New research and better and more aggressive treatment have begun to change sickle cell disease from an inherited condition that often condemned children to painful and short lives into a condition that can be managed with less pain and has a better life expectancy.
“I don’t like to use the word ‘breakthrough.’ We are making progress,” said David Nathan, a hematologist and president emeritus of the Dana-Farber Cancer Institute in Boston, who has been studying sickle cell disease for more than 50 years. “You can get leaps, but most of the time it’s dog’s work. It is a combination of basic science and clinical investigators who are persistent.”
Sickle cell disease is one of the most common inherited blood disorders, mostly found in people of African, Hispanic, Mediterranean and Middle Eastern descent and affecting about 100,000 Americans. For the disease to emerge, it must be passed down by both parents. The syndrome causes normal, oval-shaped red blood cells to lose oxygen and collapse into sickle shapes. These mutated cells do not flow smoothly and can get lodged in veins, causing excruciating pain, anemia, severe fatigue, respiratory distress and eventually organ failure and early death.
A 1973 study put the average life expectancy after diagnosis, which usually occurred in childhood, at around 14 years. But researchers say that today many people with the disease can live far longer due to early treatment with antibiotics, better pain management and especially the use of hydroxyurea.
The Food and Drug Administration approved using the drug in 1998 to help reduce the number of pain crises experienced by adult sickle cell patients. While scientists do not know exactly how it works, hydroxyurea boosts the body’s production of fetal hemoglobin. Studies have found that higher levels of that blood component are associated with milder forms of sickle cell disease. Fetal hemoglobin continues to be produced well into the first year of a baby’s life and then switches to adult hemoglobin in most cases. Hemoglobin helps the blood transport oxygen.
Hydroxyurea has not been a cure-all. “It works in half the patients,” Nathan said. “If you give the drug aggressively, it could help 70 percent [of sickle cell patients]. It has been useful; it has been good, but it’s not good enough. It prevents the crisis of pain and acute chest syndrome, which is marked by the inflammation of lungs.”
Carlton Haywood, 37, who was given a sickle cell diagnosis at age 3, knows the benefits and the shortcomings of hydroxyurea. He has taken it since he was a freshman at the University of Virginia. From about 1995 to 2000, Haywood was hospitalized only once. Before that, one of his main memories from high school is “being in and out of hospital,” he said. In college, “I was able to manage my pain crises in my dorm room. I attribute that to my responses to hydroxyurea.”
He continues to take the drug, even though it is no longer as effective, but he has added a cocktail of daily pain medication and drugs to counter an iron overload caused by monthly blood transfusions. (Transfusions of healthy red blood cells help prevent anemia in patients with sickle cell disease.)
Each day, he said, is a struggle.
Haywood, a bioethicist at the Johns Hopkins Medical School, has to carefully consider how much pain medication to take. If he takes too much, the drugs can make him feel dopey and less sharp. He monitors his exertions and his activity levels. Stress and too much exertion can trigger his pain crises.
“Whenever I feel a crisis coming on, I increase my fluids,” he said. “I cut back on physical activity. I try to rest more, I stay in my room and I don’t walk around campus. If I take [certain] pain medication, I can’t do my work. It hits me really hard and keeps me from concentrating or retaining something.”
The disease has taken a toll on parts of his body: When sickle cells clog up, causing a pain crisis, oxygen is cut off from organs and joints. Over time these begin to die. Haywood had to have his right hip replaced in 2001, and he expects to face more difficulties, possibly including replacement of his ailing left hip.
The disease is unpredictable. While Haywood has suffered his entire life, Joi and Journi Parker, 7-year-old twins from Temple Hills, Md., have rarely been hospitalized or experienced a pain crisis since they received their diagnoses three months after they were born.
Doctors don’t know why the girls are doing so well. “We’ve had them tested four times,” said their father, Jimmie Parker. “They do have sickle cell disease, but maybe they have more fetal hemoglobin than others.”
The girls’ disease was diagnosed during routine infant testing. Their parents did not know they were carriers. After the diagnosis, the girls were given antibiotics twice a day for five years to prevent infections. After they were born, their mother, Janice Parker, quit her job as a legal secretary to stay on top of their condition. (The National Heart, Lung, and Blood Institute says that “both children and adults who have sickle cell anemia may get infections easily and have a hard time fighting them. This is because sickle cell anemia can damage the spleen, an organ that helps fight infections.”)
Their pediatrician continually monitors the girls with ultrasounds for any signs of stroke, a potentially devastating complication of sickle cell disease. Parents have brought limp or drooling children to the hospital, not realizing they have had strokes, said Emily Meier, the director of the sickle cell disease program at Children’s National Medical Center. “They’ve had silent strokes with no physical signs [before they become limp],” Meier said. “We do a MRI and see changes in the brain.”
Ultrasounds have not picked up any changes in the Parker girls.
They get a yearly flu shot and are kept up-to-date with childhood vaccines. They drink fluids constantly to avoid dehydration. And the Parker home is a temple of cleanliness, with bottles of hand sanitizer in every room. At any sign of pain, the girls take ibuprofen, and with any sniffle they are kept home from school.
“They’re not any smaller than kids their age,” their father said. “They are healthy eaters. They are not any more tired than other kids.”
As they look for a cure, scientists are focusing on fetal hemoglobin.
“It is the best treatment for sickle cell,” Nathan said. “We have patients [with] 70 percent adult hemoglobin and 30 percent fetal, and they are fine. If we can raise fetal hemoglobin to 30 percent [in all sickle cell patients], we can cure this disease.”
In 2011 doctors at St. Jude Children’s Research Hospital in Memphis studied the use of hydroxyurea in 193 young sickle cell patients to increase their production of fetal hemoglobin. About half of the babies, 9 to 18 months old, were given the drug and half were given a placebo.
“Hydroxyurea was given to young children to prevent organ dysfunction,” said one of the researchers, St. Jude hematologist Winfred Wang. “Sickle cell affects every organ in the body, especially the spleen and kidney in young children. Those [organs] did not show improvement in the study, but what became apparent were the clinical benefits. Patients on hydroxyurea had many fewer pain events, swelling of hands and feet, episodes of acute chest syndrome and hospital stays.”
Long-terms results are promising. “Kids on hydroxyurea have better immune systems,” said hematologist Patricia Oneal, co-director of the Center for Sickle Cell Disease at Howard University. “They can fight off infection, but it is going to take another decade for us to see what the actual life span is going to be [for children on this drug].”
Beyond finding a drug that boosts the body’s ability to make fetal hemoglobin, researchers are looking at correcting genetic coding, replacing bone marrow and reducing the inflammation that happens when sickle cells cause obstructions.
“Scientists are looking at biology to get at the root of the problem,” said Stuart Orkin, chairman of pediatric oncology at Dana-Farber.
There is a cure for sickle cell — in some cases — but it is risky and can require a lifetime of continued medicine. That cure is a bone marrow transplant.
Only about 500 such transplants have been done around the country, 40 of them at the National Institutes of Health, and all but a few involving children. Children’s National Medical Center will perform 12 to 15 this year, according to Meier.
“But there are risks,” she said. “We can have graft-versus-host disease with new bone marrow. Sickle cell patients have a higher risk of complicating stroke, seizures early in transplant, and they are always at high risk for bleedings, infection. Transplants are not an easy cure.”
Finding a perfect match for a transplant is not easy, even among family members, because of genetic differences. “The transplant worked 95 percent of the time in kids who have a perfect match,” said John Tisdale, a senior investigator with the Molecular Clinical and Hematology Branch of the National Heart, Blood, and Lung Institute, “but a matched sibling is found only about 10 percent of the time. That’s our experience.”
To work around this, Tisdale is experimenting on mice with sickle cell disease, transplanting them with donor stem cells that are genetically only half a match. Recently he has begun to try it in humans. “We have transplanted 11 adults with half a match,” Tisdale said. A similar human trial at Hopkins has shown promising results.
But what has Tisdale and other researchers more excited than stem cell transplants is gene therapy. Using mice, Stuart Orkin at Dana-Farber is experimenting with turning off the mechanism in hemoglobin that changes it from fetal to adult. When the mechanism, BCL11A, is switched off, “85 percent of the red blood cells in the mice carried fetal hemoglobin and, on average, 30 percent of the hemoglobin contained within these cells was of the fetal type,” according to a hospital press release.
Eric Kmiec, chairman of the chemistry department at Delaware State University, describes sickle cell disease as being like a misspelled word that scientists are learning how to correct. “A mutation is a misspelling,” he said. “We are trying to use technology as a spell checker to physically reverse the misspelling of a human chromosome.”
Meanwhile, Nathan and Joel Linden, a researcher at the La Jolla Institute for Allergy and Immunology in California, are testing a short-acting anti-
inflammatory drug, Lexiscan, that seems to inhibit the production of white blood cells that are released by the body when sickle cells begin to jam up in blood vessels.
These additional white blood cells further gum up the blood flow. In tests, the drug seemed to reduce pain crisis in sickle cells, the two scientists said.“Maybe I can inhibit that inflammation response, reduce organ damage and shorten episodes of pain,” Nathan said.
Yutaka Niihara, a hematologist at UCLA and head of the biopharmaceutical company Emmaus Medical, believes that a type of amino acid, L-glutamine, can reverse the oxidation process that causes the sickling. After receiving oral doses of the amino acid, the patients had fewer pain crises and reported more energy, Niihara said.
As scientists move these medications and procedures out of the lab into human tests, they need sickle cell patients willing to sign up for trials. “Research is on the cusp of really nailing this disease,” said Shanta Robertson, executive director of the Maryland Sickle Cell Disease Association, whose two sons, ages 14 and 15, have the disease. “But we have a lot of work to do in terms of awareness.”