Biree Andemariam, MD: I think this is the perfect time to pivot a little bit away from the description of the disease and its impact to the available treatments for managing sickle cell disease. Julie, I’ll let you start by giving us an overview of the goals of therapy for patients with sickle cell disease.
Julie Kanter, MD: I absolutely will, but I want to briefly talk about mental health. As Michael pointed out, it’s a big problem, and we do not have enough mental health providers. We have a primary care doctor in my clinic and she is phenomenal, but we need more psychologists and psychiatrists to be available and affordable and everything else. I just want to put that out there. If there was anything I could ask for at this point in 2020, it would be accessible mental health for our patients and for everyone.
Pivoting to new drugs and disease and treatment goals, it’s really important that we look at overall treatment goals in sickle cell disease. Preventing complications is probably the biggest thing we need to do. We need to look at the new ways to use medications to prevent these downstream effects, vaso-occlusive crises, kidney disease, and lung and brain disease. That is the primary goal.
The second goal we need to work on is better treatments for acute pain crisis. Opioids and aggressive opioids are very effective, but opioids have their own set of complications. We have to find something disease-modifying that we can use to target and end these crises faster and with less damage.
Biree Andemariam, MD: Thank you. That’s super helpful to lay the basis for this discussion about available treatments as we know them today. Hydroxyurea has been around a long time, and all of us have had extensive experience in treating many individuals with hydroxyurea, whether that be adults or children. Michael, what is the mechanism of action of hydroxyurea? How does it target the pathophysiology of the disease? What are the expected outcomes that you talk to your patients and their families about when you start someone on hydroxyurea? Could you also touch on safety and efficacy as we know it today?
Michael DeBaun, MD, MPH: Sure. Hydroxyurea has multiple different benefits. Unfortunately, the benefits have been put into the category of whether or not it increases hemoglobin F. The drug, quite frankly, has myriad benefits to children and adults with sickle cell disease. The mechanism of actions include the inhibition of ribonucleotide reductase, which inhibits reticulocyte production. It’s myelosuppressive, so you get a drop in the white blood cell count. We all know that sickle cell disease is an inflammatory disease, so decreasing the white blood cell count as an inflammatory marker is potentially another important strategy.
We also know that hydroxyurea will decrease the red blood cell adhesion to the endothelial markers. What’s not talked about is that hydroxyurea decreases the overall number of red blood cells. So not only does it decrease the endothelial adhesion, but it decreases the overall number of red blood cells that are likely to cause the microvascular occlusion.
Hydroxyurea also increases hemoglobin F by hypomethylation of the gamma genes. This is the most highlighted approach to why hydroxyurea should work, but I think the evidence is clear that there are children and adults with high hemoglobin F levels who still go on to have pain.
Work that was done out of Kuwait clearly demonstrated that, in individuals who live in Kuwait who have high hemoglobin F levels, as they get older, they have many of the same manifestations as children with hemoglobin SF with much lower F levels.
Last but not least, there are clearly other methods, but hydroxyurea acts as an NO [nitric oxide] donor with at least 3 documented pathways for NO donation by hydroxyurea.
In summary, it has a range of benefits or mechanisms to support its use. Now, what happens when we give hydroxyurea? The real game changer in this field was the study out of Johns Hopkins University with Samuel Charache, [MD,] that demonstrated that hydroxyurea dropped the rate of significant pain episodes by about 50% in adults. It significantly drops the rate of acute chest syndrome by about 50%, and also, importantly, drops the rate of blood transfusion therapy by about 50%. We also know that hydroxyurea increases the parameters of blood flow to the brain. Specifically, there’s evidence that hydroxyurea will drop the transcranial doppler measurement, transcranial doppler is a marker for increased risk of strokes. That benefit occurs within 3 months of starting hydroxyurea.
There are also data out of St. Jude Children’s Research Hospital that hydroxyurea may improve cognitive abilities. There are data out of Washington University [in St. Louis, Missouri,] that show it also improves the cerebral hemodynamics. In terms of the brain, hydroxyurea is not as good as blood in many cases for secondary stroke prevention. But for primary stroke prevention, hydroxyurea has a very good profile in children with hemoglobin SS and hemoglobin SC.
There are many other potential benefits, but there are also clearly some downsides in taking hydroxyurea. For men, it causes a decrease in sperm count, which is believed to be reversible. However, many of these studies are confounded by the fact that men can also have ischemia of the gonads. For women, it may also cause challenges or may be associated with premature menopause. Those data are just starting to emerge in terms of the impact of hydroxyurea on reproductive organs.
Because of the teratogenic effects, women who are on hydroxyurea to prevent pain or these other complications mentioned, including acute chest syndrome, typically have to come off hydroxyurea when they decide to have a planned pregnancy. Likewise, men who want to have a child may elect to come off of the hydroxyurea because of the known decrease in sperm count.
In terms of its myelogenic potential, I think the evidence is weak to nonexistent. It’s clear that the benefits outweigh the risks when taking hydroxyurea to prevent pain, acute chest syndrome, and decreased transfusion, improvement of brain health profile.
Biree Andemariam, MD: With so many benefits, Michael, some people in the audience might ask, “Why isn’t everybody with sickle cell disease on hydroxyurea, unless they’re planning to conceive a child?” What’s going on?
Michael DeBaun, MD, MPH: I can say this, we’ve published these data in our clinic. It’s hard to get out of our clinic by the time you’re 5 years old without being on hydroxyurea. It takes the families time to warm up, to understand what their fears and anxieties are. There’s a wonderful article published by the NIH [National Institutes of Health] that described the tangible obstacles for the prescription and uptake of hydroxyurea on the parent side or the individual side. You address those obstacles, with written language they can follow, with a handbook they can take home and discuss with other decision-makers in the household. You educate them with videos about the importance of taking hydroxyurea.
In our clinic, we had 90% of our families on hydroxyurea by 5 years of age. It’s a lot of hard work. It’s not an efficient visit, to sit down and walk through pictures of a book and read out loud the benefits and the risk to the families. But once you have a trusting relationship, my experience has been that you can improve the rate of uptake of this drug and reach in the population.
If you say to some of my 10-year-olds or 15-year-olds that we want to take hydroxyurea away, they will go to another doctor. The dialogue has changed in 2020 compared to 2000. When I have conversations with our families and I ask a 15-year-old when their last pain episode was, some of them they look around, they’re thinking, “What are you talking about?” They are oblivious to the challenges of acute pain because they’ve been taking this drug in a way that shows the benefit with minimal risk.
Julie Kanter, MD: Then they turn 18.
Wally Smith, MD: Then they become an adult.
Julie Kanter, MD: Yes. Then they decide that they’re going to think on their own.
Michael DeBaun, MD, MPH: Of course. Let me say this last thing before we go off of this subject. Because we have this center with children and adults, the adult provider can tell you point-blank who was followed in our clinic by us for 18 years and who was followed in the general community without any education. Part of that challenge that we’re describing is an orientation where they are enabled and empowered to have autonomy about their disease process.
We have our handful of individuals who are challenging, as any adolescent is, as I was challenging, and I’m sure my children were very challenging. It’s no different with my adolescent children with sickle cell disease who I follow. They are challenging, but we do break through most of the time.
Wally Smith, MD: Anybody who’s raised a child will know that children don’t often do in adulthood what they did in childhood. It’s no different with any other medication, so let’s not pick on hydroxyurea. It’s really any medication.
Julie Kanter, MD: I think that’s true.
Wally Smith, MD: Our offer rate for hydroxyurea in my clinic is 77%. Our adherence rate is probably closer to 30%. When you ask people why, they will say all sorts of things. If you want my subjective opinion, it’s because they don’t feel anything. They take the drug, and they don’t feel anything. Unless they feel something, they don’t take it. It’s inconvenient for them if they have to keep the tablets at the right place so that they remember to take them. If they forget to take them once or twice and nothing really happens, then they think it probably wasn’t doing anything, and they stop.
Then you show them their mean corpuscular volume, and they go, “Oops, I guess you busted me.” Then they start taking it again, and it goes back up. I have lots and lots of sine waves and roller coaster pictures of people taking and not taking their hydroxyurea, and sometimes coming into the hospital and not coming into the hospital, as a result of taking or not taking their hydroxyurea.
Elliott Vichinsky, MD: I’d like to make a comment. I run the thalassemia program, too, and we’re on them night and day to monitor the chelation therapy with a support team, diaries, and compliance because we’re overwhelmingly concerned about its toxicity but also its efficacy by getting the right dosing. We’ve been able to get iron levels at a safe level as new drugs come along.
The studies about sickle cell providers have shown that there are a lot of biases in the medical community, and the amount of time they invest, monitor, and educate a person in infancy to get hydroxyurea and mitigate its myths is significant. You don’t need a hematologist per se, but you need to have a team that could spend time and monitor them and how they’re doing with it.
Wally Smith, MD: And even then, it’s not perfect. We just did a $3 million NIH-funded study on adherence to hydroxyurea using community health workers. We were able to show an improvement in adherence, measured raw, but we were barely able to move some of the hematologic variables. It’s a complicated thing, and I think that you have to find a medication that people can tell is making a difference. If you ask me, that’s what it comes down to.
Julie Kanter, MD: I think you have to meet people where they are too. I take care of patients, lifespan clinics, and now a couple of different states. You have to know your patients, and they have to trust you. You have to meet them where they are. I have adults who have good reasons for not wanting to take hydroxyurea. They’ve tried it for years, and I can see it. It’s true. They didn’t feel different, and so they didn’t want to take it anymore.
Transcript Edited for Clarity