In her mid-20s, Yetunde Felix-Ukwu wore a Fentanyl patch that delivered enough narcotic to knock most adults out cold. Yet it barely kept her pain, caused by sickle cell disease, tolerable.
Even with the patch, she was hospitalized almost every month for the pain, which she said was “like being hit with a hammer, searing, throbbing, you name it.”
A debilitating genetic disorder, sickle-cell disease causes blood cells to be shaped like sickles, or crescents, and to be rigid, not pliable. Rather than squeezing in and out of capillaries and blood vessels as normal cells do, the sickle cells jam up, depriving tissues throughout the body of blood and oxygen. That can cause severe organ damage, stroke, blindness and unimaginable pain.
“Imagine heart attack pain all over the body,” said Dr. Robert A. Brodsky, director of the division of hematology at Johns Hopkins University School of Medicine. Many patients don’t live past 50.
A bone marrow transplant could help. The problem is, most patients, including Ms. Felix-Ukwu, cannot get a bone marrow transplant because they don’t have a perfect genetic match. Like a vast majority of others who have sickle cell disease, Ms. Felix-Ukwu is African-American, and the chance of an African-American finding a donor in bone marrow registries is about 10 percent, compared with a 60 to 70 percent chance for Caucasians, Dr. Brodsky said.
Dr. Brodsky and his colleagues at Johns Hopkins, however, began a bone marrow transplant trial using so-called half-match donors. The trial has found that the procedure can cure sickle cell, replacing defective stem cells that produce sickle-shaped cells with normal stem cells that churn out plump, pliable blood cells.
Since almost everyone with a sibling, a parent or a child has a genetic half match, the procedure could make bone marrow transplants available to more than 90 percent of candidates.
“It opens the opportunity for a cure for thousands of adults with the disease who previously had not had any hope of a cure,” said Dr. Michael DeBaun, director of the Center for Excellence in Sickle Cell Disease at Vanderbilt University School of Medicine. Dr. DeBaun was not involved with the half-match trial.
Beginning in high school, Ms. Felix-Ukwu, now 30, had undergone regular transfusions to dilute and temporarily replace the sickle cells in her blood, but the transfusions stopped helping. Half-match donors have been used for about a decade in bone marrow transplants for leukemia and lymphoma patients, and the doctors believed it was now safe enough to use in sickle cell patients.
Ms. Felix-Ukwu, who lives in Lanham, Md., enrolled in the Johns Hopkins study, and her younger sister, Woma Felix-Ukwu, became her half-matched bone marrow donor.
Ms. Felix-Ukwu had to undergo a grueling course of chemotherapy, radiation and immunosuppresants before receiving the transplant.
“Those three days of chemo were the hardest days of my life, including all the pain I had been through with sickle cell,” she said. But it worked. Her body started producing normal blood cells. She continued to have some pain for another 18 months or so, for reasons that are not entirely clear, but now, three years after the transplant, Ms. Felix-Ukwu is disease-free and off all of her pain medications.
“It’s absolutely amazing,” says Dr. Brodsky, who published the study this month in Blood, the journal of the American Society of Hematology. Of the 14 patients in the study who received half-matched transplants, six were cured, meaning that their bone marrow is made up entirely of the donor’s and they are no longer producing sickle cells.
Two additional patients are still taking immunosuppressive drugs, meaning that the donor’s bone marrow took, but they still have some of their own marrow. They still have a chance of being cured.
In a half-match transplant, known medically as haploidentical transplant, only 50 percent of the pertinent genes have to match up. Testing for a bone marrow match entails looking for genes in the human leukocyte antigen, or H.L.A., system, the part of the immune system that recognizes self and not self.
In a full match, 8 to 10 H.L.A. genes need to match between donor and recipient.
“If you have disparities in the H.L.A. system and you transplant stem cells that recognize the patient as foreign, the new immune system will start attacking the patient,” said Dr. Brodsky. In half-match transplants, only half of these H.L.A. genes need to match.
But half-match transplants carry the risk that the donor’s immune cells will attack the host, a potentially deadly complication called graft-versus-host disease.
To reduce this risk, patients receive the chemotherapeutic drug cyclophosphamide after the bone marrow is transplanted. This drug kills the donor’s lymphocytes that would normally attack the recipient, but it spares the donor stem cells, which have an enzyme that makes them immune to it. The stem cells then produce new lymphocytes.
“What happens is that the new cells that are generated become tolerant to the host and will not attack it,” says Dr. Javier Bolaños-Meade, the lead author on the study and associate professor of oncology at Johns Hopkins.
“The biggest paradigm shift was the post-treatment chemo,” added Dr. Brodsky.
The other shift was the trend toward a gentler pre-treatment. In a traditional bone marrow transplant to treat cancer, patients receive high-dose chemotherapy and radiation before the transplant, not only to suppress the immune system but to kill off every last cancer cell in the body. But in sickle cell, the chemotherapy just has to suppress the immune system, so doctors can use a less intense regimen.
This could potentially open it up to many more adults. Bone marrow transplants have largely been offered to children with sickle cell, not adults, who were often too weak or debilitated to endure the more intense pre-treatments.
The half-match transplant is still experimental, and because of its toxicity, it is recommended only for those with advanced disease. It was successful in only about 50 percent of patients.
“You’re putting people through a lot, and to have half of the transplants not take must be heartbreaking,” said Dr. Jane Little, director of the adult sickle cell program at Case Western Reserve University in Cleveland. “It’s exposing patients to risk you can’t take away. But it also really expands the pool of potential recipients.”
The team at Johns Hopkins is tweaking the procedure to improve the success rate without increasing the toxicity, said Dr. Bolaños-Meade. “We are working on transplanting with a higher number of stem cells to help overcome rejection,” he said.
“Clearly it doesn’t cure everyone, but in those patients in which it works, it’s a huge, huge thing,” Dr. Bolaños-Meade said.
This August, Ms. Felix-Ukwu celebrated a year without being in the hospital. She plans to go back to law school next September.
“When I look back, I wonder how I ever made it through all that pain,” she said. “Now I feel like I’m on vacation. I finally have the freedom to be able to live my life.”
