, meaning stem cells from the patient’s own body are altered. This therapy eliminates the need for a donor, and while it still requires chemotherapy, the hope is to eventually eliminate the need for it. 
  • A remarkable 91% of patients in this clinical trial were rendered transfusion-independent after receiving the novel gene therapy.

    Additional reading
  • Review article: Clinical Classification, Screening and Diagnosis for Thalassemia
  • Previous phase of this clinical trial: Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia
  • Review: Alpha and beta thalassemia

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Recorded on April 13, 2022

Erin Spain, MS [00:00:10] This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. A rare inherited blood disorder, beta-thalassemia major, diagnosed in infancy can require lifelong red blood cell transfusions in order to stay alive. However, a novel gene therapy being studied at Northwestern and the Ann and Robert H. Lurie Children's Hospital of Chicago might change that. Dr. Jennifer Schneiderman, an associate professor of pediatrics in the Division of Hematology, Oncology and STEM Cell Transplantation at Feinberg, joins me with some details of remarkable findings recently published in the New England Journal of Medicine, in which 91 percent of patients were rendered transfusion independent after receiving this novel gene therapy. Welcome to the show, Dr. Schniederman.
Jennifer Schneiderman, MD [00:01:07] Hi, Erin. Thanks so much for having me.
Erin Spain, MS [00:01:09] You were the coauthor of the study in the New England Journal of Medicine, and your specialty is pediatric stem cell transplantation. Give me a little background about your clinical work and research here at Northwestern.
Jennifer Schneiderman, MD [00:01:20] My main interests are finding new and innovative and less toxic ways of performing stem cell transplants in kids with lots of different types of disorders, but in particular kids with different kinds of cancers, and of course, relevant to today's discussion, kids with different disorders of hemoglobin, including those with thalassemia and sickle cell disease.
Erin Spain, MS [00:01:45] Now you work with a lot of these families directly. Tell me what this experience is like for them with these great outcomes that they've had after receiving this novel gene therapy.
Jennifer Schneiderman, MD [00:01:56] It's been actually really inspiring to see these patients and especially the first couple of patients who came through. I mean, they're all inspiring, but the reason I say, especially the first ones, because they were just so hopeful and I think so brave for embarking on this journey, seeing how their lives have been changed and not really being chained to their medical home as much as they had been. Seeing them be able to get away from their thalassemia has really been amazing.
Erin Spain, MS [00:02:25] Tell me about thalassemia. How does it impact the lives of patients?
Jennifer Schneiderman, MD [00:02:29] Beta-thalassemia, in particular, is a disorder of red blood cells, and this disorder has great clinical variation. It occurs in about 60,000 births per year worldwide, most frequently in people from Mediterranean countries, North Africa, the Middle East, India, Central Asia, and Southeast Asia. And basically, we all have adult hemoglobin molecules in our red blood cells. So we all have a different kinds of hemoglobin. And our most prominent type of hemoglobin when we're not babies anymore is adult hemoglobin. And we have two alpha chains and two beta chains. So the problem with beta-thalassemia is that we have mutations in the beta-globin gene that either reduce or prevent the production altogether of beta-globin. And so that makes you imbalanced in your hemoglobin molecules, where you have too many alpha chains and not enough beta chains, and that makes your red cells not survive as long. Interestingly, there are over 300 known mutations in beta and the beta-globin, so there are a lot of different variations like I mentioned. So some patients like make a reduced amount of beta-globin but don't need red cell transfusions. Those kids have beta-thalassemia minor. Some patients have mutations where they make virtually no beta-globin, and so they really don't make any normal red blood cells. And so they have thalassemia major. And those kids are also referred to as having transfusion-dependent thalassemia, and those are the patients that we're talking about today. And so those kids have the need for after they get out of infancy to get red blood cell transfusions like you mentioned, every three to four weeks for their entire lives unless they try to undergo curative therapy.
Erin Spain, MS [00:04:17] And again, these children, they are diagnosed at birth, right?
Jennifer Schneiderman, MD [00:04:21] So all the states in northern America have newborn screening programs, and most of the states have testing for thalassemias on newborn screens. If a child is not born in the United States and instead comes to the U.S. from another country, then thalassemia is diagnosed on a basic blood count or CBC. You can look at the child's hemoglobin level and the size of their red cells, and then you can do a test called electrophoresis. And so those testing put together can give you the answer as well. But kids born in the United States, you should be able to catch it most of the time in most places in the United States on the newborn screen testing.
Erin Spain, MS [00:05:02] So aside from the inconvenience of having to get transfusions every three to four weeks, in what other ways is this condition impact these children?
Jennifer Schneiderman, MD [00:05:11] Some kids, you can use a regular peripheral I.V. so they get poked every three to four weeks, or some children might need placement of a more permanent IV if they have trouble getting poked every three to four weeks, so some kids might need a central line. That's a big deal because those can get infected, so those can have long-term issues as well. It's poor quality of life for a child to have to not be in school every three to four weeks. And then in addition, when you get transfused every three to four weeks, you can run into issues. You will run into issues with iron overload from getting too much iron from your blood transfusions.
Erin Spain, MS [00:05:55] And then does this impact life expectancy as well?
Jennifer Schneiderman, MD [00:05:59] Yes. So if someone is not treated for thalassemia and they do not get blood transfusions, a child would have a big liver, a big spleen, because that's where your red cells that aren't healthy kind of get collected in your body and then also places in your body that make bone marrow. So basically your marrow spaces in all of your bones get bigger. They expand, so you get what's called bossing of the bones, so your bones don't look normal. Kids don't grow very well, but the bones can be brittle and deformed. That's a problem if you're not getting transfused. So poor growth, poor bone health, big organs in your abdomen. And then if you are getting transfused and not having your iron taken out, you run into a lot of issues with iron overload that affect your heart, your lungs, your liver, your thyroid, your pancreas. So kids can get diabetes. And for sure, if you're not transfused, the life expectancy is in the late teens. Kids who are transfused and not chelated, kids can die of heart failure by their early to mid-20s, and life expectancy for thalassemia in patients that are transfused and effectively chelated is into the forties or so.
Erin Spain, MS [00:07:14] You mentioned genetics – that there are certain populations that seem to be more at risk for this. Tell me what role genetics play in these disorders.
Jennifer Schneiderman, MD [00:07:22] In general, patients with beta-thalassemia minor have inherited only one abnormal gene, and patients with beta-thalassemia major have two damaged genes. So it's inherited from your parents. Patients with mild disease, as I mentioned before, make enough beta-globin to not need transfusions and those who don't are transfusion dependent. So it's inherited through your parents in an autosomal recessive parent, meaning you need to inherit the abnormal genes from each parent in order to have the more severe form of the disease.
Erin Spain, MS [00:07:57] There have been some breakthroughs, including a specific type of stem cell transplant. Tell me what's been happening in the field -- we'll get to the results of the study soon -- but tell me what's been happening in the past and some of the limitations of some of those treatments.
Jennifer Schneiderman, MD [00:08:13] So the only [therapy] to date before this new therapy that you will talk about in a couple of minutes, the only curative therapy has been what we call an allogeneic hematopoietic stem cell transplant. So allogeneic means from someone else and hematopoietic, just hematopoietic stem cells are the stem cells that make your hematopoietic system, which are your white cells that fight infection, your red cells that carry oxygen to your tissues and your platelets that help keep you from bleeding. So allogeneic hematopoietic stem cell transplant is just that: hematopoietic stem cell transplant from someone else. So what we do is if a family is interested in seeking curative care for their child who has beta-thalassemia major, we seek to find an appropriate donor. The safest donor to find for a child with beta-thalassemia major is an unaffected and perfectly matched brother or sister, and so we would need to find a matched brother or sister who doesn't have beta-thalassemia major also. And so one of the big hurdles in proceeding to an allogeneic hematopoietic stem cell transplant is finding an appropriate donor. So that's one issue that we need to deal with. The other types of allogeneic transplants that are successful and fairly safe is a well-matched, unrelated donor. And so if a child does not have a brother or sister, we can look through the National Donar Program Registry to see if there's a well-matched, unrelated donor. But generally speaking, for beta-thalassemia major, we don't look to find mismatched unrelated donors at this point in time. So those are really our major options for an allogeneic transplant. If we have a donor available, that's great. But going to transplant does come with a lot of risks. So in order to go to transplant, you have to give the child chemotherapy to prepare their system to receive the stem cells, because if we just gave stem cells, their immune system would fight them off, and so you can't just do that. So kids get chemotherapy prior to the transplant and then they have very low immune systems because your white count goes to zero during the time after you get the stem cells but before they start working. And you get medicines to prevent a problem called graft versus host disease, which is where the new stem cells can wake up in the recipient's body and realize that they're actually not in the right place. And they can be pretty unhappy with that. And so the new stem cells, the graft, can fight off parts of the body, the host. And so those medications cause suppression of the immune system and can put kids at risk for infections and other problems. And so there are definitely lots of risks that can come with an allogeneic hematopoietic stem cell transplant. So even if you have, you know, an appropriate donor, it's certainly not necessarily an easy road. And there are risks, including those things that I mentioned, the graft versus host disease, infections, toxicities to your organs, and there are some fatalities that can occur during these kinds of transplants. So while it does provide the potential for a cure, there are definitely a lot of hurdles that come along with it.
Erin Spain, MS [00:11:35] And how often do the stars align that there is a sibling who's a perfect match and that everything goes according to plan?
Jennifer Schneiderman, MD [00:11:43] So with each pregnancy, there's a 25 percent chance that a brother or sister is going to match each other. So it just depends on how the stars align for that. There are ways that families can go about planning to have a matched sibling who's unaffected and some families do opt to pursue those options, but not all families do. I think, you know, looking at sibling transplants for thalassemia, they definitely can be safe and effective. So in children, young children who come to an allogeneic stem cell transplant with a brother or sister who's perfectly matched, who don't have any evidence of iron overload in their liver in particular, so those who have healthy livers, there's actually greater than 90 percent survival. Kids that are under seven years of age, who have a brother or sister donor, who are using bone marrow as their stem cell source, the outcomes can actually be very good, but those are a lot of hurdles to kind of have to get through.
Erin Spain, MS [00:12:44] Enter the need for a different type of therapy. And that's where this New England Journal of Medicine article comes in and the clinical trials that you've been conducting at Lurie Children's Hospital of Chicago. Tell me about these trials and the novel therapy used and the promise that this holds for these patients.
Jennifer Schneiderman, MD [00:13:01] The concept of this is actually not necessarily new. There have been animal models used for many years looking at the use of gene therapy, how to change your own stem cells and reinfuse them to trick your new stem cells in how to make genes better or genes properly. So basically, what can happen is we can take someone's stem cells out of them, so you don't need a donor from somewhere else anymore. You can take your own stem cells, and if you have a way of altering a particular gene, then you can do that. You can take the stem cells out, you can alter the gene. You can then prepare the person by again giving them chemotherapy and give them their own stem cells back. And then once the stem cells start to work again, the goal is to have that new gene that you've inserted make the gene now properly. And so now you've overridden the problem. And the hope is that then they will make that gene properly for the rest of their lives. So you've taken out the problem, the hurdle of needing to find a donor, you've taken out the problem of graft versus host disease. You've taken out the problem of needing to use immunosuppression medicines to prevent the graft versus host disease or to treat the graft versus host disease if it happens. For right now, you've not taken out the problem of needing chemotherapy, but that's a goal for the future as well. But really, the mainstay of the concept of it is to take your own stem cells and change them so that they no longer make the wrong kind of gene. They make the proper kind of gene.
Erin Spain, MS [00:14:46] So you are in phase three of this clinical trial right now. Tell me about the results.
Jennifer Schneiderman, MD [00:14:51] We've had really exciting results. We've enrolled 22 patients in phase 1 and 2 studies and 41 patients in the phase 3 study. In phase 1 and 2 studies, 15 of the 22 achieved transfusion independence, meaning never needed another transfusion. And in the phase 3 study so far, 34 of 38 who are evaluable have achieved transfusion independence, and so what that means is that a year after transplants, they've not gotten any red cell transfusions in the year after transplant. And there are different ways of approaching these gene therapies. This particular study looked at using what's called a lentiviral vector. And so basically that a virus that can infect dividing cells to insert functional copies of the beta-globin gene and that's got a substitution at an amino acid that can insert into the stem cell.
Erin Spain, MS [00:15:56] What do you think this could do for life expectancy for these patients?

Jennifer Schneiderman, MD [00:16:00] Conceptually could improve it significantly as long as there are no real long-term side effects. So what we have to remember is that we're still using chemotherapy medicine, so there could be some long-term side effects that we're not yet aware of. Although I will say, I'll point out that the follow-up data that we are presenting at the upcoming transplant meetings at the end of this month do follow patients out close to seven years. So we are following patients out really far. Patients who have achieved transfusion independence have not needed transfusions. And so far this has been very durable and so far our patients have not shown any long-term effects from the chemotherapy. Now, whether that will be true 20 or 30 years from now, we'll have to see. But so far, it's really quite promising.
Erin Spain, MS [00:16:53] Are you able to enroll adults in the study too, or is this mostly children?
Jennifer Schneiderman, MD [00:16:58] So there were both children and adults enrolled in these studies. They were actually in the beginning, mostly adults. And then in the subsequent studies, we went down to as low as four patients who were four years of age.
Erin Spain, MS [00:17:10] What happens next at this point? This is seven years into the study. Is that right?
Jennifer Schneiderman, MD [00:17:15] Right. So what can come now is the commercialization of the product, so basically the FDA allowing the company to make this a commercial product. And so what would happen would be allowing the company to have hospitals that are deemed centers that are available to provide this therapy for patients, meaning a patient with beta-thalassemia or parents of children with beta-thalassemia would know of particular centers in the United States where they could go themselves or bring their children for this therapy. And so what would happen is they would be able to go for a consultation. There would be particular clinical guidelines that would need to be followed to make sure that it's safe to do because again, we're using chemotherapy, so we need to make sure that they're healthy enough to undergo the treatment. We give patients medicine to make their stem cells go from their bone marrow out into their peripheral blood, and we collect those and then the stem cells get shipped off for manufacturing and then they come back several weeks later, and that's when they get their chemotherapy and their stem cell transplant. One thing just to note is that the actual transplants, when they're in the hospital, from the time that they get admitted to the hospital for their chemotherapy through their cell infusion or the transplant to the recovery, they're in the hospital for about six weeks, six to eight weeks. So it's not insignificant. It's a pretty big commitment, and they feel pretty crummy throughout the time that they're in the hospital, just to not minimize, you know, what they're going through while they're getting the treatment. But for sure, the patients who have gone through it and achieved transfusion independence have all said that it's been worth it.
Erin Spain, MS [00:18:58] Thank you so much, Dr. Jennifer Schneiderman for coming on the show and telling us about these advances. We're very excited to see what happens in phase 4.
Jennifer Schneiderman, MD [00:19:07] Thanks so much.
Erin Spain, MS [00:19:18] Thanks for listening. And be sure to subscribe to this show on Apple Podcasts or wherever you listen to podcasts and rate and review us. Also for medical professionals, this episode of Breakthroughs is available for CME Credit. Go to our website and search CME.

Continuing Medical Education Credit

Physicians who listen to this podcast may claim continuing medical education credit after listening to an episode of this program.

Target Audience

Academic/Research, Multiple specialties

Learning Objectives

At the conclusion of this activity, participants will be able to:

  1. Identify the research interests and initiatives of Feinberg faculty.
  2. Discuss new updates in clinical and translational research.

Accreditation Statement

The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Disclosure Statement

Jennifer Schneiderman, MD, MS, has received consulting fees from Mallinckrodt, Inc. and BlueBird Bio. Robert Liem, MD, MS, content reviewer, has nothing to disclose. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. Feinberg School of Medicine's CME Leadership and Staff have nothing to disclose: Clara J. Schroedl, MD, Medical Director of CME, Sheryl Corey, Manager of CME, Allison McCollum, Senior Program Coordinator, Katie Daley, Senior Program Coordinator, Michael John Rooney, Senior RSS Coordinator, and Rhea Alexis Banks, Administrative Assistant 2.

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