Glaivy Batsuli, MD, Pediatric Hematologist and Oncologist and Robert Sidonio, MD, Director of Clinical Operations and Clinical Research for Hemostasis, both at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta talk about how the “Atlanta protocol” is a new way to treat pediatric hemophilia A patients and how the use of the medicine, HEMLIBRA is a game changer.
Glaivy Batsuli, MD, Pediatric Hematologist and Oncologist at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta.
Tell me about the Atlanta Protocol and what exactly is it?
Dr. Batsuli: This is a protocol we thought about because we treat patients with this disorder called Hemophilia A. It’s when you have a deficiency to a protein, a blood clotting protein. These patients require infusions of medicines in order to not have bleeding and to help keep them safe. Unfortunately, one of the consequences of giving infusions of this medicine is – because their body doesn’t recognize it, because their body doesn’t make it – their bodies can attack the medicine that’s there to help keep them safe. And that’s called an inhibitor. And the way we treat that is we give the factor medicine very often, usually every day at very high doses to try to trick your body into thinking that the medicine should be there. But it’s a very intense process. And during that period where you’re given lots of medicines, your body is making a reaction to it. So sometimes they must get treatment with a different product in order to prevent bleeding. And so with the Atlanta Protocol it’s kind of combining the ability to try to get rid of the antibodies called immune tolerance induction but we are also combining it with the use of this medicine called Emicizumab or HEMLIBRA. This is a medicine that’s recently come out and it’s been approved for patients with Hemophilia A and inhibitors. And the great thing about this medicine, it’s a subcutaneous injection – meaning it’s an injection under the skin just like a diabetes medicine like insulin. With using this medicine it’s been shown that it really prevents patients, even with these antibodies in their blood, from bleeding. So, we combined the ability to do a subcutaneous injection to prevent bleeding along with the ability to get rid of the antibodies. But we don’t have to be as intense and do it every single day at high doses because they have some bleeding protection so we can take a little bit more time with it. But with combining these therapies it’s allowing families to have a little bit more freedom in terms of not having to inject the factor medicine every day but knowing that they have safety and protection from bleeding with the subcutaneous medicine.
How often do they have to get this now?
Dr. Batsuli: So, the subcutaneous medicine, the HEMLIBRA is injected either once a week or once every two weeks and that’s injected under the skin. The immune tolerance therapy that we do enables families to inject the factor infusions just three times a week in order to try to trick their immune system into getting rid of the antibodies.
Compared to the previous which was pretty much every day.
Dr. Batsuli: It was every day, very high dose infusions. And they had to spend a lot of time because it could be a lot of volume that they had to inject into the I.V. every single day without fail. A lot of times in the younger kids we had to put a port-a-cath or some sort of central line for the families to be able to give it every day in the high volumes as well.
So how does this impact their quality of life?
Dr. Batsuli: I think it’s made a significant difference because the part where they’re getting the subcutaneous injection with HEMLIBRA they have that ability to prevent bleeds. So, we’ve heard from a lot of our mothers. They don’t worry as much that their child is going to bleed because they have that protection with the Emicizumab, the HEMLIBRA medicine. But the other side of it, we’re also addressing that inhibitor, so they know that we’re also working to get rid of that antibody response. So we’re working on both sides in terms of preventing bleeding and also getting rid of the antibody. And the great thing about the goal with these therapies for Hemophilia is if a patient has a bleed, we really want to be able to treat them with Factor 8 which is the product that is the best for their body and that they’re missing. So even if they needed surgery or they had a bleed, being able to treat with a Factor 8 product has always been shown to be superior than another product that doesn’t have Factor 8 in it.
So how long has this been around?
Dr. Batsuli: So, we started trying it in our patients probably a year and a half almost two years ago and we had a couple of patients that were doing it. And we’re big on research and really contributing to the hemophilia community so we went back and just looked at our records just to see how kids were responding to this type of treatment. And this is what was published last year, just kind of the Aflac Cancer and Blood Disorder Center’s experience with this type of treatment.
Is it just only this hospital or are there other hospitals also using this?
Dr. Batsuli: The patients we looked at were just the patients that we manage here in our hospitals. Since we published our paper, we have received communication from providers at other centers that were interested in trying it or had started a similar regimen in their patients and they were asking about guidance on how best to manage those patients.
Do you know which hospitals or what areas?
Dr. Batsuli: Throughout the country – and I know there has also been discussion of people using it in different parts of the world.
And with hemophilia a lot of the kids must take all these precautions. Sometimes they can’t take part in certain activities. Does this drug allow them to have that opportunity now?
Dr. Batsuli: With them having hemophilia there’s always certain precautions that will always be there because of their diagnosis. But I think it does provide a little bit more freedom to do some of the things that they weren’t able to do. Some of our kids were pretty debilitated in terms of they were wheelchair bound. They had trouble attending school because they were having so many bleeds, having to come to the hospital to get treatment for their bleeds and stay in the hospital for long periods of time. So I think especially with our kids with these inhibitors it’s giving them freedom just to be kids and to do things that they weren’t able to do before – and not to be confined to a wheelchair and to be able to go to school and not have to miss so many days from school.
How would parents – knowing about this how would they be able to get this for their child?
Dr. Batsuli: The nice thing is it’s not a specific medicine that we only have access to or that we’re distributing, but everyone has access to it. It’s an approach as opposed to a specific medicine that we only have access to. The nice thing is the HEMLIBRA has been FDA approved so anyone can go through their insurance company for approval. And the immune tolerance therapy is just using Factor 8 infusion. It’s up to the provider to decide how they want to do that, so everyone has access to this approach. It’s more so just a different mindset of how to approach these patients.
If a parent sees this story or sees the research on it they can bring it to their doctor?
Dr. Batsuli: Yes. They can go talk to their provider and have a discussion on what’s the best approach for that patient because every patient is an individual and they’re all different.
Is there any difference in insurance costs when you’re combining the two medicines together?
Dr. Batsuli: There are people starting to look at the financial impact of the treatments. I think the important thing to think about with hemophilia is we think about treatment throughout the lifespan and the total cost throughout someone’s life to treat the disease. And there is going to be more research needed into exactly how this compares to our traditional methods. So far, we’ve been able to do this treatment in patients that we thought would benefit from it. We haven’t received any denials from insurance companies which has been a great thing for our patients. But that is still to be determined.
Anything I didn’t ask you that you feel that people should know?
Dr. Batsuli: I think it’s a very exciting time in Hemophilia A treatment because – especially for these patients with inhibitors – for 20 30 years these patients really didn’t have good options. They were kind of stuck with other bypassing agents that didn’t quite treat bleeds as well as Factor 8. I think with the onset of all these new therapies for hemophilia and so many people looking at different ways to approach the disease it’s very exciting for families now to have options in terms of how to treat their child and to know that there’s lots of different options for their child to live the healthiest life that they can with this diagnosis.
Robert Sidonio, MD, Director of Clinical Operations and Clinical Research for Hemostasis at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta
What exactly is the Atlanta protocol?
Dr. Sidonio: The Atlanta protocol is a protocol that our group developed last year, and it’s a modern approach for the care of hemophilia patients that have inhibitors, which are neutralizing antibodies against factor VIII. It’s a complication that’s common in patients, particularly those that have severe disease. We took a new drug, emicizumab, and we combined it with an older way of managing or getting rid of an inhibitor, which was high repeated doses of intravenous factor VIII. So, we put together a protocol that we thought would be more acceptable to patients and potentially work better.
What is factor VIII?
Dr. Sidonio: Hemophilia A is the result of factor VIII deficiency. If you have hemophilia A, you’re missing or have defective amounts of this critical clotting factor. Hemophilia A has been around since the beginning of time. About one in 5,000 males are born with this disorder. It can happen spontaneously, so you don’t have to have a family history to be at risk. About half of hemophilia A patients have a severe form in which they make no factor VIII. And then about a 1/3 of those patients go on to develop antibodies against the factor VIII, which makes the infusions of factor VIII to correct their bleeding problem impossible and ineffective.
So, factor VIII is what people need to help with the clotting of the blood?
Dr. Sidonio: It’s one of the many clotting factors that you need to stop bleeding. So, when you get a cut, FVIII as well as other clotting factors help you form a clot and stop the bleeding. It’s one of the clotting factors that’s critical to preventing you from bleeding to death or having other significant bleeding. We all have traumatic events every year – if you trip or you cut yourself shaving, your body has ways of stopping the bleeding. But those that have factor VIII deficiency or hemophilia A will continue to bleed and bleed because they’re missing that critical clotting factor. We are trained to care for children with cancer as well, but we have chosen to specialize in bleeding and clotting disorders. People such as Doctor Glaivy Batsuli and I focus our practice on all the kids with bleeding disorders at the Aflac Cancer and Blood Disorders Center. We likely have 400-500 children with hemophilia in Georgia alone.
For the Atlanta Protocol, can you describe exactly what you do with the condition?
Dr. Sidonio: In Hemophilia A patients that have developed inhibitors or antibodies against factor VIII, we have to sort of trick the immune system into accepting the factor VIII infusions again. The way that you do that is to give very large repeated doses of the factor VIII. Over time, the body eventually accepts the FVIII and then you can go back to infusing them again and control bleeding better. The traditional way was to give very high doses of FVIII every day. So that would require getting up in the morning, starting an I.V. on a young child, and infuse every single day. And that still offered inferior protection against bleeds. So, what our group did is we took a new medication called emicizumab that controls bleeding but doesn’t do get rid of the inhibitors, and we combined it with a less aggressive factor VIII regimen, so they only need it three times a week. That means weekly or every other week emicizumab injections and three times a week intravenous FVIII infusions.
You did a study before this started. Can you talk a little bit about that study?
Dr. Sidonio: We had participated in the clinical trials for emicizumab and during the study we had a couple of internal discussions about whether combining this new medication and FVIII as immune tolerance would work. So, we decided to organize a protocol led by Dr. Batsuli and we discussed our idea with our patients because we felt this was something that we really felt would work. So, myself, Drs. Meeks, Zimowski, Batsuli got together, developed a protocol and implemented it in 2018. We had seven patients that agreed to this protocol in which we combined factor VIII with emicizumab. As of today, we have three patients that have completely gotten rid of their inhibitors or antibodies and they’re now able to get factor VIII to control their bleeding. If they ever have surgery, we can use the factor VIII to treat them which is a much better approach.. Additionally, these patients bleed less than prior to tolerization and hopefully, over time, they can stop giving themselves FVIII on a regular basis. At this point we’ve had seven patients that underwent the study, three of them have no evidence of inhibitors, and an additional one that has partially tolerized (inhibitor mostly gone). We have a few patients that are still undergoing the treatment and one of them that has decided to pause the treatment, just totally understandable in a young child trying to do this. Even though it is more acceptable than the old way to do ITI, It is still somewhat intensive in the first 6-12 months.
Was Jaylynn one of the first patients?
Dr. Sidonio: Yes, Jaylynn was one of our patients. We believed he might have been patient number three. He attempted the traditional way of getting rid of inhibitor multiple times, which meant he had to get up every morning and infuse with very high dose, high volume, factor VIII and despite all this work he was still at risk for bleeding. He did that for many, many years and had issues with his central intravenous, a plastic line put in temporarily under his skin so we can have better access to his veins. He attempted that many times over the years. And we could just never get him fully cured until we decided to use the Atlanta protocol. Most recently, in his last visit he had no evidence of an inhibitor again. We’re very excited for him. He’s one of the first patients in the world to be tolerized using this regimen.
What does this mean for the quality of life for a kid that has hemophilia?
Dr. Sidonio: When eimcizumab became available for inhibitor patients and it meant they could a medication under the skin instead of through their veins and oferring good bleeding protection. The only issue is that it does not rid the body of antibodies to factor VIII. We wanted to get rid of those antibodies so hemophilia patients could consider new therapies in the future. We want to give them access to new studies and approaches to care for hemophilia. For example, gene therapy will be available sometime in August of this year, and we want patients like Jaylynn to have access to that when he’s an adult. We don’t want to limit their future options. What we don’t want to do is regret not having undergone immune tolerance 15 years later after the typical time to develop an inhibitor (12 months to 36 months of age). We feel the Atlanta protocol offers a palatable, more practical way of treating. Patients can choose the time of day that they want to infuse. They don’t have to infuse in the morning like they did before. And they only need to infuse three times a week versus every single day. You can imagine having to stick a child once to twice a day and doing it for two to three years. That’s difficult on a child. They become emotionally exhausted. So, it really affects their quality of life and the entire family’s quality of life. It’s very emotional to watch the process of an infusion in a young child. Anything to reduce this the burden on these families is very welcomed.
Have the other two patients shown any improvement? Or are they going to try to keep on doing it until they see effects?
Dr. Sidonio: The patients still undergoing their therapy are seeing improvements but it’s just a slower improvement. We’re still trying to fine tune what is the optimal dose of factor FVIII, what is the optimal frequency. Some of the patients may need to be given it more often or maybe even a higher dose. There are still some characteristics of patients that put them at risk for not ever being able to achieve full tolerance. We have some patients that will probably never be tolerized, unfortunately unti something new comes along. We’ve sort of accepted that they have a good therapy and will need to await some new breakthrough. We have two big clinical trials where we are hoping to answer some of these questions with more patients in multiple centers. We had success in a small setting with seven patients, and the next step is to demonstrate this in more patients in multiple cities in the US and throughout Europe and Canada.
Is this approach currently available to any child that has hemophilia?
Dr. Sidonio: Our group created this protocol and it’s not proprietary so any hemophilia provider can offer this approach to their patients. When you participate in a study we are able to collect a lot of important data in a uniform way and hopefully answer why some kids respond and why others do not. We can also find out if there are some things that we can modify to make it successful for everyomne. We know that some patients will not be successful no matter what we do. We hope the hemophilia patient community is excited about this new approach and participate in these studies. Both study descriptions are available on clinicaltrials.gov. One called Emi Pups and Nuwiq ITI study is only available in the US. The other larger studys is called MOTIVATE and it is available in multiples sites in the US, some sites in Canada and in multiple countries in Europe. The latter study is a collaboration with Dr. Carmen Escouriola from Germany.
Is there anything that I didn’t ask you that you feel people should know?
Dr. Sidonio: I actually met the person that demonstrated the concept of ITI in the first patient in 1977. He is a retired German doctor who felt strongly that ITI would work and offered it to his patient with success. So, we were inspired to take the similar concept, develop a protocol and offered it to our patients some 40 plus years after the first ITI strategy was implemented. We embraced the spirit of innovation and decided to offer it to our patients and thankfully it worked out for our patients. Now we have another way of treating patients for something that hasn’t had any significant improvement for 20 to 30 years.
Do you call it Atlanta protocol or is there another approach or name that it is called by?
Dr. Sidonio: Traditionally, any protocol in which you’re trying to attempt to get rid of an inhibitor is named after the city in which it’s developed. For example, there’s one called the Malmo protocol in Sweden and a protocol called the Bonn protocol in Germany. So, we followed the same tradition. And since we developed it here, we wanted to give a shout out to Atlanta.
Interview conducted by Ivanhoe Broadcast News..
END OF INTERVIEW
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