Sixteen-year-old Courtney Davis remembers to take her daily medication for sickle cell disease, an inherited blood disorder, in an unusual way.
Broadway, her Maltese-Yorkshire dog, barks for attention at a certain time each evening.
“I always take my medicine before I take out my dog,” Courtney says, explaining her bedtime ritual.
A high school junior, Courtney enjoys cheer, dance, musical theater and history class. She wants to be an attorney one day, and she’s doing her part to succeed. She enrolls in Advanced Placement classes and takes part in extracurricular activities.
Most importantly, she faithfully takes a drug called hydroxyurea to manage her sickle cell disease.
Sickled cells and traffic jams
Sickle cell disease can cause pain crises, pneumonia and organ damage. The disorder occurs because of problems with hemoglobin. This molecule in red blood cells ferries oxygen throughout the body.
Babies born with sickle cell disease are protected early in life by fetal hemoglobin. However, when the fetal hemoglobin level begins to drop off as children age, the flexible, round red blood cells become rigid and rod-shaped. That sickle shape makes it difficult for the blood cells to squeeze through tiny blood vessels.
The resulting traffic jam can cause life-threatening problems. Hydroxyurea can keep hemoglobin levels high, reversing the effects of sickle cell disease.
Jeremie Estepp, MD, a hematologist at St. Jude Children’s Research Hospital, and his colleagues recently published a paper in the American Journal of Hematology. The findings may resolve a debate about the best dose of hydroxyurea. This issue is crucial for Courtney and others with the disease.
The Goldilocks effect
Courtney started taking hydroxyurea when she was 3 years old. Now, doctors recommend children with the disease begin taking it at 9 months. Estepp says about 400 to 450 patients in the St. Jude Hematology Clinic take the medication.
When taken daily, hydroxyurea helps prevent abnormal sickle-shaped red blood cells from forming. The drug also reduces other problems related to the disease.
Hydroxyurea improves the efficiency of oxygen-carrying proteins in red blood cells.
Like the bowl of porridge in “Goldilocks and the Three Bears,” the dose of hydroxyurea needs to be just right—not too low and not too high. A dose that’s too low is not as effective as it could be. A dose that’s too high can cause a drop in the number of white blood cells, which fight off infection.
So what’s the best dose?
Some doctors use a minimal effective dose, increasing the dose until improvement occurs. Others use a maximum-tolerated dose (MTD). They find the highest possible dose that avoids unacceptable side effects. Still other doctors combine the two regimens, using elements of both approaches.
Do the HUSTLE
As part of the federally funded HUSTLE study, Estepp and other researchers followed 230 patients with sickle cell disease for four years.
For new patients, physicians started with a dose that was low, safe and well tolerated. Then doctors gradually increased that dose to achieve MTD. The goal was to minimize the risk of complications by giving the highest dose of hydroxyurea possible to provide the best response in patients’ white blood cells, hemoglobin and fetal hemoglobin levels.
More than three-quarters of participants reached the MTD level. During four years of follow-up, their average level of fetal hemoglobin at MTD was above 20 percent. By keeping the fetal hemoglobin at that level, doctors found success.
When fetal hemoglobin fell to 20 percent or less, children were twice as likely to be hospitalized for any reason, and more than four times as likely to be admitted for fever.
“If a physician can induce the patient’s fetal hemoglobin to above 20 percent, you effectively reduce the number of times the patient is admitted to the hospital for pain, acute chest syndrome or for any reason at all,” Estepp explains.
Avoiding pain and suffering
Courtney’s mother, Audrey, vividly remembers her daughter’s first pain crisis.
“She screamed at the top of her lungs,” Audrey recalls, remembering the toddler’s attempt to walk a few steps. “I’m holding my child when I look down and see her toes are double the size they should be.”
Audrey’s nephew died of sickle cell anemia complications when he was 2 years old, a tragic reminder of what’s at stake.
Audrey understands the importance of reducing the complications and hospitalizations associated with sickle cell disease. Courtney was hospitalized more than 20 times in 16 years, most recently with acute chest syndrome, a life-threatening complication.
Worth the effort
More than 90 percent of sickle cell patients at St. Jude regularly take their medications, a rate much higher than that of many other institutions.
“We expend a lot of effort to keep patients engaged in clinic,” Estepp says.
After beginning hydroxyurea, patients must wait up to six weeks to notice improvement. Then they must wait an additional eight to 10 months to achieve MTD. As a result, progress seems to occur in slow motion, as patients experience fewer and fewer complications. Because of that lag time, medication adherence can be difficult to maintain.
Estepp attributes the hospital’s high adherence rate to the resources St. Jude provides. A large team of doctors, nurse case managers, social workers and other staff provides ongoing support.
“We’ll even send a car to get them,” Estepp says, referring to patients who miss appointments for lab checks. Patients can also fill their prescriptions at St. Jude, a convenient and time-saving benefit.
The bottom line
For Estepp, the implications of his study are clear.
“The findings mean that if you’re treating somebody with hydroxyurea and they are not at maximum tolerated dose and have a hemoglobin of less than 20, you should increase their dose,” he says. “You could potentially reduce the risk of hospitalization by 50 percent.”
Unfortunately, not every patient can achieve a 20 percent fetal hemoglobin level. Doctors cannot predict how well a patient will respond to hydroxyurea. Also, researchers do not fully understand why some patients respond better to the medication than others.
“I don’t think Courtney’s at 20 percent yet,” says Audrey, referring to her daughter’s fetal hemoglobin level. But Audrey says the level has increased with treatment. As a result, Courtney’s health has improved, reducing the number of complications and hospital admissions.
“I just feel better,” Courtney says. “I have so many fewer pain crises than I did when I was younger.”
A promising future
Estepp and his colleagues continue to flesh out the best dosing strategy for hydroxyurea. A pilot study is underway for a multicenter trial to evaluate a low fixed-dose of hydroxyurea versus escalation to MTD. That study should help investigators better understand the benefits of elevating fetal hemoglobin in young children.
Estepp is also interested in expanding access to hydroxyurea worldwide and opening combination therapy studies.
Courtney will likely be one of the first to enroll in an upcoming combination therapy clinical trial. She is excited about combining another medication with hydroxyurea to possibly achieve even greater benefit.
For Courtney, excellent clinical care has offered her the chance to live a normal teenage life: walking her dog, preparing for college and hanging out with friends.
“St. Jude is such a loving and amazing place,” Courtney says, reflecting on her years as a patient. “I know that there are people who are working so very hard for me to improve.”
From Promise, Winter 2018