Matthew M. Heeney, MD

 I want to give us all an opportunity to give some advice or practice pearls to all of our viewers including other hematologists, maybe focusing a bit on red blood cell health or other areas that you think are important including decreasing long term organ damage. I’ll start with you Elna. What advice or practice pearls do you have for our audience?

 I think it is the shifting paradigm that yes sickle cell is an anemia and it causes pain, but the thing that reduces survival and still has maintained the early mortality in sickle cell disease patients compared to the general population is not necessarily the pain or the pain episodes. It is the progressive organ dysfunction and so we should slowly move away from the deception of sickle cell being a mild disease. We should consider it like diabetes or hypertension and that the organ damage is also a silent killer. If we shift that paradigm the way we approach them and how we approach our practice even towards them, we will shift an emphasis in embracing and offering disease-modifying agents to almost all of our patients and having the discussion of the impact of end organ dysfunction and damage in overall longevity and mortality.

 Thank you so much, Elna. Nirmish, you’re next.

 I would just extend the conversation in the sense that educate and be real, continue to educate. I love the descriptions that came up in our conversation today. As I told Matt, I’m going to use some of those. I’m very graphic about drawing pictures and being in the room and getting them to really understand and see what’s happening inside of them because that gives them a little bit of control of knowing what’s happening to themselves. Otherwise, it’s a chronic disease that they have no control of. What control can you give them? It’s educating them about the disease and being able to tell others about what’s happening to them. I think the pearl for me is to educate them and that includes education about these new therapies, and the new drugs that are available now. I even actually started to talk to them about the new drugs that potentially could come.

When we talk about gene therapy, I still kind of give a teaser about it. We’re not there yet. It’s all about being real with them. We don’t have the data. I’m trying to get them to understand that’s why research studies are occurring; this is what we hope that patients can be involved enough with. The patients, I can’t say this enough, they’re really smart. They’re really savvy about connecting to others and they want the information. They just take it up and soak up this information and I think it’s good for the community. Those are some of the pearls. And I mentioned it before, talk about these new medicines when they don’t need it. Talk about everything but pain until you have to talk about pain. Elna brought this up, that there might be the pediatrician inside of us trying to think about the whole world and not the adult side, but I think that our adult colleagues, and I know Biree you do this as well, I think we’re understanding that the quality of life is a big deal. Thus, I think those are some things to consider as we have our colleagues continue to see patients with these new drugs.

 I’ll leave you with 2 more images or analogies that I use because I think that there’s nothing sexy about having a chronic disease and a lot of it is just persistence of the patients, families, and providers in meeting the treatment goals and treatment plan. As I tell families when they’re going for their annual ophthalmology visit or their annual TCD [Trans Cranial Doppler], there’s nothing sexy about this. It’s like changing the oil in your car. It’s a pain. It’s annoying. It costs a little money. But if you don’t do it, what happens to the car? All the kids know the answer to that. It breaks down. Thus, that’s why [there is] this constant persistent pressure to keep on the plan is really very important.

The other one that I find useful to try and sometimes improve adherence to the treatment plan is the idea that organs are like a rock on the beach and the waves every day hit the beach, and they hit that rock and every day you don’t see anything. It’s just like the damage which is done every day with sickling even though you have no symptoms. There’s some clinical inexorable accrual of organ damage is what my mentor used to call it. There’s a little bit of damage every day that’s imperceptible. When you come back to that beach at the end of high school and you see the rock there, it’s still getting pounded by the wave and then you go away to college and then you have kids and you come back and all of a sudden there’s no rock on the beach. It’s just sand. It’s that daily pounding of that rock by a wave that you don’t notice the rock changes, but it’s becoming sand slowly and that’s what we’re trying to prevent with the daily damage of sickle cell disease on your organs.

Hydroxyurea and other disease-modifying agents are trying to prevent that from the daily point of view so that, as Nirmish pointed out or Elna pointed out, we’re trying to improve the overall health and organs of our patients who we present to our adult colleagues so that they can ultimately hopefully have a prolonged life and that sickle will no longer be an either immediately life-threatening or life-limiting disease, but hopefully have normal lifespan and quality of life. That’s really the goal. It’s hard. It’s hard to do that as a child, as a teen, and as an adult with so many other pressures on us but to encourage them to continue to follow the treatment plan with what we have while also being cognizant of what’s coming and what might be until something better comes along, as I say. Let’s follow this plan now. My promise is to keep them informed of what’s potentially available, both experimental and approved, and then they can choose collaboratively with us to potentially take on some of those new therapies.

Thank you, Matt. I really love the imagery in those analogies. I think we’ll all start to use them. I just wanted to add that I think when I speak to colleagues, clinicians of any specialty, patients, the community, family members who help to support their loves ones living with sickle cell disease; I really tell them that the tide is changing in sickle cell disease and it’s changing pretty quickly. Not only do we have more therapies available now, but our understanding of new potential targets is also growing exponentially and we’re seeing that playing out in the clinical trials that are available and that will be emerging in the near future. I think that sickle cell disease as we know it is changing. It is changing. Our patients may not feel that way today, but I do talk to my pediatric colleagues including some of you on the webinar today and I’m always heart-warmed when I hear the hydroxyurea story, for example. My colleagues say that ever since we’ve been giving it to babies starting at 9 months of age, we have such a healthier kindergarten class when we see those 5-year-old’s go off. That just warms my heart.

I think as an adult practitioner I’ve not yet begun fully to that extent to see the effects of novel agents or disease-modifying therapies or even transplant for that matter because we don’t do enough of it in the adult world. But I think that that tide is really changing. Just like hemophilia, for example, where we’ve come a long way, the expectation in hemophilia management is no leads. When we think about HIV care and we were making people toxic, sick with therapy as we knew it a few decades ago, and now people can be on 1 pill once a day. I think that there’s the potential in the very near future, hopefully in all of our lifetimes, to see that amazing impact on those affected by sickle cell disease. I’d say the future is definitely bright. I want to thank Elna, Nirmish, and Matt. And I want to thank you all for watching this 

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A panel of experts in hematology discuss the future directions for sickle cell disease and share practice pearls for disease management. 

Practice Pearls for the Management of SCD

 Now, Matt, I want to ask you to look into your crystal ball, and we’ve talked a bit about markers of red cell health, right, specifically laboratory markers of red cell health. How do you think in the future we may be able to use those markers to define sickle cell disease severity and possibly be able to correlate those markers with treatment efficacy as new treatments emerge?

 Well, some of these new biomarkers, again, I hope that at the most basic level that they’ll help us to risk stratify patients and to better understand the heterogeneity of the population as Nirmish and Elna described. I joke with parents that when I have a new baby with me, if I have 100 new SS babies, 10% will go on to have a stroke, historically, by the time they leave my care. Twenty-five percent of them will have a severe acute chest. And 10% or 20% of them will almost never see me because they’re perfectly well. That heterogeneity of clinical phenotype is really challenging. Thus, my hope is that some of those biomarkers will help us discern some of that and risk stratify. And then, depending on what the biomarker is, it may be a target of one of the therapies and demonstrably changed and that will be a good read out, objectively, for providers and patients to monitor the activity of their disease, and of the efficacy of their therapy. That’s really the goal, but it’s been a challenge to identify these biomarkers and to identify ones which are easily obtainable, reproduceable, and widely available that will then change practices like that. I think those are the biggest things.

 Thank you, Matt. Now, Nirmish, let’s talk about some of the agents under clinical trial investigation that are focusing on red cell health. What is the unifying mechanism of action, so to speak? How might these treatments be a little bit different? And what does the future hold for us in terms of these agents that are targeting red blood cell health?

 We’ve had this conversation about ways to try to help red cell health, and a lot of it’s really coming back and focusing on how do I decrease …? And in the end, how do I correct the oxygen dissociation curve? That can be through upregulating fetal hemoglobin. It can be by modulating the pyruvic highness receptor by activation of that. There are a couple of different medicines or mechanisms that are being evaluated. The one that has a little bit more data and is a little bit further on are those agents focusing on the PKR [pyruvate kinase-R activator]. And in that sense, there are at least 2 companies that are working on this and have data that’s come out in a couple of different conferences. I think they’re pretty exciting at this point. We’re showing that when you decrease the homolysis by shifting the oxygen dissociation curve again back to where hemoglobin A should be, and hopefully that we have an improvement in hemoglobin, we have a direct reduction in homolysis markers, and the key part here is hopefully also having a clinical end point. Also show that this is tied to something that benefits for these trials, pain.

The preliminary data so far is that we’re maybe increasing hemoglobin to about one and a half grams per deciliter in a couple patients. It does seem to be improving red cell health. We have some data coming out at least for … that it’s improving glutathione. It’s improving phosphoserine expression on the surface of the cell and it’s something that actually persists even after the drug stops. All of these things that go wrong is not again eloquently described a very complex pathophysiology. All the things that are going wrong with red cell health seem to be with this preliminary data is to be something that’s being targeted and potentially beneficial for patients.

 Thanks, Nirmish. Matt, do you want to piggyback on that and maybe give your opinion on the 2 agents looking at the PKR pathway?

 Well, much more expertise here in the group than me on these 2 drugs but I do think that they are beginning to potentially show some benefit. I think using the similar sort of mechanism as seen by voxelotor to try and increase the oxygen affinity and therefore increase the overall hemoglobin in patients, but still very early trials. This purported idea of increased red cell health that we’ve been discussing already this morning, the idea of improving the ATP [adenosine triphosphate], or the energy availability to the red cell, may provide some benefit beyond even sickle cell disease but in other hemolytic anemias potentially where these drugs could be released. But also, improvement in other rheologic and sickling features in sickle cell. I think there’s some promise here. I think we still need to learn more about them, the differences between them if there are any, the safety of them in terms of potentially needing to be careful in terms of how you start and stop the medications and then again who the optimal patients are. Is it reserved for those patients who are particularly anemic, if improving hemoglobin is the primary goal, or will they have other benefits in sickle cell disease such as reduction of vaso-occlusion and the consequences of that? Thus, there is still quite a lot to be learned, and there are very early trials but I’m glad that there’s interest in completing these trials and interest in new therapeutics.

Matthew M. Heeney, MD, and Nirmish Shah, MD, hypothesize about the ability of emerging sickle cell disease biomarkers to assess risk-benefit and disease severity in patients. 

Utility of Potential SCD Biomarkers in SCD Management 

 I want to open this question to the panel a bit more. This is worth a discussion in terms of longevity of the data we have in front of us when making clinical decisions with patients on new agents or even recommending clinical trials. I wonder what your feelings are, Nirmish and Matt, about longevity of data and the end points in clinical trials that Elna [Saah] outlined so well for us.

 That’s always a question. We need brave participants in trials to help us move the field forward. There’s no promise of good longevity of efficacy, but our hope is that there will be. As Nirmish spoke about earlier, we need to use the medications that have recently been approved and use them in different settings to balance the incredible pressure—because of the unmet need—to approve drugs early. But we want to make sure they’re effective. We still need ongoing investigations of current drugs.

In the terms of the curative approaches, Elna is correct. For some of these experimental approaches, like gene therapy, there are requirements for decades of follow-up in patients. That’s appropriate too because we don’t know the long-standing effects of genetic modification. I find it very important to have end points that are relevant to patients.

One of the biggest challenges with oxygen dissociation curve-shifting agents is that by increasing your hemoglobin by 1 g/dL, you may improve mortality years from now. It’s extremely difficult to explain to a 14-year-old that taking this medicine every day makes you different from everyone else, but it makes you live a little longer. Every 14-year-old thinks they’re going to live forever. It’s hard to explain to persuade them to be adherent to their medication when they don’t see any meaningful symptom reduction. We have to have some mix of immediate benefit that the patient can hopefully recognize—even that’s challenging in my age group —but also some promise of future benefit in terms of the protection from end-organ damage we described.

 really mean? The cessation of that accumulation of end-organ damage and the cessation of acute complication. It’s a tough balance to get effective medicines to people quickly and safely, not only immediately but also in the long term.

We need to be real with patients about the data. To Matt’s point, we have a certain amount of data, and this is all I can speak to. Patients are coming to us and asking about gene therapy. They want a cure, and rightfully so. But even if there’s approval the end of this year or next year for sickle cell disease, as Elna brought up, we have only 2 years of data for about 20 patients. Based on the California registry and the UK registry, patients with sickle cell disease have an increased risk of hematologic malignancy at baseline.

If you look at data coming out of the University of Illinois Chicago, patients with sickle cell disease who get chemotherapy for any reason have an increased risk for complications. It’s not surprising that you give chemotherapy to a hyperplastic marrow and sickle cell disease. As a comparator, patients with β-thalassemia aren’t having this. They’re being transfused their whole life. Their marrow is in a very healthy state. We need to be very clear with patients that this is what we know. Then [we need to] make that decision with the patient, based on the data, about what we recommend as the next step. We’re having a great conversation there are many research studies going on right now. We’re thankful that our patients are trying to push this ahead. We’re starting to get to the point that I have almost too many studies and I have to triage the next best thing to evaluate in a research study for my patients.

 That’s where the ongoing post approval setting studies are important, because they look at the real-world evidence of approved agents. And this is very much so in gene therapy. We don’t know what the long-term durability of gene therapy is going to be beyond first patient on study. It depends on how long it’s been that they’ve received treatment. Those are going to be key to watch and support to get data for the long term.

Nirmish Shah, MD, and Matthew M. Heeney, MD, discuss the need for ongoing clinical trials and diversity in them to bolster data and improve provider confidence in emerging therapeutic options for sickle cell disease. 

Increasing Confidence in Emerging Therapies

 Let’s talk about future directions, keeping in mind the unmet needs in sickle cell disease therapeutic management. Elna, there are dozens of clinical trials ongoing in various stages of development for sickle cell disease. This is an exciting time, with lots of new pathways, targets, and mechanisms of actions that we’re only beginning to consider. They’re super-exciting, including potentially curative gene therapy. As you think about the clinical trials underway and novel agents that may be ready for prime time for prescribing in the near future, I want to ask you about 2 things. In terms of clinical trial data, how important is longevity of data when thinking about new and emerging therapies? What are the clinical trial end points that you think are most important to be investigated?

 When you’re looking at disease-modifying agents, the longevity of the data is a little different, and the end points that matter will also be different. The disease-modifying agents aren’t curative. We’re kicking the can down the road. We’re trying to not only increase longevity of the patients but also improve the longevity of their end organs. Adding end points [can help] assess end-organ damage: renal, microalbuminuria, cardiac, pulmonary hypertension, neurological pain. The FDA had papers in the past couple of years looking at clinical end points of trials and also biomarkers validating those. They have to incorporate the longevity of the data. We saw this with the voxelotor studies, in which the end point was no longer the number of VOCs [vaso-occlusive crises] or pain. The BABY HUG hydroxyurea study also showed that we were looking at splenic function and the validating effect of modifying the disease. In the voxelotor studies, they looked at rising hemoglobin as an end point. Beyond that, when patients feel better, and you get the hemoglobin [level], you’re not treating a number while looking at a patient. Are there organs that we can follow like they did in the BABY HUG hydroxyurea study. Are we looking at renal function? … Are we looking at circulation markers? Are we looking at oxygenation? How do we incorporate these other biomarkers? Are we going to follow them?

Part of what the studies are incorporating—the FDA is mandating them because most of them are fast-tracked to approval—is a lot of real-world evidence and long-term follow-up. In some of these patients, it takes 5, 6, 7 years to monitor their organ function and see if there’s any difference. If there’s any preservation, we won’t be able to do it because it’s not a randomized study. The longevity is important. How long are we able follow these patients and report on their organ function over time? Five years, 10 years, decades? Once we add the combination, does that make a difference?

When it comes to curative therapies, we had the recent report last February of secondary-malignant neoplasms in patients treated with gene therapy who had sickle cell disease but not thalassemia. How long does the FDA require them to be followed? I think it’s 13 years…. Ten to 13 years makes sense because from oncology treatments for solid tumors with secondary-malignant neoplasms, we know that you have those that occur within the first 5 years and others that tend to be a little later. The accumulating agents will show up at 10 years.

Declaring victory will not be possible until you follow these long patients. If you did gene therapy on a patient at 5 years, you’d follow them for 10 years, until it’s 15 years. Also, from the front end, we’re doing biological studies to understand the propensity for people with sickle cell disease. Do they have increased malignancy risk? Are they hematopoietic clonal proliferation in term of significance? How much of these clones are bystanders? How many are significant? If you add chemotherapy, does that increase the conversion rate? Adding all this, we need long-term data 5 to 15 years to analyze the risk better.

Dr Elna Saah highlights the role of data longevity, clinical trial end points, and metrics when evaluating novel treatments for the management of sickle cell disease.  

Matthew M. Heeney, MD

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