A Cure for Sickle Cell
Date: June 7, 2013
The way Yetunde Felix-Ukwu remembers it, her childhood in the Maryland suburbs of Washington, D.C., unfolded in a blissfully normal run of years stretching right up to the day in seventh grade gym class when she collapsed while running drills.
“I was sitting in the nurse’s office afterward, and I started feeling this intense pain all over my body,” she recalls. “I was so scared, and I couldn’t stop screaming and wailing.”
Soon Felix-Ukwu found herself atop a gurney as paramedics rolled her through school hallways filled with classmates in the midst of a period change. “You’re so self-conscious about everything at that age,” she says. “It was a horrible, horrible feeling, having everyone see me like that.”
Such a day was bound to come sooner or later. Five years earlier, her parents had learned that their daughter had the genetic blood disorder sickle cell anemia. Now, at last, the disease was showing itself.
“When I look back, it feels like that day was pretty much the beginning of it all,” Felix-Ukwu says. “Everything changed. The pain attacks kept coming, and I just kept going in and out of hospitals all the time.”
Felix-Ukwu is now 30 years old, so she came into the world about the time of a famous bone marrow transplant. The 1983 procedure at St. Jude’s Research Hospital in Memphis was a last-ditch effort to save an 8-year-old girl from acute myeloid leukemia.
The next year that girl’s doctors reported that she was cancer-free. But that’s not why the case landed in The New York Times and The New England Journal of Medicine. Going into the transplant, the girl had suffered from sickle cell as well. Afterward, she showed no sign of that disease either.
The cure ranked as a first in modern medicine, but in the years that followed it added up to more of a curiosity piece than a significant breakthrough. Too many daunting obstacles stood in the way of offering the treatment to sickle cell patients in meaningful numbers.
In the first place, the procedure would be open only to patients with a sibling who ranked as a “full match” in genetic tests. That alone knocked more than three-quarters of the population off the candidate list. To make matters worse, the eligible few still left on the list faced risks that were just too high. One in three bone marrow transplant recipients died in the 1980s, and those who made it had elevated risks for a number of life-shortening health problems.
Unlike blood cancers, sickle cell isn’t the kind of disease where you can wait until the patient is knocking at death’s door. By that point, victims of the disease have suffered so many strokes or so much organ damage—or so much of both—that they’re too weak for a bone marrow transplant.
Though transplant outcomes improved over time, the numbers still didn’t reach a point where the risk-benefit ratio started to make sense in sickle cell. Robert Brodsky, director of the Division of Hematology at Hopkins, estimates that over the last three decades a mere 400 transplants have been conducted worldwide on sickle cell cases.
But this state of affairs may finally be changing, with Brodsky and a multidisciplinary team of colleagues in oncology and immunology leading the charge. In recent years, the oncologists have been working to develop new and safer transplant protocols, while the immunologists have been focusing on ways to build a bigger donor pool.
“Once those two things start to come together, that’s when this starts to look like a perfect regimen for sickle cell,” Brodsky says. His team is now testing the notion that they can employ bone marrow transplants to deliver a measure of genetic therapy for patients, reformatting their immune systems and wiping them clean of flaws like the tendency to produce sickle-shaped blood cells. Brodsky likens it to installing a new hard drive in a computer.
Early results are quite encouraging. If these results hold up, the 100,000 people suffering from sickle cell in this country—and millions more around the world—may for the first time have realistic hope of a cure.
Interestingly, the newest development in this project carries an echo of that transplant in Memphis 30 years ago. One patient enrolled in the tests at Hopkins suffered not just from sickle cell but also from lupus, an autoimmune disease in which the body’s immune system mistakenly attacks healthy tissue.
After undergoing a bone marrow transplant, this woman now shows no sign of either disease—which raises a tantalizing question: If this new breed of bone marrow transplant works in sickle cell, might it also work in other diseases whose causes lie in faulty immune-system functioning? Could this sickle cell project turn out to be the first chapter in a much larger story with the potential to impact many more millions of lives down the road?
Some 300 million people around the world carry a benign genetic glitch known as the sickle cell trait. Over the long haul of human history this trait made the evolutionary cut by delivering better-than-normal odds of surviving malaria.
Not surprisingly, then, it’s most prevalent among populations with roots in malaria-stricken places. One in four West Africans carry it (both of Felix-Ukwu’s parents are immigrants from Nigeria). Among African Americans, the number is 1 in 10. It’s present at lesser levels among populations with roots in South and Central America, the Mediterranean, the Middle East, and South Asia.
When two people with sickle cell trait come together to have a child, there is a 1-in-4 chance both parents will pass along this genetic glitch. That’s when sickle cell disease enters the picture. These babies don’t get the genes they need to make normal blood cells; instead, their bodies make rigid, misshapen cells that have all kinds of problems navigating through the body.
The course of the resulting disease is devastating. Victims endure lives in which their bodies are frequently racked by off-the-charts pain and their minds are constantly clouded by painkilling drugs. They have a hard time making it through school and succeeding in the workplace. They end up at higher risk for strokes, renal failure, pulmonary hypertension, and blindness. Most never get to celebrate a 50th birthday.
Once her disease finally showed itself, Felix-Ukwu began experiencing two distinct types of sickle cell pain. The first was a day-to-day affair. It wasn’t any fun, and she generally needed some painkillers to deal with it, but this pain didn’t usually prevent her from making it through a school day.
“I remember wishing for a day when I didn’t dread waking up,” she says. “You know that halfway stage between sleeping and waking? That’s when the everyday kind of pain hits—you’d always feel it before you were even awake.”
The other type is crisis pain, and this showed up in sudden, unpredictable waves, delivering agony on an entirely different level—one that usually necessitates immediate hospitalization. “You’d be out in public, doing fine, and out of the blue you’d just start screaming and crying,” she says. “It’d feel like you got hit by a Mack truck. Then the truck backs up and hits you again. And then again.”
Brodsky, who has seen more than his share of sickle cell cases, says it’s impossible for healthy people to truly grasp the level of pain involved in these crises.
“The closest I can come to describing what these people go through is this: Kidney stone pain is nothing to a sickle cell patient,” he says. “They’ve been through a whole lot worse.”
As she made her way through high school and into college, Felix-Ukwu had good years and bad ones. Good years brought one or two hospitalizations, while bad ones brought 10 or 12. On average, sickle cell patients pile up more than $1 million in lifetime medical expenses. (By comparison, a bone marrow transplant might cost $250,000.)
The treatments these patients currently receive can help ease the pain they endure, but they don’t really impact the course of the disease. Just one drug, hydroxurea, is officially approved for sickle cell. Pioneered as a treatment at Hopkins in the 1990s, it can help reduce the frequency and intensity of crises, but it remains unclear whether or how much it extends life spans.
Most sickle cell patients receive a lot of blood transfusions, too. During crises that are particularly acute, they often have their entire blood supply swapped out and replaced with healthy donor cells via exchange transfusion. This, too, helps shorten a crisis, but once again, it doesn’t seem to change a patient’s long-term prospects.
Almost inevitably, sickle cell sufferers find themselves relying on heavy doses of painkilling narcotics. “That’s one of the worst parts of this,” Felix-Ukwu says. “The medicine is so mind-altering and just awful, but it’s like a necessary evil—without it, the pain is too debilitating.”
Felix-Ukwu managed to beat the odds and get through college, but the journey took her through three different schools over six and a half years. The academic struggles she had along the way often left her doubting her intelligence and abilities.
But then she enjoyed a stretch of healthy months and made it through one whole semester at the University of Maryland, College Park, without landing in the hospital. She earned a perfect 4.0 that term, and she put that grade transcript on display in a little frame.
“I’d look at it so I could remember how that’s the year I wasn’t sick,” she says. “And I’d remember how that’s the year I realized that I really was smart, that I really could do it, and that it really was the sickness that was making things so hard.”
Chemotherapy regimens developed in the 1960s by Hopkins oncologist George Santos helped pave the way for the first successful bone marrow transplants. The drug cocktail he put together to prepare patients for surgery had the dual goal of wiping out a patient’s own immune system and killing off as many cancer cells as possible.
Santos was aiming to create as clean a slate as possible for the arrival of new donor bone marrow. Called “myeloablative,” this mass-destruction approach tends to push up against the outer limits of what a patient’s body is able to tolerate without suffering permanent damage or even death.
“Trust me, it’s something you wouldn’t wish on your worst enemy in the world,” says Hopkins oncologist Javier Bolaños-Meade.
In recent years transplant physicians like Bolaños-Meade have been tinkering with kinder, gentler regimens. They’d begun to realize that not every case required the all-out clean-slate approach; sometimes creating a smaller measure of breathing room would suffice to allow transplanted marrow to take hold and graft. That meant adopting a more conservative approach in deciding which cells got targeted for destruction and when that happened.
In the past 10 years, these nonmyeloablative transplants have gone from experimental to established. Bolaños-Meade says they’re now the regimen of choice in half or more of the bone marrow transplants performed at Hopkins on cancer patients.
This new flexibility to work with lower toxicities in chemotherapy was one key step toward changing the risk-benefit ratio of transplants in favor of sickle cell patients. Nonmyeloablative regimens were first tested on sickle cell patients in a study at the National Institutes of Health, and they got successful grafts—hence, cures—in nine of 10 cases, with no deaths.
But the study, published in 2009, was open only to the small pool of patients lucky enough to have a fully matched sibling donor.
“It was an important study because it showed that nonmyeloablative transplants would work,” Brodsky says. “But in order to find their 10 patients they had to screen something like 112 candidates. So the critique of it in my mind was, ‘C’mon, that works out to helping about 9 percent of the sickle cell population—not exactly a quantum leap.’”
The question remained: Can we expand the donor pool? Brodsky dubs this “the holy grail of bone marrow transplantation.” It’s a problem immunologist Ephraim Fuchs first started working on during a research fellowship at NIH in the 1980s and one he would return to after coming to Hopkins in the early 1990s.
The thinking behind the full-match requirement is straightforward. “The basic job of the immune system is to preserve self and attack nonself,” Bolaños-Meade explains. “The idea is that if the donor’s bone marrow looks exactly like the recipient’s bone marrow, the immune system won’t see it as nonself and won’t go on the attack. That means you’ve hit the jackpot.”
Fuchs wasn’t the first to look for a way around the full-match requirement, but the early experiments along these lines had all failed. After teaming up with Hopkins immunology colleague Leo Luznik, Fuchs set out as others had before to see if transplants might work in so-called “half-matched” donors. The average person has four or five of these available to them—parents and children are guaranteed to qualify, and there’s a 50 percent chance for each sibling and half-sibling as well.
Building on work conducted by researchers in Japan, Fuchs and Luznik focused their efforts on a chemotherapy drug called cyclophosphamide (which had also been in the toolbox of transplant pioneer George Santos). This drug turned out to be a game changer because of its ability to kill off red blood cells with great efficiency, while sparing stem cells, which have an enzyme that protects them from the drug.
Fuchs and Luznik started in the mouse model and worked their way up from there. One key turned out to be using the cyclophosphamide not just in a preparatory regimen, but also at carefully prescribed intervals in the days after a transplant.
Fuchs describes the results of this work in a characteristically low-key manner: “We were actually able pretty quickly to get results similar to the ones everyone was getting with fully matched siblings.”
The voluble Bolaños-Meade, on the other hand, is still barely able to contain his enthusiasm when the conversation turns to this business of finding the transplantation holy grail.
“When I was a fellow here about 10 years ago, if someone had told me I was going to be transplanting people who were half matched, I would have said, ‘You are crazy, and you need to be committed to a mental institution,’” he says. “It’s absolutely amazing—but here we are!”
And that new place, Brodsky adds, is one where more than 90 percent of the sickle cell population has an eligible donor. It was in 2006 that he and his colleagues set out to test the hypothesis that the risk/benefit ratio of bone marrow transplantation had finally changed enough to deliver hope for a large number of sickle cell patients.
Felix-Ukwu’s journey into law school was a star-crossed affair from the start. She had a pain crisis the morning of her LSATs, but she doggedly managed to finish the test before the pain drove her to a hospital.
In 2007, she enrolled at the University of Maryland School of Law. It was during this stretch that she started seeing doctors at Hopkins. Those doctors, including Brodsky, would sometimes marvel among themselves over the amazing sickle cell patient who’d made it all the way into law school.
But this is when Felix-Ukwu’s disease took a turn for the worse. Her pain crises and hospitalizations started coming one right after another. “If there’s one thing sickle cell taught me, it’s how to be a fighter,” Felix-Ukwu says. “But this got to the point where I’m just barely hanging on. I’m in the hospital half the time. I’ve dropped half my classes. Still I’m like, ‘I will not quit!’”
Then, in January 2009, the worst sickle cell crisis of her life commenced, bringing pain at levels not even she had ever experienced.
“They were giving me enough pain medication to put down two horses,” she says. “The pain specialist people were in my room all the time. I’d watch them increase the dosage a little bit, and I’d see how nervous they were, how they were like, ‘Please God don’t let her stop breathing.’”
She withdrew from law school after that crisis.
But it was during these dark days that hematologist Charles Hesdorffer (who has since moved on from Hopkins) delivered a glimmer of hope. When he showed up to speak with Felix-Ukwu and her mother, the first thing he did upon arriving in her hospital room was drop a big stack of papers on a table.
“I’m here because I am thinking that maybe the way things are going, you’re not going to be able to live the life you want to live,” he said. “I’d like you to read this. There is something in here that’s new, but it might work for you.”
Felix-Ukwu read through the papers with her family, then put the possibility on a back burner. It was after the next pain crisis hit that she made a decision.
“I was tired, just so tired,” she says. “I couldn’t keep living this life where I couldn’t accomplish the things I wanted to accomplish. So I was like, ‘Where do I sign up?’”
The sickle cell trial that had everyone on Brodsky’s team so excited got off to an inauspicious start. Perhaps skeptical after so many years of hearing how bone marrow transplants weren’t right for them, sickle cell patients and their doctors greeted news of the trial with little enthusiasm.
No one enrolled that first year. No one enrolled the next year, either. When Bolaños-Meade finally got to conduct a transplant in 2008, the graft failed, and word of that outcome was soon making the rounds in the sickle cell community.
“In the first three years, we did a total of three patients,” Bolaños-Meade says. “But fortunately the transplants were successful in the second and third patients.” Fourteen more patients received transplants in the two years that followed. Felix-Ukwu was among the earliest transplants in this group.
Initial results were published last year in the journal Blood. Eleven of the 17 transplants succeeded. Three of those successes were with full-match donors, and eight were with half matches. There were no deaths and no lasting health complications. (Just two prospective participants were turned away because they didn’t have either a full- or half-match donor.)
The sample size remains small at this point, but that’s a cure rate approaching 60 percent—quite a jump from the 9 percent the NIH researchers achieved when requiring fully matched donors. And while the physicians involved don’t expect the mortality rate to stay at zero forever, they are hopeful that it will remain quite low.
“You can see why this starts to shift the landscape in sickle cell,” Bolaños-Meade says. “We were looking before at maybe 10 percent of patients being eligible for a transplant that succeeded 85 or 90 percent of the time. Now we’re looking at 90 percent of the patients being eligible. Even if the cure rate stays at 60 percent, that will be helping many, many more people.”
But Bolaños-Meade and his colleagues don’t think the cure rate will stay at 60 percent. They’re optimistic that it will get better—perhaps significantly so.
The nonmyeloablative chemotherapy regimens used in the trial were by design quite conservative. A more aggressive regimen might have resulted in fewer graft failures, but the physicians here were determined at this early stage to take a safety-first approach.
“Failed grafts are not the desired outcome, of course, but at least patients don’t die,” Brodsky says. “They go back to their sickle cell life in the same shape they were before.”
One strategy in particular is fueling optimism about the cure rate. Research on cancer patients has demonstrated that engraftment rates increase if donors receive a growth factor in advance of the transplant. This enables physicians to transplant a much larger number of donor bone marrow cells. The technique has been used so far in six sickle cell cases at Hopkins (all of them after the transplants reported in Blood), with five of those grafts taking hold successfully.
“I don’t think we’ll ever get the engraftment rate to 100 percent,” Brodsky says. “But I think it’s feasible to get it up 75 percent and maybe a little higher. The amazing thing is, these patients are then completely cured. They don’t have sickle cell anymore.”
Brodsky and his colleagues are already eyeing the first of the next steps on the horizon. A proposal to test this new breed of bone marrow transplants on patients with lupus is now awaiting approval by an institutional review board.
“Auto-immune diseases like lupus are really blood diseases,” Brodsky says. “The people with the disease, their kidneys are failing and their rashes are developing because of the abnormal things their lymphocytes are doing. It’s the same in other diseases. There is nothing basically wrong with the joints of patients with rheumatoid arthritis, and there is nothing basically wrong with the central nervous system of multiple sclerosis patients. The defect is in the lymphocytes.”
He ticks off a number of other conditions—thalycemia, scleroderma, and Crohn’s disease among them. “If you can use a transplant to give people with conditions like this a new, healthy immune system, you might be able to cure them. So we’re going to try it in lupus next, and we’ll see how this thing develops.”
Remember that old saying about how sometimes the cure is worse than the disease? That’s pretty much how life went for Felix-Ukwu when she received her bone marrow transplant in August 2009.
The procedure is a highly demanding affair. Even at nonmyeloablative levels, the chemotherapy regimen is grueling. After the transplant, Felix-Ukwu needed to be at the hospital for testing seven days a week for two months. Her mother took a leave of absence from her job as a pharmacist to serve as her daughter’s full-time helper.
In pretty short order Felix-Ukwu was passing her blood-count tests with flying colors and her doctors were saying she was cured of sickle cell. She re-enrolled in law school for the semester starting in January 2010, and she made it through all of three weeks of classes before she had another pain crisis and landed in the hospital.
“It was the most devastating thing,” she says. “I just remember thinking, ‘The bad blood is all gone! How could this be happening?’”
The truth is, no one really knows. “We’re learning new things here about pain and sickle cell,” Brodsky says. “We don’t fully understand yet why these people continue to have pain episodes, sometimes for 18 months or so after the disease is gone. Is it like phantom limb pain? Is it a conditioned response? Is it mixed up with trying to take away some of their pain medicine?”
Felix-Ukwu’s doctors asked her to be patient and give it another six months. The pain episodes kept coming, and they asked her to give it another six months. At one point in this stretch she landed on antidepressants.
And then, finally, the day she’d been waiting so long to experience arrived. When it came, it took the form of a random thought popping into her head out of the blue: “Hey, wait, when’s the last time I was in the hospital?”
That last time was in 2011, nearly two years after her transplant. Since then, she and one of her brothers took a celebratory vacation to Europe. She went on a dream trip to Nigeria, too, exploring her family roots. Back home these days, she enjoys serving as a volunteer informal adviser to other sickle cell patients who are having transplants at Hopkins.
She’s also back in school, seeking a master’s degree in public policy at the University of Phoenix. “It is such a good feeling to know that when I don’t get a paper done, it’s just because of my own laziness,” she says with a laugh.
The thing she might be most proud of is the fact that it’s been more than a year since she took any painkillers.
“I still have so many medicine bottles around the house that it looks like I could start a pharmacy,” she says. “I refuse to throw the bottles away. It’s just so cool to look at them and think about where I’ve come from and what I’ve been through.”
A New Frontier in Organ Transplants
Eliminating immunosuppression could boost prospects for all types of organ donor recipients—and make re-transplantation unnecessary.
Another frontier lies on the horizon for this new breed of bone marrow transplants. In addition to testing it on other diseases rooted in faulty immune systems, Hopkins immunologist Ephraim Fuchs is aiming to see if these transplants can boost the prospects of organ donor recipients.
Since the first successful organ transplant in 1954, millions of people around the world have lived longer, healthier lives thanks to donated kidneys, lungs, livers, pancreases, and hearts.
But these patients need to be on a lifelong regimen of immunosuppressive medications, and those medications put them at elevated risk for heart disease, infections, and some viral cancers, Fuchs says.
In addition, transplanted organs often don’t last through a patient’s lifetime. Even with immunosuppression, the recipient’s body slowly but surely starts to reject the new organ, with graft loss occurring at a rate of about 4 percent per year.
Fuchs estimates that half of kidney transplant recipients, for example, require retransplantation within 15 years.
But what if organ transplant recipients didn’t need to be on immunosuppression? What if they first received a new bone marrow and then got an organ, both from the same donor? In theory, that should eliminate the need for immunosuppression—and the need for retransplantation.
Fuchs and Hopkins colleague Lode Swinnen have now completed writing a protocol to test the concept, and their project is being funded by the National Institutes of Health through its Immune Tolerance Network, a consortium of academic medical centers devoted to improving the lives of transplant recipients.
“I’m hoping the trial can open here later this year,” he says. “If we can eliminate the need for immunosuppression, we can really help these patients. And if we can eliminate the need for retransplantation, that would make a lot more organs available to people who are now just sitting on waiting lists.” JD