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Cord blood transplantation for sickle cell anemia: Bust or boom?

Ever since the initial report in 1984 of successful hematopoietic cell transplantation (HCT) in a child who had acute myelogenous leukemia and sickle cell anemia, and who was cured of both, hematologists and transplantation physicians have struggled with how to make this curative therapy available to a wider group of affected individuals (1–3). During the intervening years, a better understanding of the natural history of sickle cell anemia has emerged, and views about who might benefit most from this intensive procedure have evolved to include more, not fewer individuals (4, 5). In addition, alternative sources of hematopoietic cells such as umbilical cord blood have been identified, and there has been considerable progress in how cord blood might best be utilized for transplantation (6). Together, it is possible that advances on both these fronts might engender the referral of highrisk individuals to transplantation before they develop devastating complications of sickle cell anemia. Ideally, one would treat these persons by utilizing hematopoietic cells in cord blood that harbor a modulated risk of graft-versus-host disease and thereby facilitate transplantation in a population with human leukocyte antigen genetic diversity. Success on this path would certainly expand the application of HCT for this disorder and cure a larger number of individuals. The report by Adamkiewicz et al. in this issue illustrates the potential for success and failure in translating the idea of unrelated donor cord blood transplantation for sickle cell anemia into reality. This small series included seven children who had experienced a stroke, which was the reason why cord blood transplantation was pursued. Eight transplantation procedures utilizing six different preparative regimens and five different regimens for post-grafting immunosuppression were performed. Five of seven patients (71%) experienced significant adverse events of graft rejection or death. Currently, 43% survive disease-free after unrelated cord blood transplantation (UCBT) due to a successful second cord blood transplantation in one patient, and one of seven (14%) subjects died of transplantrelated causes. These preliminary findings suggest the possibility of success after unrelated donor cord blood transplantation in high-risk patients. It is the introduction of transplantation in patients like these at risk of progressive neurovascular injury, and who are also very likely to need long-term transfusion support with its attendant risk of life-threatening transfusional iron overload, where risk–benefit considerations might achieve a suitable balance. But to tip the balance in favor of transplantation, the problems of graft rejection and graft-versus-host disease after unrelated donor cord blood transplantation will require better control. This strategy also must be pursued, as the authors conclude, through implementing a uniform investigative protocol with unambiguous eligibility criteria that are cooperatively designed and carried out by skilled investigators in a multicenter setting. These investigations must also employ stringent guidelines that ensure the safety of research subjects. It is quite possible and even likely that the successful translation of UCBT for sickle cell anemia will hinge on our ability to establish bidirectional donor–host immunological tolerance, and that this will involve the administration ofmore intensive immunosuppression thanwe are accustomed to using in this clinical setting. This represents a shift from the notion that marrow ablation and elimination of sickle cell progenitor cell populations are the principle objectives in carrying out a successful HCT. There are many reasons why this might be, and the authors speculate about several of these, not the least of which is that the immunological milieu of sickle cell anemia is one of inflammation, where innate stimulation of graft-versus-host Pediatr Transplantation 2007: 11: 582–583 Copyright 2007 Blackwell Munksgaard