One of the gravest medical conditions diagnosed in infants is severe combined immunodeficiency (SCID), a group of rare, inherited immune disorders sometimes referred to as “bubble baby disease.” Children with SCID lack the means to fight infection and usually don’t survive past their first year, unless they receive a transplant of blood-forming stem cells to replace their missing immune system.
Now a study examining how well these children fare after transplantation shows that this treatment has become very effective, especially if done early in life. In fact, the success rates of transplants were found to be high for patients who received stem cells from a matched donor as well as for those whose transplant was half-matched.
Of those receiving transplants within three and a half months after birth, 94 percent were alive five years later. Overall, approximately three-fourths of children who received transplants survived for at least five years.
“This study confirms that transplants for SCID work well in very young children, but it also shows that any child with this disease can be treated with a high likelihood of a cure with a transplant from a parent or an unrelated donor, not just a matched brother or sister,” says Richard O’Reilly, Chair of the Department of Pediatrics and Chief of the Pediatric Bone Marrow Transplant Service. Dr. O’Reilly is the senior and corresponding author of the study, which was published in the July 31 issue of the New England Journal of Medicine.
Development of a newborn screening test has made it possible to detect SCID before symptoms appear, but to date only 21 states have implemented this test as part of routine newborn screening. “This really illustrates the importance of widespread screening for SCID so that doctors can intervene early,” Dr. O’Reilly says. “By the time symptoms of infection appear, the circumstances for transplant are often less favorable.”
Success Rates High Regardless of Donor Match
The study was conducted by the Primary Immune Deficiency Treatment Consortium (PIDTC), a collaborative network of 13 major centers in North America. The PIDTC looked at outcomes in 240 infants with SCID who received transplants at 25 centers between 2000 and 2009 using a variety of approaches. Some received stem cells from siblings who were a close tissue match, while others who did not have a matched sibling donor received stem cells from a parent or a donor unrelated to the recipient, or from umbilical cord blood.
A critical factor appears to be ensuring the child has no infection at the time of transplant. This proved to be more important than how closely the tissue match is between the child and the stem cell donor. “The results underscore the idea that avoiding infection is key to success,” Dr. O’Reilly adds. “If you treat children before they are infected, their likelihood of survival is very high.”
The closeness of a match is determined by human leukocyte antigens (HLA), proteins that help regulate the immune response. If a donor’s HLA proteins closely resemble those of the patient, this reduces the risk of post-treatment complications such as graft-versus-host-disease (GVHD), in which transplanted immune T cells recognize the patient’s own cells and tissues as foreign and attack them. Because HLA markers are inherited from both parents, siblings have a one-in-four chance of being a perfect match.
In the study, the best results, not surprisingly, were seen after transplant from matched sibling donors. The five-year survival rate for HLA-matched siblings was 97 percent. Even among patients who did not have matched sibling donors, overall five-year survival rates were high — 77 to 93 percent — if they were transplanted in the first three and a half months of life.
“Historically, the idea had been that the only good transplant for SCID was an HLA-matched transplant from a brother or sister,” Dr. O’Reilly explains. “The data from this study show that this is no longer true — the children receiving T cell–depleted transplants from half-matched parents or transplants from unrelated donors also do very well.”
Absence of Infection Very Important
Among those receiving a transplant when they were older than three and a half months, survival outcomes were high in the absence of infection. Ninety percent of patients who never had an infection survived for five years or more, and for those who did contract an infection that was later cleared from the body, the five-year survival rate was 82 percent. In contrast, only 50 percent of infants who had an infection at the time of the transplant survived five years.
Patients without a matched sibling often received chemotherapy before the transplant, which increases the chance that the donated stem cells will take root and build a fully functioning immune system. But with infected patients, the study showed, pre-transplant chemotherapy reduced chances of survival due to toxicity.
“An important finding of this study is that if the infection can’t be cleared, you are better off skipping the pre-transplant chemotherapy if a matched sibling is not available, since this will usually result in recovery of at least one major part of the immune system — cell-mediated immunity,” Dr. O’ Reilly says. “Findings such as these are essential to helping us develop better transplant strategies and less toxic regimens, adjusting them for each patient.”
MSK’s Leadership in SCID Treatment: No More “Bubble Babies”
MSK has played a pioneering role in advancing stem cell transplantation in general and the treatment of SCID in particular. The first successful transplant of stem cells from an unrelated donor was performed at MSK in 1973, specifically to treat a child with SCID.
In 1981, MSK introduced a groundbreaking technique for improving the success of unmatched transplants. Before stem cells are infused, T cells are removed from the transplanted bone marrow in order to prevent potentially lethal GVHD. Thereafter, new T cells that grow up in the child don’t recognize the child’s cells as foreign, but rather provide vigorous immunity against infections. This procedure, called T cell depletion, has become standard, permitting successful stem cell transplants from half-matched parents; it was the method used in the majority of cases examined in this study.
Dr. O’Reilly explains that SCID has propelled the field of stem cell transplantation. “Most of the important benchmarks in the development of transplantation and cell therapies have come from the studies of these relatively rare children who have a lethal genetic disorder of their immune system,” he says.
He pointed out that the strides made at MSK and elsewhere in a relatively short time have allowed children with SCID not only to survive but also to lead normal lives. In the 1970s and 1980s, SCID was popularly known as the “bubble baby disease” because its victims became famous for surviving their dire condition by living in a sterile environment devoid of all pathogens.
But what once was considered an extraordinary medical accomplishment is no longer necessary. “Paul Simon had that song [“The Boy in the Bubble”] where he says, ‘These are the days of miracles and wonder,’” Dr. O’Reilly says. “Our research provided a way to cure babies in the bubble. We don’t need the bubble anymore, and this study confirms that.”
Read more about this study in USA Today and US News & World Report.