Treatment Options for Sickle Cell Disease

Bone marrow transplants and gene therapy for sickle cell disease: treatment options to consider.

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Treatment Options for Patients with Sickle Cell Disease

Wednesday, August 11, 2021

Presenters: Alison Towerman MSN, RN, CPNP and Hemalatha Rangarajan MD

Presentation is 47 minutes long with 27 minutes of Q & A.

Many thanks to bluebird bio whose support, in part, made this webinar possible.

Summary: Sickle cell disease disproportionately affects African Americans. However, stem cell transplants and gene therapy offer promising treatment options. This presentation describes these treatments, their outcomes, and which treatments are appropriate for which patients.


  • Matched sibling donors are ideal for bone marrow transplants but not available for most sickle cell patients. Other options come with added risks and potential complications.
  • Gene therapy is promising new treatment for sickle cell disease but is expensive and only available through clinical trials for now. Families are encouraged to explore this option through their treatment center.
  • Both transplants and gene therapy may require strong chemotherapy which can cause infertility. However, lower doses of chemotherapy may be effective in treating the disease while increasing the chance of retaining fertility after treatment.

Key Points:

(00:04:12) Early childhood screening for sickle cell disease has reduced the risk of early death.

(00:13:25) Transplant involves months of preparation, ongoing care, and recovery but can be a life-changing cure that improves quality of life.

(00:16:41) The benefits of transplant must be weighed against risks of chemotherapy, radiation, and side effects such as infertility and graft-vs-host disease (GVHD).

(00:19:01) Gene therapy is a promising alternative with no GVHD risk.

(00:20:38) With strong chemotherapy and matched sibling donors, transplant survival rates and cures are above 90%.

(00:28:39) Matched unrelated donors bring a higher risk of GVHD.

(00:32:07) Current data shows that among non-sibling donors, no one donor type is necessarily better than another. Donor choice should depend on transplant center experience, clinical trials, family preferences.

(00:34:24) Gene therapy is another treatment option that replaces or alters genes associated with the disease.

(00:40:07) Only patients with severe sickle cell disease are eligible for gene therapy.

(00:43:55) Several factors influence decisions about having a transplant including severity of disease, availability of matched donor, and patient age.  Matched sibling donor transplants remain the best treatment option if available.


Note: In this presentation the speaker(s) sometimes uses the terms “BMT” or” bone marrow transplant”. For purposes of this presentation, both of those terms also apply to patients who have been through a stem cell transplant.

Transcription of Presentation:

(00:00:00 [Susan Stewart]:  Introduction of Speakers. I want to thank Bluebird Bio who kindly supported the webinar this evening. And it's now my pleasure to introduce to you tonight's speakers. Dr. Hemalatha Rangarajan and Alison Towerman.

Alison Towerman is a pediatric nurse practitioner at St. Louis Children's Hospital in St. Louis. She's been caring for children and adolescents with sickle cell disease for nearly nine years. Alison is interested in promoting disease modifying therapy for improved quality of life, and providing children with sickle cell disease an opportunity for a cure. She helped establish a survivorship clinic at St. Louis Children's Hospital for patients with sickle cell disease who had undergone a transplant, recognizing their unique long-term issues, due to their disease. She's also a member of the Sickle Cell Transplant Advocacy & Research Alliance or STAR Consortium which is a large nonprofit organization focused on research to cure sickle cell disease.

Dr. Hema Rangarajan is a pediatric stem cell transplant physician who specializes in the care of children and young adults with sickle cell disease. She practices at the Nationwide Children's Hospital in Columbus, Ohio. Her research interests include optimizing transplantation strategies and supportive care measures, and exploring the use of non-sibling donors in patients with sickle cell disease who undergo a transplant. She's currently working with colleagues nationally on clinical trials to reduce the toxicity and complications of bone marrow transplant without compromising its effectiveness, and making transplants more available to sickle cell disease patients. She's a member of the Scientific Executive Committee of the Sickle Cell Transplant & Advocacy Research Alliance, or STAR Consortium.

Please join me in welcoming Ms. Towerman and Dr. Rangarajan. Alison.

(00:02:18) [Alison Towerman]   Overview of talk and disclosures. Good evening, everyone. On behalf of the Sickle Cell Transplant Advocacy & Research Alliance, Dr. Hema Rangarajan and I have the pleasure to present to you an overview of bone marrow transplant and gene therapy for sickle cell disease. These are our disclosures.

We hope that by the end of our talk, you all will have received a good outline of the process of bone marrow transplant and gene therapy for sickle cell disease, a summary of the outcomes and a comparison between the two options.

(00:02:56)  [Alison Towerman]   Review of sickle cell disease and its prevalence among African Americans. Just as a refresher, sickle cell disease is an inherited disorder that affects the hemoglobin, which is the protein in red blood cells that carries oxygen to tissues throughout the body. Normal red blood cells are flexible and disc shaped, but here they become rigid and sticky and sickled in shape. They block blood vessels and they break apart easily and therefore oxygen delivery to organs is decreased.

Sickle cell disease occurs in about one in every 365 African American births. And about 100,000 Americans are affected. You can see from this picture here, that just about every part of the body can be affected. Lack of blood flow and oxygen delivery to tissues leads to pain crises and organ damage. Sickle cells can get trapped in the spleen causing splenic sequestration, and damage to the spleen puts individuals with sickle cell at risk for infection. Sickle cell can also cause problems in the lungs leading to acute chest syndrome and often, most scary, sickle cell can block blood flow to the brain and cause stroke and cognitive impairment.

(00:04:12) [Alison Towerman]    Early childhood screening for sickle cell disease has reduced the risk of early death. Fortunately, with the inclusion of sickle cell disease on newborn screening, beginning in the 1960s, we have been able to identify affected individuals shortly after birth and initiate preventative care promptly. Early initiation of penicillin prophylaxis has significantly reduced the risk of death from overwhelming infection, as has the administration of appropriate vaccines. And screening exams like Trans Cranial Doppler have helped us identify children who are at risk for stroke, and then allow us to take steps toward prevention with transfusion therapy. And development of disease modifying therapies like hydroxyurea has helped reduce painful episodes, preserve organ function, and improve quality of life. Importantly, caregiver education helps families understand when it's necessary for them to bring their child into the hospital immediately so that they can get urgent care.

(00:05:15) [Alison Towerman]  Early death remains a problem in sickle cell patients. However, we still have a long way to go. Early mortality remains a problem with median survival being 48 years of age. Publications from both 1994 and 2019 show that the proportion of people alive with sickle cell disease dropped down significantly after about 40 years of age, despite 60% of them being on hydroxyurea therapy in the 2019 publication. So bottom line, survival rates have remained stagnant since the 1990s, and there's still a lot of work to be done for patients with sickle cell disease.

(00:05:56) [Alison Towerman]  Bone marrow transplants and gene therapy now offer possible cures. Good news though, we are making forward steps and the possibility of a cure is now a reality. Both bone marrow transplant and gene therapy provide the opportunity for a cure.

Bone marrow transplant is a procedure in which healthy blood forming stem cells from someone other than the individual with sickle cell are collected and then infused into the affected individual to replace their disease forming cells.

And in gene therapy, on the other hand, the individual's own stem cells are collected, altered using gene modifying techniques to correct the defect that causes the disease, then reinfused back into the individual's body. So just to reiterate, bone marrow transplant involves using cells from someone else, while gene therapy involves using the patient's own cells.

(00:06:55) [Alison Towerman]  Bone marrow transplants replace defective stem cells with healthy ones. The bone marrow is the tissue inside our long bones and can kind of be understood as the blood cell factory where all the cells of our blood are produced. Stem cells are housed in the marrow, and stem cells are the initial cells that develop into all other types of cells in the body, including red cells, which again are affected by sickle cell, white cells, which are the cells that form the immune system and fight infection, and platelets, which help the blood to clot.

So, by replacing the marrow that contains these defective stem cells with marrow that contains healthy stem cells from another person, we can eliminate the effects of sickle cell. And also we give chemotherapy before infusing the new marrow to get rid of the old stem cells and really make space for the new factory to set up shop.

(00:07:51) [Alison Towerman]  Bone marrow transplant was first recognized as a cure for sickle cell in 1984, when a patient with sickle cell was actually diagnosed with leukemia and transplant was done for her leukemia, but was found to treat her sickle cell disease as well. This, of course, led to further investigation and the first international multi-center clinical trial of bone marrow transplant in children suffering from severely symptomatic sickle cell was reported in 1996, showing a 91% survival rate using matched sibling donors.

Since that time, advances have been made in the medications we give prior to transplant and in our approaches for supporting patients during and after transplant, which Hema we'll discuss further. We've been able to develop strategies for using stem cell sources other than sibling donors, which is great. But despite these advances less than 3,000 patients have been transplanted for sickle cell disease worldwide.

(00:09:01) [Alison Towerman]  Transplant candidates must meet certain eligibility requirements and be committed to a long processs. Because of complications that can arise throughout the transplant process, which we'll go over shortly, transplant really it's reserved for patients that meet eligibility criteria. Traditionally, indications for transplant include a history of stroke, at least two episodes of acute chest syndrome, three or more pain crises or irreversible organ damage.

But you can also see from the table on the right here that there are many other indications for which people may qualify for transplant. And in addition to physical indications, patients and families, really they have to be willing to accept the risks and responsibilities that come along with transplant. It's a long process with a lot of ups and downs and patients have to be committed to taking their medications and following directions from providers, regardless of how weary they may start to feel. And because it can be both physically and emotionally taxing, a good support system and access to resources is necessary.

(00:10:08) [Alison Towerman]  Finding a well-matched stem cell donor is important. So once someone meets the criteria to undergo transplant, how do we decide where to get stem cells from? Well, ideally we would get donor cells from a full sibling who's matched. And to determine whether someone is a match, we evaluate 10 proteins on the cells of the patient and the same 10 proteins on the cells of the potential donor. These proteins, they act like flags, and they help the immune system distinguish between the body's own cells and other substances that are seen as foreign and that should be destroyed. We want these proteins to match between the donor and the patient so that the white cells from the donor do not see their new home as foreign, and then start to attack.

We get half of these proteins from a mother and half of these proteins from our father. So each parent is automatically a half-match to the patient.

You can see from the chart here, that there are four combinations that can result in children from one set of parents. This sibling on the left, the first child, got the blue half from her mom and the red half from her dad. And then the second child got the blue half from her mom and the yellow half from her dad, and so on. And then the child with sickle cell at the bottom, got the same combination as the first sibling. So, that sibling would be a match. This would be the ideal situation, but because there are four possible combinations, each sibling only has a 25% chance of matching the sibling in need. You can imagine that many individuals have no siblings that are actually a match.

(00:11:56) [Alison Towerman]  Matched related or unrelated donors are hard to find for African Americans. In fact, as you can see here, in African Americans only about 18% of individuals have a matched sibling. When there's no sibling that can be used as a donor, we have to look at unrelated donors, who are usually volunteers that are identified through a bone marrow registry. Unfortunately, even then there is less than 18% chance of finding a donor whose proteins match for African-American individuals. You can see from this picture here, how different that is from other ethnicities. And that's partially because of the lack of African-Americans signed up for the donor registry. And then as I mentioned before, each parent is always a half match. So availability would be universal if we wanted to use them as a donor, but because only half the proteins are matched in that case, the process for transplant is a bit more intense, which Hema will discuss more.

(00:12:55) [Alison Towerman]  There are three sources of stem cells for transplant. There are three ways we can collect stem cells for transplant. The first is a bone marrow harvest, which is actually the gold standard. And in this case, a procedure is done to collect the stem cells directly from the marrow, usually in the hip bone.

[Alison Towerman]  Stem cells can also be collected from the umbilical cord of a newborn, or through a procedure where a machine is used to collect blood through an IV and stem cells are then separated out.

(00:13:25) [Alison Towerman]  Transplant involves months of preparation, ongoing care, and recovery. It's important to recognize how long a process of bone marrow transplant actually takes. So for months leading up to the transplant, the patient undergoes evaluations to ensure organs are healthy enough to withstand the transplant process. And then for a few weeks prior to transplant day, the patient undergoes preparation or what we call conditioning where chemotherapy, and maybe radiation can be used to clear out the patient's own bone marrow, make space for the new marrow and weaken the immune system to prevent rejection of the new cells.

And then on transplant day, the patient receives the donor stem cells through an infusion, which is very similar to receiving a blood transfusion. And then after transplant, we wait for the new stem cells to take hold in the patient's body and to start making new blood cells. This can take many weeks and patients may require blood and platelet transfusions to support them in the meantime, and medications to prevent infection are also very important during this time. When the bone now starts to make new blood cells, we say that the patient is engrafted.

(00:14:43) [Alison Towerman]  During the early months after transplant, there is a large risk for infection and other complications. The months following engraftment can be considered the early recovery phase during which there's still a large risk for infection and other complications. And patients really have to be closely monitored. And then after about six months, most patients' immune systems start to recover and they can stop taking a lot of their prophylactic medications, but they're still followed closely by us for years.

(00:15:10) [Alison Towerman]  Really the most important take home message here is that transplant is not a surgery. It's not a one and done procedure for the patient where they come into the hospital and they go out and it's quickly. It's a long process and it requires close monitoring and it comes with a lot of responsibility.

(00:15:30) [Alison Towerman]  Transplants can be a life-changing cure that improves quality of life. So why go through all of this? Because of the possibility of a cure and because if transplant works, the benefits can be life-changing. The damage that was being done to organs by sickle cells no longer occurs. And while previous damage cannot be reversed, further damage is prevented. In fact, follow up studies have shown stable to improved heart, lung and spleen function, as well as improved blood flow to the brain, improved imaging of the brain and prevention of cognitive decline.

And not only is physical health protected, but quality of life is improved. Patients often say that they have more energy and they just feel better, overall. They're able to participate in activities and maintain relationships and pursue goals without the possibility of unpredictable pain crises and hospitalizations winning over them. Studies looking at health related quality of life have shown improvement in psychosocial and emotional wellbeing in addition to physical wellbeing.

(00:16:41) [Alison Towerman]  The benefits of transplant must be weighed against risks of chemotherapy, radiation, and graft-vs-host disease (GVHD). It's important to remember the risks, though, that come along with transplant. There are short-term side effects that can occur from the chemotherapy given during preparation for transplant, such as vomiting and mouth sores, which can lead to nutrition problems; hair loss, and low blood counts, as well as severe infection that can occur from the immune system being so weak. There's also a significant social and emotional toll that can be taken when patients are isolated for so long while the immune system recovers.

Graft-versus-host disease can occur when the new donor immune system sees the patient's body as foreign and starts to attack it. And there's even the possibility that the body entirely rejects the new donor cells. And in this case engraftment doesn't occur. And the patient's sickle cell disease actually returns. This happens in about 10% of patients who receive a transplant from a matched sibling donor, but the risk is higher when other donor sources are used.

There's also long-term side effects that can occur from the chemotherapy conditioning that's given, including damage to organs, and a very low risk for cancer, but we're still learning about these long-term effects. And infertility in particular is a side effect that we're still learning about and one which a lot of people may not be willing to risk. And then death from infection is also a possibility and of course, another risk that has to be carefully weighed.

(00:18:20) [Alison Towerman]  Graft-versus-host disease occurs when donor cells attack the recipient’s body. As I briefly mentioned before, when new donor stem cells are not entirely matched to the patient, the new stem cells from the donor that developed into white cells can recognize the body as foreign and may start attacking. This is what we call graft-versus-host disease. And it can have effects that are mild or severe. The skin, the gut and the liver are usually involved, but really any organ can be affected. We call it acute when it occurs early after transplant and chronic when it occurred late after transplant. And we use medications that suppress the immune system to control GVHD and stop the cells from attacking.

(00:19:01) [Alison Towerman]  Gene therapy is a promising alternative with no GVHD risk. The risk of this happening is different based on the type of donor source, but of course, if the cells come from the patient's own bone marrow, as they do in gene therapy, there is no risk for this, which is one of the reasons why gene therapy is so exciting. GVHD, infertility and mortality are three major side effects that they really seem to be the most worrisome for our patients, but we are working to overcome these issues with different preparative regimens and advances in gene therapy, which Hema will now delve into.

(00:19:40) [Hemalatha Rangarajan]  Transplants and gene therapy can have various outcomes.  So, thank you, Alison. And good evening everyone. Over the next 20 minutes or so, I'm now going to give you an overview of the outcomes after bone marrow transplant for sickle cell disease, and also discuss the process of gene therapy and outcomes after gene therapy for sickle cell disease.

(00:19:59) [Hemalatha Rangarajan]  When transplants for sickle cell first began, they involved very strong chemotherapy.  So at the outset, when transplants were being performed for sickle cell disease, only strong chemotherapy was used, such as the agents that I've shown you here: they're called busulfan, cyclophosphamide and ATG. Now, these transplants that were performed were mostly predominantly only for matched sibling donor transplants.

And before transplant, you receive the medications that are shown in the picture below, that is the chemotherapy. And after transplant, that is after the day of transplant, usually patients are put on medications to prevent the occurrence of graft-versus-host disease for several months.

(00:20:38) [Hemalatha Rangarajan]  With strong chemotherapy and matched sibling donors, survival rates and cure after transplant are very high. Now, using these strong chemotherapy-based transplant regimens, and matched sibling donors, I'm showing you a table that describes the outcomes of these transplants. And these are studies which have enrolled a very large number of patients, with pretty long follow-up. As you can see here in this table, the overall survival. Overall survival refers to the possibility of surviving the transplant process, because after all it is a risky medical procedure. As you can see, after a strong chemotherapy regimen, the survival rates are pretty high, as high as 95%.

What about event-free survival? That is the possibility of being alive or surviving transplant without sickle cell disease, that is the cure. You can see that some studies have reported as high as 93% [event-free survival].

(00:21:28) [Hemalatha Rangarajan]  Failed transplants can occur in up to 10% of cases and GVHD in almost 25% of patients. And the possibility of the transplant not working - that is what we refer to as graft failure - was anywhere from two to 10%. Now, graft-versus-host disease (GVHD), that Alison talked to you about, still affected nearly a maximum quarter of our patients.

(00:21:47) [Hemalatha Rangarajan]  So following these strong chemotherapy regimens, what we also learned was that patients who receive stem cells either from bone marrow or cord blood from their siblings, did equally well, that is, with similar outcomes in both of these subsets of patients. However, for all practical purposes, we usually prefer to wait until the donor is older, that is, a sibling is older, and either use bone marrow as the source of the stem cells, or bone marrow and cord blood.

(00:22:21) [Hemalatha Rangarajan]  Strong chemotherapy poses significant risks: infertility, graft-versus-host disease, death and effects on the brain.  However, despite the advances in the earlier days, use of strong chemotherapy was still associated with those three complications that Alison mentioned: infertility, graft-versus-host disease and deaths. Another important complication that is increasingly recognized is the complication that affected the brain. This can present as seizures. It can cause headaches and it can even cause bleeds in the brain. And this affected nearly one-third of our patients. Therefore, there was increasing recognition that you need to consider less toxic chemotherapy regimens in our sickle cell patients so that we can reduce the risk of these complications.

(00:23:02) [Hemalatha Rangarajan]  Less strong chemotherapy has been used in transplants for sickle cell patients. Now, when we talk about the strength of chemotherapy regimens that are used for transplant, we can grade them based on their strength as a very strong regimen. And very strong regimens are referred to as myeloablative. Or you can give medium strength regimens, which are referred to as reduced intensity. Or the least intense, least strong regimens which are referred to as non-myeloablative. Now, why do we consider these regimens? Because the hope is that by using this medium or less intense regimen, our patient's risk of infection, infertility, death, and graft-versus-host disease will be reduced.

(00:23:43) [Hemalatha Rangarajan]  Even partial replacement of recipient cells with donor cells can cure sickle cell disease. Another important clinical observation that actually moved the field towards the use of less intense or less strong regimens, was the fact that you don't need to have 100% donor cells in your body to be cured of sickle cell disease.

For example, in the illustration that I'm showing to you, in the picture below on the extreme left side, you have a transplanted patient and all his cells are donor cells. That is the five of the five are donor cells. And this is a situation we refer to as 100% donor chimerism, or 100% donor cells.

Whereas in the middle situation, you have a situation where only four out of the five cells are donor cells, therefore 80% are donor cells. On the extreme right, the last case scenario, you have a situation where, in this patient, only one out of the five cells are donor cells. And therefore only 20% of the cells are clearly donor cells. But despite this, in all these case scenarios, a patient is cured of the sickle cell disease. This is because the donor red cells survive longer in the body than sickle red cells. Therefore, by using a less strong regimens, we can still achieve a cure in our patients.

(00:25:01) [Hemalatha Rangarajan]  Overall survival and cure rates remain high even with medium strength chemotherapy which has less brain toxicity. So, what are the outcomes after using medium strength chemotherapy regimens with a matched sibling donor in transplants for sickle cell disease?

Now, in this table, once again, I'm showing you the studies that involve a large number of patients. And I'm just focusing on the most important points. As you can see here, the overall survival, that is surviving after transplant is pretty high ranging anywhere from 91% to 100%. The event free survival, that is being alive without sickle cell disease, is also very high between 91 to 100%. Graft failure, that is the possibility that the transplant did not work, was low, a little under 10%. Whereas graft-versus-host disease, although slightly lower, still affected a maximum of a quarter of our patients.

Suffice to say that outcomes after this type of transplant are very similar to strong regimens, but most importantly, the brain toxicity that I talked to you about is dramatically lower, ranging anywhere from 3.3 to 11%. To recollect, using strong regimens, we saw about one third or 33% of our patients being affected with brain toxicity. Most importantly, in one study, they also showed that menstrual cycles resumed for girls who underwent this type of transplant, suggesting that fertility may be preserved using less a strong regimens.

(00:26:31) [Hemalatha Rangarajan]  The least intense chemotherapy still has good outcomes and less harm on fertility, allowing for post-transplant pregnancies. Now, what about the least intense regimen? That is the bottom of the pyramid that I previously showed you. This is a newer type of transplant, which was initially performed more for adult patients, because adults with sickle cell disease tend to suffer from more complications. Always the rule of thumb is the older you are the greater the risk of transplant-related complications.

Now, in this type of transplant, surprisingly what was noticed was that patients did not develop GVHD. There was minimal to no graft-versus-host disease, as you can see in the extreme right side. And there is a slightly higher risk of graft failure using this type of transplant, as high as 15%. The risk of the death was extremely low, whereas the event free survival, that is, being alive without sickle cell disease ranged anywhere from 87 to 100%. But most importantly, there were 21 pregnancies reported in a recent study, proving proof of principle that using this type of transplant, we may be able to preserve fertility, which is extremely exciting for our patients.

(00:27:39) [Hemalatha Rangarajan]  Most patients don’t have a matched sibling donor and require alternative donors. But unfortunately, we know that in most case scenarios, we always don't have the luxury of a matched sibling donor. And like Alison mentioned to you, in those circumstances, we have to search for other donors.

Now, who are the other donors for a patient with sickle cell disease? You can consider looking at donors who are not related to you but matched on all the 10 proteins. And we refer to them as matched unrelated donors. Or you can get stem cells from a cord blood that has been stored from a person who is not related to you. Or you could consider a donor who's related to you, like your mom, dad, or even your sibling, who are only matched on half of those proteins, so they're called a half-match or a haploidentical donor. For all practical purposes, we always compare the outcomes of these alternative or non-sibling donors with our gold standard of matched sibling donors because the matched sibling donor transplants have the best outcomes.

(00:28:39) [Hemalatha Rangarajan]  Transplants with matched unrelated donors bring a higher risk of GVHD. So, what are the outcomes after matched unrelated donors, that is donors who are not related to you, but are matched on the 10 proteins. Now, I just want to focus on the most important finding from these types of transplants, is the high risk of graft-versus-host disease. As you can see on the extreme right, using this type of transplant, the rates of graft-versus-host disease are extremely high at 62%. Although, more recent studies have shown a slightly lower rate with most patients having only a milder form of graft-versus-host disease, this still remains an area of active research, and we recommend these types of transplants only in the context of a clinical trial.

(00:29:20) [Hemalatha Rangarajan]  Umbilical cord blood transplants have reported high failure rates and high rates of GVHD rates. Similarly, let's look at outcomes after a cord blood transplant. Now, the number of patients who have been transplanted using this type of transplant is pretty small. However, irrespective, we have learned that when using this type of transplant, graft failure - that is the possibility of a transplant not working - was high, nearly half to 63% of the transplants in this group. Now, more recent studies are showing better outcomes, like the last study in 2021, using what is called an expanded cord blood, the failure rate was only 8%. However, graft-versus-host disease, as you can see on the extreme, right, was still high at 69%. Once again, this remains an area of active research.

(00:30:10) [Hemalatha Rangarajan]  Transplants with half matched donors (haploidentical donors) have seen increasing success rates and lower, or more mild, cases of GVHD. So, what about half-matched donors or haploidentical donors? This is certainly exciting because our patients still have struggles to find a matched unrelated or even a cord blood donor. Half-matched might expands the possibility of having a donor for all our patients. However, these types of transplants using half-matched donors, earlier on, were associated with a high risk of the transplant not working or causing graft-versus-host disease, all of which are mediated by the white cells in the body. Since that time, there has been considerable improvement and now we are able to overcome these events purely by getting rid of the white cells responsible either for the failure of the transplant or graft-versus-host disease, either by using chemotherapy after transplant to destroy white cells or removing the white cells, even before the graft or the stem cells are infused into the patient.

(00:31:07) [Hemalatha Rangarajan]  Outcomes after non-myeloablative transplants using low dosages of chemotherapy. And what about the outcomes after this type of transplant [non-myeloablative]? Now, this is a newer type of transplant and more and more patients are being recruited into clinical trials. As you can see, I have highlighted the most important studies that have reported their outcomes. And surprisingly, as you can see here, the graft failure rate – the transplant did not work - was 10% or under. Patients are surviving because we have come a long way with our supportive care practices ,and you can see 84 to 100% of the patients were surviving on these studies. Event free survival, that is alive without sickle cell disease and surviving the transplant process, is also approaching as high as 93%. Now, graft-versus-host disease still affected a quarter to one third of our patients. However, we know that in some of these studies, the type of graft-versus-host disease that is seen is mild. There is still research ongoing and they have a lot to learn and improve upon.

(00:32:07) [Hemalatha Rangarajan]  Current data shows among non-sibling donors, no one type of donor is necessarily better than another. Donor choice should depend on transplant center experience, clinical trials, family preferences. So, this next slide I am comparing, side by side, the outcomes of all these different types of non-sibling donor options. On the horizontal axis, you have the outcomes, that is engraftment: did the transplant work? What were the rates of acute graft-versus-host disease that is graft versus host disease that occurred early after transplant? What about chronic graft-versus-host disease, that is, graft-versus-host disease that occurs late after transplant? Deaths, that is mortality. And did you survive without sickle cell disease?

If you're looking at the graph, you realize soon enough that one donor is not better than another. For example, in cord blood, on the extreme right ,52, that implies that only half of the transplants worked. Acute and chronic graft-versus-host disease still affected about 42% of cord blood transplantation and also 35% of the matched unrelated donor transplant, whereas the possibility of being alive with any of that from 48 to 73%.

So based on current data, we say that, currently, no one donor is better than another, and all these types of transplants should be done preferably on a clinical trial. The choice usually depends on a transplant center’s preference and experience, what clinical trials are available, and also on family preference after fully informed discussions with the family.

(00:33:29) [Hemalatha Rangarajan]  The younger the patient, the better the outcome. So we also know over time that there are some very important factors that impact outcomes after transplant for sickle cell disease. The most important one being age. The younger you are, the better the outcomes because you have less organ damage and you're able to withstand chemotherapy much better. In fact, for every one-year increase in age at the time of transplant, your risk of having a failed transplant or death increases by almost 9%.

(00:33:59) [Hemalatha Rangarajan]  Younger donors are the preferable source of stem cells. The best type of donor is always a matched sibling donor, preferably, if 12 years or younger, you have the best outcomes. The outcomes after matched sibling donor transplants are so good, that we can even consider transplant for patients with less severe disease nowadays. Amongst non-sibling donors, however, currently no one [donor] is better than the another based on current data.

(00:34:24) [Hemalatha Rangarajan]  Gene therapy is another treatment option by works by replacing or altering genes associated with the sickle cell disease.? So, gene therapy is an experimental technique that uses genes to treat patients with diseases such as sickle cell disease. The approaches being studied include replacing a defective gene, that causes disease, with a healthy copy of the gene; inactivating or knocking out a gene that is functioning improperly; or controlling the production of another gene; or introducing a new gene into the body to help fight a disease.

(00:34:57) [Hemalatha Rangarajan]  In gene therapy diseased cells are removed from the body, genetically altered, and returned as healthy cells. Now, how is gene therapy being done for patients with sickle cell disease? On the left side, I'm showing a picture of the process. So, in this process, patients with sickle cell disease receive a medicine called plerixafor, and this medicine helps to push those stem cells - that is, the mother cells that are inside the bone marrow factory - into the blood. After this is done, the patient is connected to a machine that collects the stem cells. And these are the stem cells that produce the sickle red cells. And these stem cells are then genetically modified in such a way that they now produce red cells that do not sickle. Now, these genetically modified cells are then given back to the patients, just like a blood transfusion.

However, for this process patients still need chemotherapy. You, need chemotherapy to create space in that factory, in order for the genetically modified cells to come and start working. The advantages of gene therapy are that you do not have to search for a donor. There's no need to search for that ideal donor. And because you're getting your own stem cells back, there is no risk of the donor cells fighting against your own body. So there is no risk of graft-versus-host disease. The disadvantages are, we still need chemotherapy to get gene therapy done. Therefore, the risk of infertility is still present.

(00:36:27) [Hemalatha Rangarajan]  Gene therapy is expensive and only available through research trials. It is extremely costly, and it's now only available in the context of research trials. We still don't know the long-term effects of gene therapy. There are several, almost three decades, of experience with transplant, but this is not the case with gene therapy. The longest follow-up is a little under six years. We still need longer follow-up as required by the FDA, up to 15 years, to make sure that this type of therapy is completely safe for our patients. There's also a theoretical risk that if you genetically modify the cell, you may cause some damage to other genes that prevent cancer in the body. So you should monitor these patients for cancer for several years.

(00:37:09) [Hemalatha Rangarajan]  There are currently two techniques for doing gene therapy. So how is gene therapy done? I'm going to shed light on two techniques that are now currently recruiting patients on clinical trials and have reported outcomes. The first strategy I'm going to refer to as the postman technique. In this strategy, we use viruses called Lentivirus to act as a postman. Now, the postman carries a message of interest and delivers it to its target cell. In this case, it's the stem cell. Once the stem cell receives this message, it learns that code and starts producing a protein, which in this case, is the hemoglobin, that does not cause the red cell to sickle. Therefore, these stem cells are genetically modified stem cells will now produce hemoglobin that does not cause red cells to sickle. And using this postman technique, the first patient who received gene therapy was in France. He's a 13-year-old boy, and this was reported in 2017.

Now, another strategy in gene therapy is to turn off the switch, and to re-awaken of production of baby hemoglobin. Now, before birth, all of us use baby hemoglobin and therefore red cells do not sickle. After birth, if you're unaffected [do not have sickle cell ] you will have two copies of an adult hemoglobin. Or if you have sickle cell trait, you have one copy of a sickle and one copy of an adult hemoglobin. And in both these cases, the red cells do not sickle.

But in a person with sickle cell disease who has two copies of sickle hemoglobin, their red cells sickle. We have now discovered the switch that switches off or switches on the baby's hemoglobin production. And this switch is called the BCL11A gene.

Now when you have more baby hemoglobin in your body, you survive longer, you have less symptoms. And you also have less hospitalization rates if you have sickle cell disease. So, if we can somehow turn off the switch after birth, we can increase the baby hemoglobin production.

(00:39:12) [Hemalatha Rangarajan]  Genomic editing like CRISPR use “scissors” to alter genes. So, gene therapy strategies using this technique try to turn off the switch. And that is done by a technique called genome editing tool, which is basically using something called genetic scissors. Now, you probably have heard of the most popular one in the media, called CRISPR. Now these genetic scissors can essentially cut a piece of the gene carrying the master switch. So if you cut it, then you release the brakes and allow baby hemoglobin production, so effectively curing the person of their sickle cell disease.

Similarly, another strategy, which is now being tested, that has yet to recruit patients, is a cut-copy-paste method where we use the scissors to remove a defective gene, and then copy a healthy copy of the gene and paste and insert it. So these two strategies are now being tested in clinical trials, with the first strategy having recruited patients.

(00:40:07) [Hemalatha Rangarajan]  Only patients with severe sickle cell disease are eligible for gene therapy. Now who is eligible for gene therapy. Once again only patients with severe sickle cell disease are eligible for gene therapy because this is still a novel therapy. It includes patients who have had two or more sickle cell events, which we call a vaso-occlusive crises, in the last two years prior to enrollment. Or additionally, they must have failed or they're not tolerating their hydroxyurea. Now you have to be older for most trials, 18 years or older and 50 years or younger. However, there are some trials that have a lower age limit of seven or even 12 years and older.

Now, you're ineligible for current clinical trials if you have brain disease such as stroke, a silent infarct or even Moya- Moya disease; if you have had a prior bone marrow transplant; and if you have a matched sibling donor you are not eligible for gene therapy.

(00:41:01) [Hemalatha Rangarajan]  Outcomes reported from gene therapy clinical trials for sickle cell patients. So, what are the outcomes of the gene therapy trials for sickle cell disease? Now, these are the reported outcomes that I'm showing you in our table. As you can see, the clinical trials shown here you can easily Google. The strategies are shown here, which could either be the postman method or the scissors method. The number of patients who have received gene therapy for sickle cell disease is a little under 50.

Most of these regimens use a strong chemotherapy regimen. The last clinical trial has used medium intensity regimen. As you can see, the outcomes are on the extreme right side. There are three patients who have had a sickle cell event after gene therapy at the last report, but since then, they have not had any further episodes. In the second trial, which is shown on the second bullet, there have been two deaths, one due to a heart issue, which was present even before gene therapy, one due to a blood cancer that developed after gene therapy, and there's another patient who developed a blood cancer, but he's alive and currently receiving treatment. There's another patient who developed an anemia requiring transfusion, but currently all investigations have shown that all these events are unrelated to gene therapy.

(00:42:27) [Hemalatha Rangarajan]  Trials show that sickle cell patients have few to no sickle cell crises after gene therapy . So what are the other outcomes that are of interest after gene therapy that I want to show you? On this slide I'm showing you the outcome of 19 patients who received the postman method of gene therapy, that is, insertion of an adult like hemoglobin that does not cause the red cells to sickle. Now, each horizontal mark represents a patient, with each diamond dot representing a sickle cell crisis, with red being severe and blue being all others. As you can see, before gene therapy, all these patients had several episodes. And most importantly, after gene therapy, they have had almost none as shown by the yellow horizontal bar.

In this slide I'm showing you the outcomes after gene therapy using the scissors method, that is deleting the master switch and allowing baby's hemoglobin production. As you can see, there have been seven patients that have been treated on this trial to date. And on the extreme left side, you can see, on average, these patients have had about four to seven sickle cell crises in the preceding two years. But following gene therapy, they have remained free of sickle cell crisis events for as long as 22.4 months.

 [Hemalatha Rangarajan]  So to summarize, I've talked to you a lot about the outcomes after transplant and gene therapy for sickle cell disease. When weighing your options, you may find this flow chart very useful.

(00:43:55) [Hemalatha Rangarajan]  Several factors influence decisions about having a transplant including severity of disease, availability of matched donor, and patient age. In this flow chart what I'm trying to depict for you is that, first and foremost, you need to know if you have sickle cell disease that is severe or not. If it is severe, and you have a matched sibling donor, then transplant is definitely an option. Consider it when you're younger, because the outcomes are better. If there is a clinical trial, we highly recommend you consider a clinical trial. And also a less intense regimen, especially in older patients.

(00:44:21) [Hemalatha Rangarajan]  Patients who do not have a matched donor or brain disease, may be eligible for gene therapy. If you do not have a matched sibling donor and you have severe disease, your options really depend on whether you have brain disease or not. If you have brain disease, then you're not eligible for current gene therapy trials. Therefore, your only option is, perhaps, using non-matched sibling donors. Most importantly, I'm recommending that you do this in the context of a clinical trial.

If you do not have brain disease and you're younger, you may be eligible for gene therapy. Obviously, that lower age limit varies between clinical trials, or you could consider a transplant using non-matched sibling donors. However, all the patients have the option to consider either a non-matched sibling donor or gene therapy.

(00:45:03) [Hemalatha Rangarajan]  With less severe disease and no matched sibling donor, supportive care may be the best option. On the other hand, if you do not have severe disease and you have a matched sibling donor, and you're younger as shown on the right side, you may consider transplant, but you have to carefully weigh the risks and benefits with your provider. But if you don't have a matched sibling donor and you do not have severe disease, we recommend continuing on the current supportive care that you are receiving, which includes hydroxyurea in most circumstances.

(00:45:29) [Hemalatha Rangarajan]  Matched sibling donor transplants remain the best treatment option. if available. So to conclude, matched sibling donor transplants for sickle cell disease provide excellent outcomes. And it's being considered in patients with less severe disease nowadays. Younger age is always associated with improved outcomes after transplant using either matched sibling or non-sibling donors.

(00:45:48) [Hemalatha Rangarajan]  Current data does not favor one non-matched sibling donor over another, and as I mentioned, it depends on center and even family preference and availability of clinical trials. Gene therapy has made rapid strides, however longer follow-up is needed.

(00:46:06) [Hemalatha Rangarajan]  So this last slide gives you a list of very useful resources to peruse either for looking up educational materials related to transplant or gene therapy. And these are also very useful websites to look up clinical trials that are close to you and recruiting patients for sickle cell disease, either for transplant or gene therapy. With that I conclude our presentation and we are happy to take any questions.

Question and Answers

(00:46:35) [Sue Stewart]     Q & A.  Thank you so much, Dr. Rangarajan and Alison Towerman. We can now take some questions from the audience. And again, if you would like to ask a question, just use the chat box and type in your question, and we will ask that of the doctor and the nurse practitioner.

(00:46:55) [Susan Stewart]  So the first question that came in is, is there a cutoff age for transplants in sickle cell disease? At what age are you too young or too old to have a transplant?

(00:47:09) [Hemalatha Rangarajan]      Thank you. That's an excellent question. Generally we wait for the child to be around three years, at least a minimum of three years, to be considered for transplant. Because prior to that, we cannot give a quick clinical estimate of how severe the disease is. It's only with time that we can tell how severe the disease is. So usually we prefer not to transplant patients younger than three, but like I said, if you're 12 years or younger, your outcomes are the best in both settings.

(00:47:45) [Susan Stewart]      Great. Thank you. The next question is what's involved in post-transplant follow-up care for sickle cell disease patients. What exactly do they have to do? How long does it last?

(00:47:58) [Hemalatha Rangarajan]   So, that's a great question. And I think the follow-up care is pretty long. Obviously, initially when you undergo chemotherapy and transplant, you remain in the hospital for approximately four to six weeks until your bone marrow recovers and the new donor cells start working. And after that, you get discharged and you have pretty intense, frequent follow up in the outpatient clinic - sometimes twice a week, sometimes once a week - to make sure everything's okay ie. the medications are working, and we do not have graft-versus-host disease. I would say that the follow up is pretty long and intense at least for the first year after transplant. But it gets easier. When things go well, the frequency of the visits also decrease. Be prepared for hospitalizations related to any complications that may arise after transplant like graft-versus-host disease or infections.

(00:48:57) [Hemalatha Rangarajan]      But generally what I would like to point out is with the more recent regimens that use the less strong chemotherapy, for some of these transplants we are able to discharge our patients pretty much after two weeks after transplant, even within a week. These are newer transplants that really can be another session by itself, but it does vary, but on an average, we're looking at intense follow-up up to at least six months to a year. So by then the bone marrow is completely recovered.

(00:49:28) [Susan Stewart]  All right, thank you. The next question is about gene therapy. This person is a little concerned about putting her child in a clinical trial and wonders whether gene therapy is available outside of a clinical trial.

(00:49:42) [Hemalatha Rangarajan]  No. So, that's a great question. And gene therapy is not available outside the setting of a clinical trial. I think clinical trials help us understand what we're doing correctly. And it also means that we are monitoring our patients. And there's a big oversight on the investigators who are conducting these trials. And we obtain useful information. Although it seems like research, it is done with the best intention to get useful information. It is done with the intent that patients' rights are protected. So gene therapy is very novel, and FDA will not allow it to be done outside of the context of a clinical trial. And we would still recommend that patients who consider this, look at clinical trials because these are very well monitored with big FDA oversight.

(00:50:37) [Susan Stewart] Great answer. The next question is about the donor. This person wants to know whether the age of the donor matters. Is it better for the donor to be younger or older?

(00:50:49) [Hemalatha Rangarajan]  That's a great question that we did not touch upon. Graft-versus-host disease is what I call the holy grail of transplant, because we're always trying to perfect our techniques so that we don't encounter this dreaded complication. So the older the donor the greater the risk of graft-versus-host disease as well. As studies have shown, the best outcomes, again, if you want to fine tune it further, is with the young donor and the young patient. It's the ideal situation that does not happen in every situation. But yes, if we had a plethora of donors, we would certainly go for a younger donor.

(00:51:25) [Susan Stewart]  All right. This question is about recovery after transplant. This woman says that her son recently had a BMT for sickle cell disease, but she's still unclear as to what determines immune system recovery. How do you measure how strong his immune system is eight months after transplant?

(00:51:46) [Hemalatha Rangarajan]  So there are several ways we can determine how strong your immune system is after transplant. Your doctor will do some testing in the blood where we look at different types of immune cells, either by numbers or by function. So we actually look at numbers and say, "Hey, how many numbers of these types of blood cells do you have in your body? For example, there's a type of cell called CD4 cell. And if you reach a threshold of 200 and above, we say that your immune system has recovered to almost near normal. Another way of checking is to check vaccine responses. That is you receive vaccinations. And did you mount an immune response? Or did you mount a response to the vaccine?

(00:52:29) [Hemalatha Rangarajan]   So there are many lab tests that are done frequently, and it's pretty much a standard of care that our patients undergo. We can determine how well the immune system is recovering pretty much around six to eight months. There's some degree of recovery that is already happening, provided that you don't have graft-versus-host disease that needs some medications that suppress the immune system.

(00:52:55) [Susan Stewart]   All right, the next question is about transplant and gene therapy. This person said that they had a stem cell transplant for sickle cell disease back in March of 2019. She's two years out of transplant. However, her chimerism level has declined since transplant. She's wondering if she would qualify for gene therapy.

(00:53:18) [Hemalatha Rangarajan]  So, unfortunately right now, the way the gene therapy trials are designed, they exclude patients who've had a prior bone marrow transplant. This is because gene therapy is a little new, and they're still trying to learn. And you've already received chemotherapy before, so it pretty much goes against getting enrolled on these trials. Now, things may change in the coming years.

And I already talked to you about chimerism and how even 20% is sufficient. The chimerism may stabilize and that may be sufficient for cure, but you can certainly consider another transplant if that is something of interest and it's acceptable. But right now, no, gene therapy is not a consideration or it's ineligible. It makes you ineligible if you've had a prior transplant.

(00:54:11) [Susan Stewart]  All right, this next question comes from a physician or a nurse. I'm not sure which. What hurdles, social, psychological, financial have you seen in your patients undergoing transplant? And what seems to be your patients' biggest struggle through transplant?

(00:54:28) [Hemalatha Rangarajan] I think the biggest hurdle, in my experience, when I take patients with sickle cell disease to transplant, is economic and financial hardships that our patients go through. We do have some of our patients from parts of the society that have a good support system. I often struggle when I know a patient is the ideal candidate, but does not have this good support system because if you cannot follow through with transplant, if you cannot make it to the appointment, if there is not adequate support system, things may fall apart and you can have a really bad complication. So amongst most of the barriers, I think in my experience, the predominant barrier is the social economic, financial barriers that I'm very acutely aware of when I consider patients with sickle cell disease for transplant.

(00:55:21) [Hemalatha Rangarajan]  And this can also make or break deciding if I can take the patient. Unfortunately, it's the reality that we face day in and day out. So I hope that answers your question and there's a lot more. The families have to be prepared. Sometimes this is entering uncharted territories. Complications may happen that you did not expect. You're all a team. We work together as a team. We go with understanding that sometimes there may be complications that we may encounter, but we go with a full informed consent and we hope that all of us work together for the best outcome.

(00:55:59) [Susan Stewart]   All right, this next question is a bit technical, but maybe you can explain it so people understand. This person wants to know why their sickle cell patients undergoing transplant have a higher risk of developing a complication after transplant called TMA, which I'm not even going to try to say the full name because it's so long. I'll leave that up to you.

(00:56:21) [Hemalatha Rangarajan]  TMA is called thrombotic microangiopathy. That's a great question. In fact, at our center itself, we have reported some patients with sickle cell disease with the same complication. This is an area of research. TMA essentially means that you are at risk of damaging the cells that line the blood vessels in your body. You have blood vessels everywhere. The research question is essentially that even prior to transplant, patients with sickle cell disease have blood vessel issues, that is, issues with preservation of the cells lining up their blood vessels. So, they may be at higher risk of this complication happening after transplant. This is still an area of active research.

(00:57:08) [Hemalatha Rangarajan]  And I think it remain to be seen whether patients with sickle cell disease are at higher risk, and we’re all on high alert after recognizing a few patients with this complication. And some of the medications that we use may precipitate or bring this on, and we're closely monitoring our patients. And hopefully they'll have more data in the coming years. Same thing. Yes. This is a complication that we recognize and we all are trying to stay on the top of it.

(00:57:35) [Susan Stewart] All right. The next question goes back to money. This woman would like to know whether insurance covers transplants for sickle cell disease.

(00:57:46) [Hemalatha Rangarajan]  Yes, insurance covers transplant for sickle cell disease, especially if you meet the criteria for severe disease. Sometimes, we will have to convince the insurance companies, but in most cases we have been able to, but there are always support systems that we can help and we can get second opinions and bolster our case for getting transplants performed for that patients. In most cases, yes. Transplant is covered.

(00:58:13) [Susan Stewart] And what if a person is participating in a gene therapy trial, does insurance cover that?

(00:58:20) [Hemalatha Rangarajan]  So it does. It covers as far as the supportive care that we have to do, because essentially if you look at it, gene therapy and transplant both use chemotherapy. Most of the clinical trials for gene therapy are funded very well. And that covers a lot of the costs of the process itself. So when you participate in a clinical trial, you'll find that many of the costs are actually covered by the trial itself. Especially for gene therapy, this certainly is the case. We are able to cover the standard of care that we would do even in a transplant with insurance, but yes, we will be able to cover the standard of care.

(00:59:04) [Susan Stewart]  And as long as you're talking about chemotherapy, we have a question here asking whether the chemotherapy you get in gene therapy is as strong and toxic as the chemotherapy you get in the stem cell transplant.

(00:59:20) [Hemalatha Rangarajan]  So in stem cell transplant, they use a combination of chemotherapy, usually one or two drugs, or sometimes three to four drugs. But in gene therapy right now, they're using one drug mostly, and most of these drugs are strong. So they are comparable, they are similar and they are strong. Now, I did mention this one gene therapy trial, which uses a medium strength chemotherapy regimen. They use a single agent, but there have been only three patients recruited to date. Remember all these gene therapy trials have recruited, I mean, altogether, not more than 50 patients. So we're still learning. I think there is a very important recognition in the field of gene therapy that perhaps in the coming years, we can use less strong or even non-chemotherapy based regimens for gene therapy. We have several more research questions that could be answered, and this is open area of active research.

(01:00:14) [Susan Stewart]  All right. The next question is about infection after transplant. This parent wants to know what she can do to prevent her child from getting an infection after transplant.

(01:00:25) [Hemalatha Rangarajan]  So there are several things you can do. Definitely take the medications prescribed by your physician because patients who undergo transplant are put on medicines to prevent infections from happening in the first place. always include careful hand washing, masking up. Even before COVID, our patients after transplant were doing masking and social distancing, anyway. So, I would continue to do that, especially in the current era and just if somebody has a fever or cough cold, they shouldn't be coming into the house in contact with your child or your family member with sickle cell disease who has undergone a transplant. In most cases it may be unavoidable if it's a sibling, but just careful hand-washing, wearing a mask when you're outside ,avoiding crowded places, depending on the time after transplant would be sufficient. And your providers, they'll also be able to go through all this with you.

(01:01:21) [Susan Stewart]  So you mentioned COVID and there's another question here. The person wants to know whether people who have sickle cell disease before transplant or after transplant have a higher risk than the general population of getting COVID. And a follow-up question is should their children get a vaccine for COVID?

(01:01:45) [Hemalatha Rangarajan]  So a great question. I think very relevant. Yes. Sickle cell patients who get COVID are at greater risk of complications and deaths. We know that from recent studies. Now, are they at greater risk of getting COVID? I would say the risk is very similar provided you practice masking, social distancing and do the measures that are recommended, You should be fairly safe. But after transplant, all transplant patients have a greater risk of complications if they get COVID. They may not be able to mount immune responses appropriately. They may not be able to get rid of the virus and have more complications. So we are all on high alert. And like I said, our patients are already masking and social distancing, and we continue to advise them to do so.

(01:02:34) [Hemalatha Rangarajan ]  Should they get COVID vaccine? Absolutely, yes. Especially if you're eligible. Now we have 12 years and older. Prior to transplant, yes. Even after transplant, we are recommending that after three months after transplant, all our patients who have undergone a stem cell transplant get the COVID vaccine. The benefits outweigh the risks. And we are strongly recommending yes to the COVID vaccine.

(01:03:01) [Susan Stewart]   All right. This mother wants to know why patients sometimes get aspergillus infections after bone marrow transplant.

(01:03:10) [Hemalatha Rangarajan]  So aspergillus is a type of fungal infection. A fungus is an organism. In the air, we breathe, we have something called spores that we can inhale. After transplant, your immune system completely comes down to zero basically. Because we have to bring down the immune system of the patient so that the new cells can come and start working. If they did not do that, then the immune system of the patient will recognize the new cells that come into the body and say, "Hey, you don't belong to me, so go away." So it's kind of like a necessary thing to do that we bring down the immune system to complete zero as far as possible, especially with the stronger regimens.

(01:03:54) [Hemalatha Rangarajan]  Now, when your immune system is down, then your ability to fight infections is not the strongest. And, therefore, most things that may not have caused bad infections in you because you had a strong immune system will now cause problems. And that includes fungal infections. And it can be air you breathe, or you may have had a prior infection with the fungus, which was small and it didn't go away, but just became worse after transplant. So there are several reasons.

(01:04:22) [Hemalatha Rangarajan]  We definitely recommend that our patients mask up and don't go to construction zones, etc. where there may be new fungal spores, etc. So, there’s a lot more to it, but, definitely, a weak immune system, an inactive immune system is one of the causes why you get a fungal infection after transplant. That is why it is important that you take the medication that your doctor prescribed you.

(01:04:46) [Susan Stewart] This individual wants to know where she learns about clinical trials and how does she get her child into one?

(01:04:54) [Hemalatha Rangarajan]   So, great question. I know these slides are available to be viewed later and you can download and print them out as well. On slide 45, we actually gave a list of resources to look on their websites. And on all these websites, you have a link for clinical trials. I've shown you here that you can enter and you can find out by your zip code, what is closest to you. So certainly these sites will give you the full information. And please feel free to reach out even later with any questions regarding this.

(01:05:28) [Susan Stewart] Next question is how do you weigh the risk of graft-versus-host disease, versus standard treatment, versus the gene therapy or transplant?

(01:05:41) [Hemalatha Rangarajan]  Yes, that's a great question. And I think that was what we were trying to show you, the algorithm slide on slide 43. It really depends on the age of the patient, the motivation of the family, how well they understand the benefits and risks and how much sickle cell disease is affecting the quality of life of the person. Certainly, if you're younger, you have a sibling donor and you have severe disease, in this day and age, all of us would recommend transplant. When you get older, the risk for transplant increases, but now we have regimens that use less strong conditioning regimens that we could also consider with less complications. So it is a tricky question because most of the time when we decide to take a patient to transplant, we’ve had several conversations, consultations with the family.

(01:06:32) [Hemalatha Rangarajan]  We go back to our original providers, the hematologist and ask them how well do you think the family will cope with complications that may arise? It's almost like we have several specialists sitting together and deciding along with the family, if this is the best thing to do. So it's not a one day decision, it can be several months. And even like two years before you decide to take the plunge or not decide to take the plunge. So these are conversations that are always ongoing for several months prior to the actual decision

(01:07:02) [Susan Stewart]  Next question is about diet. Do you have to be on a special diet after you have a transplant for sickle cell disease?

(01:07:11) [Hemalatha Rangarajan]   So there have been studies early on that show you should be on a special diet that puts you at less risk of infection, but more and more we're learning that just a normal diet and sensible approach to your diet should be sufficient. Or we say, you should not take stale food or food that has been lying around for a long period of time, or like raw fish, etc. But generally a normal diet is usually recommended, although some people might differ saying, you should not take fruits that cannot be peeled, but this is just an area of research. But more and more we're recognizing a normal diet should be sufficient, even post-transplant.

(01:07:49) [Susan Stewart]  All right. This is from a mother who said her daughter will be having a transplant with a sibling donor. She wants to know if you would recommend that she talk to another parent whose child has gone through transplant.

(01:08:04) [Hemalatha Rangarajan]  Yes, absolutely. I think this is something all of us providers we ask our patients, "Would you like to talk to somebody who has gone through this process because they'll give you an unbiased approach?" And I think in our list of resources, we have a peer to peer support program also listed. Absolutely. I would ask the provider, if you could get in touch with somebody who's had a transplant, if possible the same type of transplant. And that does not always happen. It's may not be possible because some families may be unwilling, but you may always find that person who's willing to talk. It's always useful because you get an unbiased approach to your daughter and child's care.

(01:08:42) [Susan Stewart]  And I might mention in response to that as well, BMT InfoNet has a program called Caring Connections, which you can reach if you go on our website, and click on the Get Help tab. And you can be connected by phone with someone who's been through transplant for your particular disease, your same age, etc. Very helpful. If you don't have a computer to get online, you can call us at (847) 433-3313, and someone will help you.

All right. We are running close to the end. And I think we'll take one last question. It's kind of a comment or a question, but one of the listeners said since not all anti-fungal medications work for aspergillus, why don't transplant centers tell you that upfront?

(01:09:35) [Hemalatha Rangarajan]  So we try to prevent fungal infections before and after transplant by putting you on medications. But you are absolutely right. Sometimes despite doing that, we get breakthrough infections. Everything is not under our control, we recognize that. And the fungal medications vary. There are different types. You can go very strong depending on the type of transplant. So without knowing the particulars of any patient in detail, to tell you that in most cases, the fungal medications we give people will prevent most infections in general. But it really depends on the balance of how weak your immune system is and what stage of transplant you are, and with your risk factor that puts you at risk of a fungal infection. So, there's lots that goes on, and sometimes it's beyond. The discussions can be very detailed as you can, but it's impossible to cover everything. But I recognize yes that sometimes all the medications will not prevent any infections. We will have some breakthrough infections. So hopefully that answers your question.

(01:10:47) [Susan Stewart] And then one last question, do all children who go through transplant for sickle cell disease have infertility, or does it depend on age?

(01:10:59) [Hemalatha Rangarajan]  So, almost all patients, especially using the traditional strong chemotherapy regimen, have had infertility, more so in boys., Especially the sperms are more vulnerable to the damage from chemotherapy. So in the younger age, it's harder because you cannot ask the kid to give a sperm sample, but in the older kids, we certainly can. Most transplant centers now, we do some things called fertility preservation techniques, where we approach the family. We would not take the patient to transplant unless they've had a fertility preservation consult, that is talk to somebody who can talk to about the long-term infertile period and what you can do to possibly preserve testicular tissue or piece of the egg, or preserve some sperm, if possible, especially in older boys.

(01:11:56) [Hemalatha Rangarajan]  Now with the less strong regimens, in the least strong that I mentioned to you, they had 21 pregnancies. There were actually seven men who fathered kids without even using assisted reproductive techniques. So that's also an area of research where we are trying to bring down the chemotherapy intensity, so that fertility is preserved. So if you use strong or possibly medium strength regimens, infertility is pretty much always there. And that is something we are very aware of. And I know that for many families, this is unacceptable.

(01:12:30) [Susan Stewart]  All right. And actually we just had one more question, pop up. Do you suggest therapy or counseling for patients after transplant? In general, my son is doing well coping following his transplant, but my husband and I understand the psychological impact due to isolation and lack of social interaction with peers.

(01:12:53) [Hemalatha Rangarajan]  So I think everybody's coping levels is different, but you're absolutely right. I have had to encounter similar situations, especially with my teenage patients. It's a difficult time during their life periods, especially to go through such a major life changing event, but yes, you should consider counseling, especially if you think they're having impact due to isolation or lack of interaction. And that is something you can proactively talk about with your providers. Your providers are here to help you. You can openly let them know that this is an ongoing issue and almost all major transplant centers have psychology teams that meet with the children, or young adults who are patients with sickle cell disease, independent of the transplanter providers, so that they can confidentially counsel them. But yes, absolutely. That's a great question. And I think we underestimate how much our children, our young adults get affected.

(01:13:57) [Susan Stewart]  And I might add that BMT InfoNet actually just today unveiled a new directory on our website called the Mental Health Directory. And it lists more than 80 mental health specialists who are actually familiar with transplant and graft-versus-host disease, and who are available to counsel patients and their caregivers. And it has people for pediatric patients as well as adults. So I encourage you, if you're interested, to go to the BMT InfoNet website,, click on directories, click on mental health. And if there's nobody at your transplant center, see if there's a community psychologist or social worker near you who might help.

So with that, I think we need to close it. Thank you again, Alison and Hema for educating us on this very important topic. And I want to thank you the audience for your excellent questions. They really did help round out the presentation.

This presentation was recorded and it will be available on BMT InfoNet's website sometime next week, if you'd like to listen to it again. And you'll also be able at that time to download the slides, if you want a copy of the slides. I want to thank again, Bluebird Bio for sponsoring this webinar. And I want to ask the audience when you leave the webinar, please take just a minute to complete the exit questions. Your feedback about tonight's event is very important to us, and it helps us to improve and plan for future events. So everyone have a wonderful night and thank you.


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