Curing sickle cell disease: Mission accomplished?

A s a hematologist and stem cell transplanter I read the report from Justus et al., ‘‘Allogeneic donor availability for hematopoietic stem cell transplantation in children with sickle cell disease’’ in this issue of Pediatric Blood and Cancer with keen interest [1]. In their brief and statistically sound article, the authors conclude that for patients of approximately 4 years of age with sickle cell anemia the likelihood that they would have a ‘‘suitable’’ umbilical cord blood (UCB) stem cell source for transplantation is over 90%. The authors caveat that this is only a single institution study with a small sample size notwithstanding, these are impressive numbers that speak to years of important clinical and laboratory research coupled with the creation of an impressive donor acquisition infrastructure. However, the authors statement, that for sickle cell disease hematopoietic stem cell transplant is curative but limited by the availability of donors requires some circumspection regarding, I am sure, the unintended conclusion— mission accomplished. The results of recent clinical trials [2] support the concept of the efficacy of matched related donor hematopoietic stem cell transplantation as a curative modality in select patients with sickle cell disease. But on many levels, we have a long way to go. The risk of transplant related morbidity and mortality are quite real. The overall survival for children with sickle cell disease undergoing a matched related donor (MRD) transplant of 95% using reduced intensity conditioning regimens is impressive but not perfect. Such outcomes, however, do support the use of MRD transplants when disease severity warrants and when the risks of the procedure inform the decisions of responsible physicians and educated parents. Thus, we are well beyond proof-of-principle and it is reasonable that safe and effective stem cell transplants for the majority of children with sickle cell disease would dramatically change the plight of those affected. However, as Justus et al. make clear matched sibling donor availability is quite restricted in an autosomal recessive inherited disease affecting young families; in the range of 15%. As a consequence, we must await the results of well-designed multi-institutional clinical trials utilizing alternative donors in addition to UCB; matched unrelated and most recently haploidentical [2]. Considering the 90% availability of a UCB donor a combination of these donor sources will theoretically lead to a donor-for-all. However, complicating the transplant decision making calculus is the evolution of dramatic improvements in quality of life and outcomes for children with sickle cell anemia. The advent of surveillance, early immunization, and penicillin prophylaxis made possible by newborn screening programs [3] coupled with the appropriate use of red cell transfusions with improved iron burden mitigation and hydroxyurea have dramatically improved outcomes for children with sickle cell disease. Unfortunately while the survival of children with sickle cell disease has improved dramatically, with over 90% living into adulthood [3] there appears to have been no such improvement in life expectancy, when these children enter adulthood. Perhaps we will see a reduction in mortality and an improvement in quality of life in affected adults as a consequence of improved access to care as well as the appropriate use of hydroxyurea and red cell transfusion but this is unpredictable. Forecasting long-term outcomes in adulthood for a particular child with sickle cell disease is at best difficult especially in light of what may be a decline in life expectancy for adults with sickle cell disease from 1979 to 2005 to 42 years for women and 38 years for men [4]. Thus physicians and parents are faced with a choice between short-term transplant morbidity and mortality versus organ failure and early death in adulthood. The decision could be further complicated by hope, as new modalities are being explored [5]. While, it is fair to say that donor availability is necessary for curative hematopoietic stem cell transplantation in sickle cell anemia it is far from sufficient. Thewide availability of UCB donors must not result in an uncontrolled anecdotal experience that cannot adequately inform the transplant decision making process. Furthermore donor availability should not be seen as the rationale for the lackluster pursuit of other promising modalities. A funded clinical trials network exploring non-transplant modalities is essential. Finally, even assuming that in time the results of clinical trials reveal a highly effective transplant algorithm for sickle cell disease, we must confront the elephant in the room. The majority of the world’s population affected by sickle cell disease resides geographically and economically in places where hematopoietic stem cell transplant is not available to the majority of the population in need; of the approximately 300,000 children born in the world with sickle cell disease 75% are from Africa and 50% are from only three countries – Nigeria, India, and the Democratic Republic of Congo. In contrast, only approximately 10% of patients with sickle cell anemia reside in high-income countries where stem cell