General Updates | Transplantation and gene therapy in SCD and thalassemia: donor types and indications

I think the thalassemia… I might have to answer this question in two different ways. So in thalassemia, I think the indications are slightly different and a bit more universal than indications for transplant in sickle cell. 

So if I start with thalassemia, which is a little bit more perhaps straightforward in some ways. So for children, I’m going to talk about children first. So the children with thalassemia, particularly transfusion-dependent and only transfusion-dependent thalassemia, I think it’s fair to say that it’s very well established that if you have transfusion-dependent thalassemia and you have a sibling donor who is either a thalassemia trait or has no trait, would serve as a suitable transplant and a donor for a matched sibling transplant. And that would provide cure for the patient and make the transmission free. And doing it early on in life means that they won’t have the kind of disease burden of long-term iron or long-term thalassemia that the patient will accrue as they get older. 

It becomes a little bit more complicated if there are no sibling donors, in which case alternative transplants might be considered. There has been a lot out there in terms of getting these types of transplants investigated for thalassemia patients, particularly transfusion-dependent thalassemia cases. I believe that the data for unrelated donor transplant in the context of thalassemia is emerging as a very good option in experienced hands. So this may well become established care in the future going forward. And that would be either a bone marrow source or a peripheral blood stem cell source from an unrelated donor. And given the unrelated donor is likely to be more peripheral blood stem cells, in which case, obviously, it’s unrelated donor peripheral blood stem cells, you really want to be careful about reducing the risk of graft-versus-host disease. And, you know, what you don’t want is chronic graft-versus-host disease because you don’t want to swap one chronic disease, which is thalassemia, to another chronic disease, which is chronic graft-versus-host disease. So that is, I guess, the main challenge. But it is increasingly perhaps evident that unrelated donor transplant is a viable… fully matched unrelated donor transplant is a viable option for patients who do not have sibling donors. When it comes to other type of alternative donor sources, such as unrelated cord or haploidentical related transplants, I think the outcomes are not good enough at the moment for us to offer that as a sort of routine treatment. So that’s thalassemia. 

Adult thalassemia transplant right now is available in many centers that you can provide sibling donor transplants, although they are, as the patient gets older, I think the complications and the risk of rejection is high. I think the risk of rejection is high at an older age as well as at a very young age. And I think the tolerability of the conditioning regimens can be tricky, so the key is to find the right conditioning regimen that you can use to get these individuals transplanted. I do not think there is any evidence that unrelated donor transplants in this context is safe and effective or any other type of alternative donor transplants in adults with thalassemia. 

So moving on to sickle cell, I think sickle cell is a little bit kind of less universal, as it were, compared to transfusion-dependent thalassemias, because sickle cell disease is a very clinically heterogeneous condition. So there might be patients with barely any symptoms or symptoms very well controlled with currently available treatments, whereas there might be children and adults with sickle cell anemia who have very significant symptoms. And therefore, there are, hence, due to this heterogeneity, there are some criteria for transplant. So if we were to do the very straightforward thing, so strokes, for example, recurrent acute chest syndrome or recurrent pain despite being optimally managed medically with hydroxycarbamide or blood transfusions, et cetera, would be a good indication for sibling donor transplants. This is both in children and adults. 

The approach to children and adults transplant in terms of their conditioning regime and in terms of the outcomes are very different. Right now, young people, so children, are offered myeloablative conditioning and often their body organ status is such that they can tolerate myeloablative conditioning. Whereas in adult patients who have had years of organ damage accrued as a result of sickle cell disease will not be able to tolerate myeloablative conditioning that easily. Therefore, much less, you know, non-myeloablative conditioning is used. And then there is that balance between sort of the risk of rejection versus the risk of kind of long-term problems with mixed chimerism and risk of developing cancers as a result of exposing themselves to radiation and so on. 

So right now for adult transplants, the move is towards making it as much sort of donor-derived chimerism as is feasible, although trying best not to make it too myeloablative so that the patient does not kind of, does not have such toxicities in the conditioning treatment that, you know, they have transplant-related mortality. So it’s a fine balance and this is work in progress, you know, trying to fine-tune the best possible transplant. And this is in the context of, obviously, in the context of matched-sibling donors. 

When it comes to other alternative donor transplants in both children and adults with sickle cell, the more established type of transplant is a haploidentical transplant. So that, particularly for children, opens up a huge number of donors because almost every child will have a parent that can donate. Whereas in older patients, it might be a little bit more tricky, usually it’s a sibling that you have to approach for donating. Generally speaking, the adults, their parents tend to be much older and have their own health issues. 

Haploidentical transplants, not just in the context of hemoglobinopathies, but also in the context of many other conditions, is an increasingly acceptable type of treatment with very special modifications to the conditioning protocol that allows minimizing of the very obvious graft-versus-host disease that will happen as a result of that 50% mismatch. However, I think the outcomes of haploidentical transplants in sickle cell is very promising, both in children and adult. And it remains to be seen whether that is going to be adopted as a standard routinely available procedure for patients who do not have sibling donors but require transplant. 

Moving on to the other alternative donor transplants, such as a fully matched unrelated donor transplant or an unrelated cord transplant, these are very, very tricky. These have been repeatedly proven to be quite disastrous. There’s been lots of transplant-related mortality, particularly in the older patients. So these are currently not available as a viable option. 

Moving on to gene therapy, which is available to certain countries, and we’re very lucky in the UK that it is available as a gene editing type of technology. The indication for gene therapy in beta-thalassemia is much more universal, very similar to what we do in the allogeneic transplant context. So if they are transfusion dependent and they haven’t got a sibling donor who is available, they will be eligible for gene therapy. In the UK currently, the guidelines suggest that you are eligible from the age of 12 onwards. The upper age limit has not yet been determined, but owing to the fact that there’s myeloablative conditioning involved, there’ll be very few people beyond 40 to 45 that will be able to tolerate myeloablative conditioning. Once the collection happens and the gene editing takes place in an external commercial lab, the main challenge for a thalassemia patient is really tolerating that conditioning regimen. And if they do tolerate that myeloablative conditioning, then it becomes very straightforward. There is no graft-versus-host disease. The patient can go home as soon as they’re engrafted, and there is no need for any immunosuppressive treatment afterwards. Long-term follow-up is mandated because it’s a genetic interventional procedure, and that is embedded within clinical practice to have long-term follow-up for up to 15 years. 

In terms of sickle cell gene therapy, again, slightly different from thalassemia gene therapy. So you have patients who have, similar to the indications for transplant, patients who have very severe disease but do not have a matched sibling or a haploidentical donor, are above the age of 12, possibly below the age of 45, although there’s no upper limit for sickle cell transplants either. The key is to identify whether they will tolerate the myeloablative conditioning or not. The main thing that is challenging for sickle cell patients for this kind of ex vivo gene editing therapies is that they tend to have really problematic mobilization of their stem cells. So that is something that has become quite a big roadblock, and so the sooner we are able to have better mobilization protocols, and of course, with experience and in expert hands, it improves. So the better it will be. Going forward, I think, you know, if there are other techniques that can be used for gene therapy where myeloablative conditioning is not necessary, then that would be perfect. Right now, only patients who have recurrent pain crisis with sickle cell are eligible for gene therapy. Anybody with any kind of cerebrovascular disease is not eligible, and that is also a big disappointment for patients who perhaps felt that they could have received a transformative treatment but are not able to.

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