By Kimberly McGhee
Illustration by Emma Vought and Brennan Wesley
The more than 70,000 people in the United States who suffer from sickle cell disease (SCD), a hereditary blood disorder, know what it is like to carry the enemy within.
Their blood, which should be the very source of vitality, instead brings painful crises and a shortened life expectancy. The sickled red blood cells that give the disease its name injure the vasculature as they pass through, their sharp ends scraping the epithelia and causing inflammation and eventual thickening that can provoke painful crises, stroke, and organ damage. The resulting congestion clogs the spleen, leaving SCD patients prone to infection. The sickled cells can damage the kidneys and affect renal function in some patients. Patients with severe SCD may experience acute chest syndrome, a potentially life-threatening condition in which the lungs are “whited out” on chest radiography and air exchange is compromised due to sickled red blood cells. As a result of such complications, the average life expectancy of patients with SCD is 42 years.
Hematopoietic stem cell transplant, which replaces the bone marrow of patients with SCD with the healthy marrow of a matched sibling donor, is the only known cure for SCD. A rigorous conditioning regimen of potent chemotherapeutic agents precedes transplant in these patients to ensure that their own blood cell production is destroyed. If the graft is successful, the stem cells thrive and replenish the bone marrow, which begins producing healthy red blood cells, preventing further painful crises and halting the progression of organ damage.
Despite their promise, fewer than 500 of these myeloablative bone marrow transplants from matched sibling donors have been performed in patients with SCD in the US (2011 data). This low number is due in part to the fact that only one in four patients has a matched sibling donor and in part to the rigors of the conditioning regimen and the risk of infection, transplant complications, and sterility. These considerations can dissuade some patients and parents from pursuing transplant.
In an effort to expand the donor pool for children with SCD, preserve fertility, and minimize complications, MUSC is trialing a new reduced-intensity conditioning (RIC) regimen for bone marrow transplant from unrelated donors in patients with severe SCD as part of the national SCURT study, which is sponsored by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0601; NCT00745420). According to Jennifer J. Jaroscak, M.D., Associate Professor in the Division of Pediatric Hematology and Oncology at MUSC Children’s Hospital and principal investigator for the MUSC site of the SCURT study, “For children who don’t have a sibling match, we hope to demonstrate that bone marrow transplant from unrelated donors will be effective and safe enough that people would consider this potentially curative option.”
A number of studies have established the efficacy of matched sibling bone marrow transplant as a treatment for SCD and demonstrated the durability of its benefits. In a 1996 article in the New England Journal of Medicine, Walters et al1 reported the results of bone marrow transplants from matched sibling donors in 22 SCD patients aged less than 16 years. At approximately two years after transplant, the stem cell graft was successful in 16 and had failed in four. Sickle cell recurred in three of the four patients with failed transplants, and the fourth developed marrow aplasia. Two children died of complications (central nervous system hemorrhage or graft-vs-host disease—a condition in which the donor’s immune system attacks the host). In patients with successful grafts, painful crises ceased and organ damage stabilized. In 2001, Walters et al2 updated and expanded their findings, reporting that 55 of 59 children with sickle cell anemia or related conditions who received bone marrow allografts from matched siblings were still alive at a median follow-up of 42.2 months, and 50 were free of SCD. Five patients experienced graft failure and return of SCD, and four patients died of intracranial hemorrhage or graft-vs-host disease. Overall survival was estimated at 93%, and event-free survival at 84%. Follow-up of these patients continues to assess whether their life expectancy is increased after transplant.
Despite its promise, bone marrow transplant to cure SCD presents parents of the affected children with a difficult choice. To convince parents to allow their relatively healthy children to undergo destruction of their bone marrow, risk losing their fertility, and run the 10% risk of death due to graft failure or graft-vs-host disease in order to stave off eventual complications is challenging to say the least. The worst symptoms of SCD are relatively well controlled during childhood, but the unseen organ damage continues to occur. Those who opt for transplant do so because, for them, the promise of the long-term benefits of better quality of life and prevention of further organ damage outweigh the risks of transplant-associated complications. However, many parents of younger children do not consider transplant because of the risk of complications, and when they do, face long odds of finding a sibling match for their child (only one in four siblings will prove a good match).
The new trial of RIC for bone marrow transplant from unrelated donors should help ease parents’ fears and enable more SCD patients to benefit from transplant. Unlike myeloablative conditioning, which relies on high doses of potent chemotherapeutic agents to destroy the bone marrow, RIC uses immunosuppressive agents and milder chemotherapy to suppress, not destroy, the host’s bone marrow and immune system. This period of suppression (approximately six weeks) provides the donor bone marrow and immune system time to become established. Immunosuppressive therapy is also required for the first six to nine months after transplant to prevent graft-vs-host disease, but, in contrast to solid organ transplants, immunosuppression will not be necessary once the patient’s new immune system and bone marrow become established.
“Finding a safer way to do bone marrow transplants enables us to consider well-matched but unrelated donors when patients with SCD do not have a matched sibling,” explains Dr. Jaroscak.
In patients with blood cell cancers, a more rigorous conditioning program is essential to destroy the bone marrow, ensuring that it can no longer produce cancerous cells. For SCD, such complete eradication of the host bone marrow is unnecessary.3,4 In fact, children are free of sickle cell symptoms when as little as 50% of their red blood cells are derived from the donor. Healthy red blood cells replicate far faster and live longer than sickled cells, meaning that the red blood cells created by the donor marrow will eventually outcompete any remaining sickled cells. The most significant safety advantage of RIC is that the patient’s own bone marrow will rebound in the event of graft failure. “Finding a safer way to do bone marrow transplants enables us to consider well-matched but unrelated donors when patients with SCD do not have a matched sibling,” explains Dr. Jaroscak.
The purpose of the SCURT Study, which is expected to accrue 30 patients, is to determine whether RIC transplant using bone marrow from an unrelated, well-matched donor is safe and effective in children with severe SCD. To qualify for the trial, a patient must have no matched sibling and have a severe form of sickle cell anemia, as evidenced by frequent vaso-occlusive crises (>2); a history of acute chest syndrome; or a history of stroke or other serious cerebrovascular events. An unrelated donor with an eight-of-eight match also has to be identified. Dr. Jaroscak has already transplanted one patient as part of the trial and has had a second accepted. If the trial meets its primary endpoint of 1-year event-free survival following unrelated donor transplant and has a good safety profile, it will establish that unrelated donor transplant is a reasonable curative option for patients with SCD.
If proven safe and effective, bone marrow transplants from unrelated donors using RIC could increase the numbers of children and adolescents who benefit from this potentially curative therapy. However, the requirement of an eight-of-eight match will limit the number of potential recipients finding an appropriate donor. According to Dr. Jaroscak, “There are about 8 million people in the National Bone Marrow Program, and depending on a patient’s specific white blood cell markers, I might find several potential donors or I might find none.” Of the 20 children she considered for the study, suitable matches were found for only three.
Cord blood could hold the answer to removing this obstacle. Because it is collected at the time of birth, when the immune system of the child is not yet fully functional, a five-of-six match is sufficient for an unrelated donor transplant.4 While it is true that the cord blood cohort of the SCURT trial was terminated early because the preset limit for graft failures (10%) was met, Dr. Jaroscak and others believe that cord blood transplant represents an important future therapy for SCD. Typically only about 20 mL of cord blood is available, enough for a younger child with a low body weight but not for an adolescent. SCURT included both younger children and adolescents, and Dr. Jaroscak, whose own research is focused on cord blood for SCD, believes that results for the cord blood cohort would have been better had it been limited to a younger population. Once the SCURT trial is complete, another cord blood trial using additional immunosuppressive therapies will be opened, with MUSC as a participating site.
While waiting for the day when RIC and cord blood transplant will make transplant available to most patients with SCD, Dr. Jaroscak takes heart in the difference that unrelated bone marrow transplants have made in the lives of study patients: “When I do a transplant for a malignant disease, I am saving a life. When I do a transplant for a child with SCD, I am changing a life, changing what his or her life is going to be like, and it is pretty amazing.”
1 Walters MC, Patience M, Leisenring W, et al. Bone marrow transplantation for sickle cell disease. N Engl J Med 1996; 335:369-376. Available at http://dx.doi.org/10.1056/NEJM199608083350601
2 Walters MC, Patience M, Leisenring W, et al, for the Multicenter Investigation of Bone Marrow Transplantation for Sickle Cell Disease Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biology of Blood and Marrow Transplantation 2001;7:665-673.
3 Shenoy S. Hematopoietic stem-cell transplantation for sickle cell disease: current evidence and opinions. Ther Adv Hematol 2013;4(5):335-344. Available at http://dx.doi.org/10.1177/2040620713483063
4 Shenoy S. Hematopoietic stem cell transplantation for sickle cell disease: current practice and emerging trends. Hematology Am Soc Hematol Educ Program 2011;1:273-279. Available at http://dx.doi.org/10.1182/asheducation-2011.1.273.