Four things to know about what’s new in sickle cell disease

sickle cell disease anemia red blood cells
(OpenStax College/Wikimedia Commons)

An expert panel convened by the National Heart Lung and Blood Institute recently issued the first new guidelines (PDF) since 2002 for the management of sickle cell disease (SCD). In addition, the National Institutes of Health recently closed the Transcranial doppler With Transfusions Changing to Hydroxyurea (TWiTCH) study, which compared treatments to prevent stroke in children found to be at high risk of developing the complication.

Briefly, here is what these and other recent developments mean for the treatment of patients with SCD.

1. The NHLBI expert panel’s recommendation that clinicians offer hydroxyurea to all children and adolescents with sickle cell disease is an important step in broadening the reach of a drug that can significantly alleviate the pain crises associated with the condition. Hydroxyurea has been used since the 1980s and increases the body’s production of fetal hemoglobin, which does not contain sickled cells. Although hydroxyurea is not FDA-approved for children, it is particularly effective in this population, presumably because children have not yet suffered the damage that adults may have. However, hydroxyurea has not been as widely prescribed as I believe it should be.

The panel’s recommendation is significant because it carries an expectation that providers will really learn how to use the medicine and how to prescribe it. The expert panel also recommends that all patients and families be educated about hydroxyurea and that adults who exhibit various complications of sickle cell disease be treated with it.

2. The expert panel recognizes that acute pain crises, the most common manifestation of sickle cell disease, are “often poorly or inadequately addressed in all types of health care settings” and recommends that pain be treated “aggressively and promptly.” Sometimes patients with sickle cell disease face challenges because they are knowledgeable about their main symptom, which is pain from vaso-occlusion. If patients are not in their home institution — they’re away at college, perhaps, or on vacation – they may show up in a hospital emergency room with pain. They say, “I have sickle cell disease. My doctor is Dr. Heeney, and I have 10 of 10 pain. I’d like you to give me IV Toradol and IV fentanyl every hour until I tell you to stop.”

This makes doctors nervous. They think, “Maybe this is drug-seeking behavior.” In addition, sickle cell patients are often very used to their pain and may have very high pain thresholds. So they may not look like they’re in much distress even though they’re suffering severe pain. It’s a very challenging symptom.

That’s why it’s so important that patients with sickle cell disease have a medical home. It’s why families often become very reliant and reluctant to leave their medical home.

3. The TWiTCH study found that treatment with hydroxyurea is as effective as monthly transfusions in preventing stroke in children with sickle cell disease who are at high risk of incurring a primary or first stroke. One of the most serious potential complications of sickle cell disease is stroke caused by vaso-occlusion in the brain. Since the 1990s, NIH has recommended that all children with sickle cell disease be screened annually by Doppler ultrasound for stroke risk and that those at high risk start monthly transfusions. As a result, the number of strokes suffered by children with sickle cell disease has plummeted.

The latest NIH study adds a potential new treatment and documents an additional benefit of hydroxyurea. However, the decision of whether to treat an individual child at high risk of stroke with hydroxyurea or transfusion is complicated. Transfusions have their own set of problems, including iron overload and allo-sensitization. This has led to a search for alternative treatments. Nobody likes to come get an intravenous transfusion every month. There’s always some worry about the next HIV or some other danger in the blood supply.

On the other hand, the doctor knows a patient missed a transfusion because she didn’t show up. With hydroxyurea, the safety net comes from the patient and family making sure that the medication is taken daily. Medication adherence is tough. If a patient doesn’t take hydroxyurea for a few weeks, the brain may not be protected. Also, as much as I am a hydroxyurea zealot, transfusions are generally better at controlling or alleviating more of the adverse effects of sickle cell disease.

These are factors that families and clinicians must address on a case by case basis to determine whether hydroxyurea or transfusion is the better way to protect the brain of a child or adolescent at high risk of stroke.

4. While hydroxyurea has basically stood alone as a medication to treat the symptoms and complications of sickle cell disease, there are now a number of trials exploring new treatment options as well as exciting research into potential new cures. Platelets are involved in pain crises associated with vaso-occlusion, so there are several studies looking at anti-platelet drugs. Inflammation from vaso- occlusion or hypoxia is also a consequence of the disease, so another clinical trial is studying an experimental drug’s ability to control inflammation. None of these new drugs may be home runs, but the sum of them may be of great benefit. We may find that hydroxyurea in combination with a new drug or drugs will prove effective.

In the background of all this, scientists are trying to get to a cure.  New gene therapy trials aim to correct the sickle cell gene or knock it down. My colleagues at Dana-Farber/Boston Children’s made a breakthrough in 2009 when they discovered that the transcription factor BCL11A is the genetic “switch” that turns on adult hemoglobin, which contains the sickled cells, and turns off fetal hemoglobin, which doesn’t. We are using this discovery to develop a different gene therapy trial aimed at stopping that switch from turning off fetal hemoglobin shortly after birth. Researchers and pharmaceutical companies are also exploring gene editing aimed at this switch as well as looking for medication targeting the same switch. My hope is that a baby born today with sickle cell disease will have more options for treating its complications and more possibilities of being cured.

Matthew Heeney sickle cell diseaseSickle cell disease specialist Matthew Heeney, MD, is clinical director of the Blood Disorders Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and an assistant professor of pediatrics at Harvard Medical School.