Hydroxyurea in Sickle Cell Disease
FEBRUARY 07, 2020
Ify Osunkwo, MD, MPH: Nirmish, let’s talk about hydroxyurea [HU]. That’s the first FDA-approved drug for stickle cell disease. It’s been around for a while, and unfortunately the uptake has been kind of poor. How does hydroxyurea work with sickle cell disease? What is the efficacy? And what do you think are the challenges of using hydroxyurea?
Nirmish Shah, MD: We have quite a bit of literature now on hydroxyurea because it’s been approved for quite a bit of time. What we have learned is that the reason it works so well is that it does a couple of things. The mechanism of action starts by essentially tricking the bone marrow to make fetal hemoglobin. Fetal hemoglobin is baby blood. As we talked about earlier, the issue with sickle cell is polymerization. The hemoglobins are stacking on themselves, stretching out the cells to become sickled. When you insert more fetal hemoglobin—which as we’ll probably talk about a little later, shifts the oxygen curve, or disassociation curve, to the left a little—you hold on to oxygen a little more tightly, and oxygen is protective because more blood cells have this fetal hemoglobin as a higher ratio and have less sickling.
In addition to the effects from the fetal hemoglobin, which we do monitor quite closely, we also look at the fact that it’s myelosuppressive, meaning it decreases all your blood cells—your white blood cells, your platelets—and it slows down your reticulocytes. A reticulocytosis is something we have to monitor. That’s why we ask our patient to come in every 3 months, 1 to 3 months, depending on the schedule. We have to be also aware that that is helpful. We want to titrate the dose to what we call maximum tolerated dose. We titrate it so that we do have some of that effect. White blood cells have adhesive proteins. Platelets have adhesive proteins. They’re activated and sticky.
As I tell my kids in my clinic, all that sticky stuff sticks together. And we don’t want to do that, so we decrease with this hydroxyurea, that effect.
Ify Osunkwo, MD, MPH: When you give somebody hydroxyurea, you said you want to titrate to the maximum tolerated dose. We’ve seen a lot of patients who say hydroxyurea doesn’t work for them. What has been your common experience as to why hydroxyurea is ineffective in some patients?
Nirmish Shah, MD: I’m going to go ahead and just say it. When a patient tells me that it’s not working, the first thing I have to ask is, “Are you really taking it every single day?” I think that that goes back to something that you had asked me and I didn’t completely answer, which was that compliance is a huge problem. I think there’s a large amount of literature to support that. No matter how you look at it, progression ratio or otherwise, our patients are not filling the prescriptions, even when we give it to them.
Julie Kanter, MD: There are reasons right?
Nirmish Shah, MD: Yes.
Julie Kanter, MD: Not to completely interrupt you.
Nirmish Shah, MD: No, absolutely.
Julie Kanter, MD: I think patients do have some concerns. One thing that is important that I have learned is telling the patients why we give it to them.
Nirmish Shah, MD: Absolutely.
Julie Kanter, MD: I explain what it is and exactly what it does, because sometimes I’ve heard that that’s not always explained to them.
Nirmish Shah, MD: I feel like I’m a broken record here, but if you don’t ask, “Why are you not taking it?” not just saying, “Well, then just make sure you start taking it every single day.” And you have to ask, “Well, what is it that you’re concerned about?” That’s exactly right. You have some patients like, “Well, I’m just worried that I’m going to lose my hair,” or “It’s going to cause cancer.” These are all things we have to educate about to try to make them understand these are the risks that may be real, with patchy hair loss or leg ulcers. A very small minority actually have those. But the benefits are that if you take it consistently, if I can get to a point where I can titrate it to a maximum tolerated dose, then you have chance to have a clinical benefit. I do think that in context, having patients understand that this takes weeks to months to really sink in is important.
Ify Osunkwo, MD, MPH: It’s not a quick fix.
Nirmish R. Shah, MD: You take 1 today, then you’ll feel better tomorrow.
Ify Osunkwo, MD, MPH: It’s not a pain medication.
Nirmish R. Shah, MD: Exactly.
Julie Kanter, MD: You can’t just take it when you have pain either, right?
Nirmish R. Shah, MD: Yeah.
Julie Kanter, MD: You really have to take it consistently.
Nirmish R. Shah, MD: Absolutely.
Julie Kanter, MD: That can be hard, too, because it can be 2 to 3 pills a day, sometimes 4 pills a day. There’s a lot of pill burden that the patients have to contend with when they’ve gone through this.
Nirmish R. Shah, MD: Exactly.
Ify Osunkwo, MD, MPH: Matt, with the hydroxyurea story, for children we calculate medicines by milligram per kilogram per day. When you get to adult care we typically calculate medicines by a standardized dosage. Have you noticed that as your young patients get older that their effectiveness of the hydroxyurea changes? What do you think is the reason behind that?
Matthew Heeney, MD: I think hydroxyurea is effective on stressing the bone marrow, and that’s what leads at least to the fetal hemoglobin induction. I think that the bone marrow, much like any other organ in a patient with fetal cell disease, gets affected and damaged over time. If you wait until adulthood to start hydroxyurea, that organ, the bone marrow, may be damaged and may not make as much fetal hemoglobin if you delay in the starting of it. That’s an idea that potentially could cause that.
There is building evidence of that, and the NIH [National Institutes of Health] has recommended offering hydroxyurea to children at 9 months of agree regardless of their clinical severity. As we’re seeing this moving forward, it seems that we can induce a higher fetal hemoglobin, which appears to be long-lasting, and then protect not only the bone marrow as an organ but the other organs—hopefully to get them to adulthood in better shape, which will allow the persistence of the benefit of the hydroxyurea.
Ify Osunkwo, MD, MPH: Biree, I see a lot of adults who come in and they’re on 1 pill a day for the past 5 years saying, “It doesn’t work for me, Dr Osunkwo. It doesn’t work. I’m not going to take it anymore.” What do you tell your patients when you see that?
Biree Andemariam, MD: First of all, I talk to them about the concept of driving the dose as high as possible to get the maximal benefit, and data [have] shown us that if you can get people to a maximal tolerated dose, you’ll improve efficacy. The efficacy we’re looking for here is a reduction in the frequency of pain crises. Hopefully some effect on chronic organ damage over time, at a minimum. That’s what I do.
This is not uncommon, particularly when I see patients who’ve been in the community for a while being seen by someone who’s maybe not as familiar with sickle cell disease. They’re often on 1 pill a day, 500 mg. As we begin to titrate up, they do oftentimes see improvement not only in their fetal hemoglobin level but, more importantly, in the frequency of pain crises.
Matthew M. Heeney, MD: I think this concept of maximally tolerated dose is extremely important, and you’re asking me about how we dose the medication. We dose it until we see myelosuppression. The ANC [absolute neutrophil count] is in a goal range of about 1500 to 3000 per mm3, and that ensures that you’re getting enough of medication hopefully without significant toxicity. That really has shown to maximize the amount of fetal hemoglobin induction. It’s also quite clear that the white blood cells are involved in the pathophysiology and that vaso-occlusive event. Even though we might consider it as a toxicity or an adverse effect of hydroxyurea therapy by suppressing the neutrophil count was probably a benefit as long as you don’t go too far.
Ify Osunkwo, MD, MPH: The other thing is that as people gain weight, their dose may change. As they go through puberty or menopause, their dose may go up or down. It’s important to have them see their provider on a regular basis. No later than 3 months is usually recommended. You can monitor these changes if they have a myelosuppression and kind of titrate down. When they’re doing well you may titrate up to get the MTD [maximum tolerated dose]. It’s important to have that close follow-up. Ask the right questions and look for and seek out: Are you having any complications? Because if you don’t ask about complications, they’re going to think you don’t care, and they’re not going to tell you. They’ll suffer in silence.
Nirmish R. Shah, MD: I would add that, going to this idea of making sure we’re communicating with the other providers while they’re on hydroxyurea—for example, we have patients who go into the hospital, are admitted, maybe go to a community hospital—and they feel as though they’re in pain, so they need to stop the hydroxyurea. It may be the case, depending on the blood counts, but it’s a conversation that is not always understood, that this is a long-term-type medication and that the acute situation needs to be reassessed. We need to make sure we’re communicating with their providers as well.
Julie Kanter, MD: You know what? Similarly, it’s important that they don’t start hydroxyurea in the hospital. We really want to make sure that providers have a relationship with patients. Because if you just give it to them knowing you’ll see them for 3 days, they’re going to go off service—they don’t know you, they don’t trust you. What if you send them home with hydroxyurea and no one is going to follow their labs, because there is a risk. Especially as patients get older, we really need to watch a little more closely. Sometimes we do as patients get significantly older and you can titrate down that dose.
Ify Osunkwo, MD, MPH: With renal disease and because your bone marrow may get exhausted, or they may have a viral infection that suppresses their bone marrow. Those are important nuances to pay attention to.
Transcript edited for clarity.