Hello and welcome to the latest episode of the VJHemOnc podcast! As part of our coverage of the 51st Annual Meeting of the EBMT, which took place in Florence, Italy, last month, we spoke to Akshay Sharma, who delved into the topic of gene therapy for sickle cell disease. In today’s podcast, you will hear this exclusive conversation, in which Dr Sharma discusses patient selection, potential complications, benefits & challenges of gene therapy, and more!

Welcome, Dr Sharma, thank you for joining us! To begin, what is the status of gene therapy in sickle cell disease, and which gene therapies are currently FDA-approved?

Akshay Sharma:

Gene therapy for sickle cell disease has been in development for the last several decades, but fortunately, because of some developments in the field of human genetics where we have identified globin regulation much better now than we used to know before, identification of transcription factors such as BCL11A that are responsible for the globin switching and development of gene editing tools such as CRISPR-Cas9, we are now in a position to actually use all this information together to provide a genetic cure for patients with sickle cell disease. 

So as you probably know, there were two different genetic therapies that were approved in 2023. One which uses a lentiviral gene addition technique, it’s called lovo-cel, and the other technique which uses CRISPR-Cas9 and gene editing known as exa-cel. And both of these therapies have had remarkable results in the patients that have been treated on pivotal clinical trials. 

I think it’s safe to say that almost 90% of the patients have had either complete elimination of their painful vaso-occlusive crisis, or they’ve had significant reduction in the number of instances that these patients have to go to an emergency department or have a pain crisis, clearly showing the efficacy of these therapies. 

However, one thing that the entire medical community is sort of dealing with right now is these are very, very new therapies based on very novel gene editing platforms. And so we don’t really have long-term consequences, long-term outcomes of these patients. We follow these patients for maybe about three to five years. We don’t know what is going to happen to these patients in 15, 20, 25 years from now. So as we start treating more and more patients, especially younger patients, a number of these questions about… What sort of immune reconstitution will they have after gene therapy? What are the complications that they may or may not have after gene therapy? Is gene therapy truly a cure or is it more like a disease attenuation? Risk of leukemia, can patients develop leukemia after undergoing gene therapy for sickle cell disease? I think all of these questions are out there and they will be answered slowly as we gather more data on these patients who have received these therapies, so long-term follow-up is really essential, but it is an exciting time to be in the field because now we have so many different treatments for these patients which until a few years ago we did not.

That’s great to hear! Can you discuss some considerations for clinicians when selecting patients with sickle cell for these therapies?

Akshay Sharma:

Patient selection is very important for gene therapy, just as it is for allogeneic hematopoietic cell transplantation. Gene therapy is a very, very long process for patients with sickle cell disease. It starts with selection of the ideal patient, preparation for collection of hematopoietic stem cells, harvesting the hematopoietic stem cells, and then conditioning the patients with chemotherapy to then administer the cells back to them. From start to finish, this process can take anywhere from 6 to 12 months. And at each step of the way, patients have to be in a certain good health to be able to collect the cells and then to receive chemotherapy. 

And so the first step involves performing a thorough organ function evaluation, looking at their cardiac function, pulmonary function, renal function, making sure that there is no history of stroke or cerebral infarct, which would preclude these patients from receiving gene therapy. And once that has been done, we can move forward with the different steps. 

It is essential to perform all these evaluations upfront because many patients, because of their underlying conditions, especially if they have pulmonary dysfunction or if they’ve had a history of stroke for which they’re receiving chronic blood transfusions, they may be at higher risk after gene therapy. For example, patients who are receiving gene therapy currently, they all need to undergo myeloablative busulfan conditioning. And we know that myeloablative busulfan conditioning is associated with a certain degree of pulmonary toxicity and neurotoxicity. And so if somebody really has diffuse pulmonary fibrosis already, perhaps giving them busulfan is not a good idea. 

Also, patients who have severe vaso-occlusive crises for which they are getting admitted to the hospital on a very frequent basis, it may become very challenging to collect hematopoietic stem cells from them in adequate quantities. 

And lastly, as I alluded to, patients who are receiving chronic blood transfusions for CNS disease, we may not be able to adequately discontinue or safely discontinue their blood transfusions after gene therapy. We just don’t have evidence to do that right now. And so these are the conditions that we need to pay special attention to, to select the patients for undergoing gene therapy.

Thank you for those insights. In terms of complications after gene therapy and the risk of infection, does this compare to what is seen with allogeneic transplantation? 

Akshay Sharma:

As we have started treating more and more patients with gene therapy, a number of things are becoming apparent to us. There are certain similarities in gene therapy to allogeneic transplantation, for example, the use of chemotherapy prior to infusion of the genetically modified cells. But then at the same time, there are a number of differences. And one such difference is that these patients who have received gene therapy, their immune system remains relatively intact after undergoing gene therapy. 

So after allogeneic transplant, we are used to seeing a prolonged period of immune deficiency. Patients are receiving graft-versus-host disease prophylaxis, which further suppresses their immune system. And then it takes several weeks to months for their immune cells to recover completely, for them to have a complete immune reconstitution. We often vaccinate or re-vaccinate individuals after allogeneic transplantation to prevent vaccine-preventable diseases for which they might have received vaccinations previously. 

Now in contrast to this, what we’ve seen is, because we only use single-agent busulfan for most of the patients with gene therapy right now, and there is no lymphoablation or no immuneablation involved in this process, many of these patients actually retain their immune system immediately after they have undergone gene therapy. So they have normal lymphocyte counts or near-normal lymphocyte counts. They also have retained immunity to many of the vaccine-preventable diseases that they have been vaccinated against. And so these patients have a very different immune reconstitution, and they may not need the same level of immune surveillance or immunoprophylaxis. 

For example, in allogeneic transplant patients, we are very used to following viral serologies, looking for EBV, CMV, adenovirus quite frequently after transplantation, and allogeneic transplant recipients are also at a very high risk of developing these infections. That has almost not happened in any patients who have undergone gene therapy. We don’t see widespread CMV, adenovirus, or EBV disease in gene therapy recipients. Likewise, the period of neutropenia is very short in these patients, so the risk of bacterial infections is also low. 

Having said that, though, mucositis is a real problem in patients with gene therapy because of the use of myeloablative busulfan. So I believe that the immune surveillance and immune monitoring practices are a little bit different, and we have outlined them in our manuscript that was recently published in Cytotherapy, talking about what are the different considerations for patients who are undergoing gene therapy. And once again, I believe that many of these patients will retain their immune memory against vaccine-preventable diseases. So it’s advisable to check for those titers against the vaccine-preventable diseases before revaccinating everybody empirically after gene therapy.

It’s interesting to hear the differences between these therapeutic approaches and how follow-up and management may differ.

Next, can you briefly discuss your recent publication on the role of palliative care in patients with sickle cell disease who are receiving stem cell transplantation or gene therapy?

Akshay Sharma:

So until now, palliative care or advanced care as it is called in some institutions was basically reserved for patients who have an oncologic diagnosis who are undergoing transplantation. The idea being that those patients have a greater symptom burden which requires different methods to deal with that symptom burden. But as we have started doing more and more transplants and gene therapy for sickle cell disease, it has become clearly apparent to us that sickle cell disease, because of all the chronic issues that patients might have, also has an equivalent, if not a higher burden of disease than many other oncologic diagnoses. So these patients, they could also benefit from having advanced care provided to them in the form of palliative care consults. 

Now, I should clarify over here, palliative care is very different from hospice care, where we are providing end-of-life care. When we talk about palliative care, we are talking about symptom control, symptom management, palliation of any adverse symptoms that the patients might be having, be that pain, nausea, or just psychological and spiritual care. 

So we and many others have developed these dedicated programs for patients undergoing transplantation and gene therapy for sickle cell disease, which are focused on providing that level of care, which is very common in the oncological world. Now we are bringing that to the classical hematology, sickle cell disease world, and providing these patients with the same level of care. So that’s what we’ve described in our recent manuscript and I hope people will find that helpful and educational.

Fantastic! Gene therapy is obviously a very novel treatment modality, having only been approved for sickle cell in December 2023. In your view, what are the main benefits and challenges with these therapies at present?

Akshay Sharma:

Gene therapy has really opened up the doors for patients with sickle cell disease who did not have a matched donor available previously. Now, matched donors are available for less than 20% of patients. So one in five patients with sickle cell disease have a matched donor available. For the remaining four out of five, they didn’t have an option previously. Here, now alternative donor transplants have really improved. We are now using haploidentical transplants for patients with sickle cell disease and the outcomes are getting better. But with the use of an alternative donor, we have to really focus on the immune complications such as graft rejection, graft failure, graft versus host disease. These patients often need GvHD prophylaxis for an extended period of time between 6 to 12 months, which also involves frequent visits to the hospital for monitoring of the levels of the GvHD prophylaxis medications. So all this is very, very burdensome. 

In contrast, gene therapy is available to almost everybody because you don’t have to find a donor. You are your own donor. So that opens up the opportunity to many more patients to undergo gene therapy. And then again, once they’ve received the gene therapy product, the immune system is back to normal rather quickly in contrast to allogeneic transplantation. There is no need for any GvHD prophylaxis. These patients should technically not have graft rejection or GVHD. And so the post-infusion follow-up is relatively milder as compared to allogeneic transplantation, which is a huge advantage for many of these patients as well. 

So there are certainly these advantages, but gene therapy is very, very new. It’s complicated. It’s hard to explain. We have been doing transplants for sickle cell disease for almost 40 years now. Gene therapy has been around for less than 10 years. And so we don’t have the same degree of data to advise our patients about gene therapy. There are several thousands of patients who have received transplantation for sickle cell disease and other hemoglobinopathies. For gene therapy, I think there are maybe about between 100 and 200 patients worldwide who have received gene therapy, any kind of gene therapy. So there is a lot less data to counsel patients about the long-term effects, both short and long-term effects of gene therapy. 

And then, of course, the big elephant in the room is the price tag. The two commercially available gene therapies, they are priced between $2 to $3 million. And I think insurance programs, payers everywhere are still trying to figure out how are we going to support these therapies? Once again, the clinical trials for gene therapy were only conducted in North America and Europe. Whereas if you look at the population density of sickle cell disease and thalassemia, these diseases are most prevalent in Africa, Southeast Asia, and South America. And none of these therapies are currently available in those parts of the world where the majority of patients with sickle cell disease and thalassemia live. So I think those are definitely challenges of access and equity that we have to figure out ways of making them more accessible. And in this regard, educational and academic institutions such as my own institution, St. Jude, and many other institutions around the world are developing low-cost methods of making these gene therapies accessible through partnership with other academic institutions and governments around the world.

It’s great to hear that work is being done to address some of the barriers to access and bring these therapies to a larger number of patients. 

Finally, can you comment on the risk of leukemia after lentiviral gene therapy? Is there cause for concern?

Akshay Sharma:

The risk of insertional mutagenesis causing leukemia has been around for many decades. Since we have started using viral vectors for gene addition, that risk has always remained there. About 20 years ago, when we were using gamma retroviral vectors, this risk was very common. Many patients who received gamma retroviral therapy for different genetic diseases developed leukemias afterwards. With the development of lentiviral vectors, fortunately, which are much, much safer, this risk had been almost non-existent until recently. And so there were two instances where this sort of risk re-emerged. 

One, when in the clinical trial that was being conducted by Bluebird Bio for their sickle cell disease gene addition technology. On that trial, two patients developed leukemia, and the trial had to be shut down, put on clinical hold for a brief duration while these two cases were investigated. Now, extensive investigations for those two patients revealed that the lentiviral integration actually did not cause leukemia in those patients. We don’t completely understand what might have caused the leukemia. It is likely that at least one of those patients might have been predisposed to develop leukemia anyway, and they just got unlucky and developed leukemia after they got gene therapy. And in the other patient, it is also possible that maybe exposure to myeloablative busulfan was what was responsible for causing leukemia. So at least in those sickle cell disease patients, leukemia was not caused because of the viral integration. 

However, there is another therapy for cerebral adrenoleukodystrophy. The trade name is Skysona. This therapy, also being marketed by Bluebird Bio, on their pivotal clinical trial for this gene addition therapy, several patients have developed leukemia after getting gene therapy and in these patients it is well documented that the lentiviral vector preferentially integrates near a proto-oncogene MECOM and then the MND promoter that is part of that lentiviral vector is responsible for the overexpression of the MECOM gene resulting in leukemia in those patients. So many patients, many children who have received this type of gene therapy have developed leukemia as a direct consequence of receiving the gene therapy and the integration of this lentiviral vector at that locus. And it is presumed that many other patients who are currently in follow-up might also develop leukemia. 

So this gives us a little bit of a pause. We hope that newer therapies, therapies that we have been developing and vetting for past several years, are better than the alternatives that we are trying to leave behind. In this case, we are trying to avoid all the complications that are associated with an allogeneic transplant with an alternative donor, graft-versus-host disease, graft rejection, the need for immunosuppression, and replacing them with a potentially better therapy. But as we have learned in the case of cerebral adrenoleukodystrophy, that newer therapy may not be better. That newer therapy may be worse than the alternative, that’s allogeneic transplantation, because it causes leukemia. 

So I think the scientific community really has to take a pause here, think about it, reevaluate our options. Because that risk of myelodysplasia and development of leukemia has resurfaced now, and we don’t want to push the community, push the scientific field backward. If we don’t pause and reassess what we are doing, how these therapies are affecting our patients, we may run the risk of losing the confidence of our patients, of the community that we serve, and we may end up completely pausing any development in this field. 

So my heart goes out to those patients and families that have developed leukemia. They volunteered to be part of these first in human clinical trials. So while I’m really appreciative of their altruism and their bravery for participating in these clinical trials, I’m heartbroken that these therapies have not helped them the way we would want to help them, that it might have brought them more harm than good and so as a medical community I feel like it is our responsibility, we owe it to these patients to study how these therapies are affecting our patients, both short-term as well as long-term. And if there are these adverse events that we can recognize, especially development of myelodysplasia, that we have to pause, think about it, fix those problems, and then move forward again.

Some important messages from Dr Sharma, and we would like to thank him for his time and valuable insights into this hot topic. 

We hope you enjoyed today’s episode of the podcast, and be sure to check out the rest of our exclusive coverage of the EBMT meeting on VJHemOnc.com for more updates from leading experts. Don’t forget to follow us on Twitter @VJHemOnc to stay in the loop, and subscribe to our podcast on Spotify, Apple, or Podbean, so you never miss an episode. Until next time!