Bone marrow transplant is currently the only curative therapy for sickle cell disease (SCD). Beginning with seminal studies led by Fred Hutchinson Cancer Research Center,1,2 researchers have documented disease-free survival of around 85 percent and overall survival around 95 percent in hundreds of children with matched sibling donors.3
Unfortunately, fewer than one in five children with SCD have a matched sibling4 and unrelated donor transplantation in SCD has met with less success. Outcomes in adults with SCD also have been less successful due to both disease- and transplant-related mortality. Seattle Cancer Care Alliance has several protocols aimed at improving outcomes for those with SCD.
The Questions and Answers below provide a patient and family perspectives on bone marrow transplantation in SCD, from M. A. Bender, MD, PhD, a clinician-researcher with an expertise in hemoglobinopathies. Dr. Bender is a physician at Seattle Children’s Hospital, director of Odessa Brown Comprehensive Sickle Cell Clinic, associate professor of Hematology/Oncology at the UW School of Medicine, and a researcher at Fred Hutchinson Cancer Research Center.
Q: About 70,000 people in the U.S. are living with SCD and yet since the 1990s only a few hundred have had a bone marrow transplant. Why still so few?
A: There are several reasons. First, many families, but also medical providers, are not aware of how well transplant can work in some settings. Thus patients are not referred. If a family is interested, then the question of finding a donor arises. The published studies with 80 percent or higher cure rates are based on matched sibling transplants. Without a good match, the outcomes have not been as good. In addition to the risk of death with transplant, there are other potential complications that intimidate people, including the risk of infertility. And finally, many people today learn to manage their sickle cell disease and live a long life with the disease, and so you can see why many families are hesitant about transplant after they learn about the potential risks of transplant.
Q: How do you help families make the transplant decision?
A: Every family brings a different mindset and perspective about treatment and so our group always customizes the message and emphasizes a risk benefit assessment. A major part of this in pediatrics is assuring that families understand what life as an adult with sickle cell is like.
Often, families focus on how well a child is doing currently and they compare that with the risks of transplant. And while many families also hear stories about increasing lifespan for people with SCD, they often are not aware of the major complications and decreased quality of life seen in many adults with SCD. Thus they see the risk, but not the full comparative benefit of transplant.
In contrast, families coming out of Africa, are often excited about transplant because in some regions of Africa no one with sickle cell reaches age 13. They have seen the devastation of the disease. Similarly, a family with a teenager on oxygen around the clock or a young adult looking at a second hip replacement by the time he’s 40—those are other situations where transplant might look attractive.
While it is wonderful many kids today are doing fine with their SCD treatments, the families often do not appreciate the long term consequences of SCD. Even if the child is in the hospital a couple weeks each year, these families often don’t want to deal with the risk of transplant, the intensity of the treatment, the long hospitalization and the risk of infertility. It’s not like leukemia where having the transplant is an acute question of life and death.
Q: But for some patients with SCD, doesn’t transplantation eventually become a question of life and death?
A: Yes and those patients with severe disease complications represent many of the people having transplants today. In general, the candidates for transplant are those with multiple severe vaso-occlusive pain episodes in a year, multiple episodes of acute chest syndrome, or stroke. But it’s a tricky balance. You may not want to risk transplant in someone who may have a relatively mild course with SCD, but because transplant is still risky, you also don’t want patients who are too sick with severe organ disease because then the transplant becomes even riskier.
Q: Is it tough to try to identify those patients who are sick enough, but not too sick, to benefit from transplant?
A: Yes and unfortunately many of our patients have come to us for transplant only after having very severe complications and stroke. Ideally we would identify patients who are still doing well but whose clinical course suggests they will develop severe complications. That is why my group in Seattle always starts educating families early to let them know there is a potential cure with transplant. Even if transplant is not an option now, it may change for them in a year. They need to hear that message over time. You bring it up before the child needs it. You start talking about when and how it will work. You introduce the transplant team and build trust. And you tell them that a major factor in the success of transplant is the availability of a matched sibling.
Q: Is there an age cut-off for transplant eligibility?
A: The original guidelines from the NHLBI had a cut-off of 16 years. That’s mainly because the conditioning regimens were just too tough for adults. They would get very sick and some would die. But now this age cutoff is part of the dilemma. Because of our better comprehensive care for SCD organ damage and morbidity may progress more slowly. Many don’t develop severe complications until they’re in their 20s.
Again, that’s why it’s important to educate the families early on, so they are ready if and when things get bad. That’s also why it’s important to find new less toxic regimens that will work with older patients. Laurie M. Burroughs, MD, here at SCCA is testing several promising nonmyeloablative regimens in patients with all kinds of nonmalignant conditions. So we are now working with Dr. Burroughs and others to open up transplant protocols for those with sickle cell disease who are between ages 16 to about age 25.
Q: Haven’t transplant doctors already made a lot of progress with alternative donors and less intensive transplant conditioning regimens for patients with nonmalignant conditions?
A: Yes but keep in mind: kids with SCD are different than kids with immune deficiencies. These differences often make a transplant more likely to be rejected. This is why children with SCD need a more intensive immunosuppressive treatment than those with immune deficiencies.
Q: What makes children with SCD more likely to reject a transplant?
A: For one thing, their immune system is still intact and capable of attacking the donor marrow. Patients with immunodeficiencies on the other hand can’t keep out a foreign infection but they also have trouble keeping out the foreign curative bone marrow. They turn the negative into a positive. The other factor is that many SCD patients having transplant have likely had multiple blood transfusions as part of their previous treatment. These transfusions are thought to prime the patient’s immune system to fight markers in the blood—the same markers that may appear on donated marrow cells. This possibility of transfusion-primed rejection is why we don’t have family members donate blood. We want to minimize the risk of rejection if a transplant with a family member is pursued.
Q: So, will the less intensive conditioning regimens now being tested at SCCA and elsewhere work for children with SCD?
A: It’s not clear. That’s why we are doing the studies. I’m certainly excited about the potential for less intensive conditioning and immunosuppression. But in evaluating all these new studies, we always need to consider the donor source, the conditioning, and the immunosuppression carefully in the different subpopulations having transplants.
Q: Overall, are you optimistic about the prospects for stem cell transplantation in SCD?
A: Absolutely. We certainly need to learn what works best and make improvements. Better ways of predicting who will develop SCD clinical complications would be helpful. And we need to educate the community. But yes, already today many of these kids do fantastic after transplantation. One reason is that, unlike children with cancer, they don’t come into the transplant after long history of harsh chemotherapy. The sickle cell disease often has taken a toll on their body, but it’s a different toll.
After transplant, they are cured. They no longer need the sickle cell treatments. The pain is gone. The lung disease and the neurological disease do not get worse. If we can make it safer and identify appropriate patients sooner, many more of my patients will benefit.
1 Walters et al. N Engl J Med 1996;335:369-376 .
2 Walters et al. Blood 2000;15:1918-1924.
3 Buchanan et al. Biol Blood Marrow Transplan 2010;16(supp1):S64-S67.
4 Mentzer et al. Am J Pediatr Hematol Oncol 1994;16:27-29.