Question: Is the sickle cell disease community best served by waiting until irreversible complications of SCD occur prior to being considered a candidate for cure by transplantation, or should less restrictive eligibility criteria be developed which take into account the more modern outcomes of cord blood transplantation, and which consider the morbidity and early mortality of non-transplanted patients with SCD?

Using the restrictive eligibility criteria suggested by Adamkiewicz et al. will allow for only patients who already have serious complications of SCD to be treated by cord blood transplantation, and few, if any, to be asymptomatic in follow-up. Less restrictive eligibility criteria should be developed.

A member of the Forum Editorial Board comments:

Although I agree with the above comments in principle, I believe that the issue is substantially more complicated in the sickle cell disease patients (compared, for example, to thalassemia major). Perhaps this is why there are polarized opinions about how best to approach transplantation for this disease. Orah Platt (with Eva Guinan) wrote a reasonable summary of the problems in 1996, and I do not believe that the issues have changed substantially since it was written, except that supportive care has probably improved. Thus, in kids who go to transplantation, they will have a higher risk of mortality (in the short-term) compared to those who do not, a substantial risk of chronic GVHD after unrelated UCBT, and the very real possibility (33% in the Yeager report) of graft rejection. To subject all sickle cell disease patients to these risks of transplantation would not take into account a balanced and responsible analysis of the risks and benefits involved. Thus, some attempt at selecting patients who are most likely to experience a morbid course or early mortality is necessary. The problem is that our clinical 'predictors' of adverse outcomes in SCD remain imperfect and unreliable. Until these improve, we are very likely to rely upon post-facto sickle-related clinical complications as indications for intensive and potentially risky interventions like transplantation.

The following is extracted from the article mentioned above. (Bone marrow transplantation in sickle cell anemia--the dilemma of choice. Platt OS, Guinan EC. N Engl J Med. 1996;8;335:426-8.)

The clinical complications of sickle cell anemia reflect the vascular damage caused by the abnormal red cells. The distressing, potentially fatal acute events — acute episodes of pain ("crises") and acute chest syndrome — are vascular events that share varying degrees of bone marrow ischemia, necrosis, embolization, and inflammation. Although not clearly associated with long-term sequelae themselves, these acute episodes constitute the main morbidity of the disease, and the patients who have the highest rates of these acute complications have the shortest life expectancy.

Five common clinical courses of the disease are presented by the authors. At birth these five patients are asymptomatic and indistinguishable in terms of their disease. Even before having symptoms, Patient 1 dies of pneumococcal sepsis. Patient 2 has few complications until he has a stroke, which leaves him with temporary hemiplegia and permanently consigns him to the currently standard but unsatisfactory regimen of transfusion and iron-chelating drugs that ultimately contributes to his early death from iron overload. Patient 3 has a low level of fetal hemoglobin, numerous painful crises, at least one bout of acute chest syndrome, and a below-average life expectancy. Patient 4 has an average level of fetal hemoglobin and an average incidence of symptoms; she will die in her 40s. Patient 5, whose fetal hemoglobin level is likely to be in the highest quartile, has relatively few symptoms and a long life expectancy.

The authors then comment on an article by Walters et al. (Bone marrow transplantation for sickle cell disease. N Engl J Med. 1996;8;335:369-76.)

In a group of 22 children with sickle cell disease who received marrow from HLA-matched siblings, 15 (68 percent) were cured. The experience to date suggests that these 15 patients will remain free of sickle cell disease, with its associated pain, need for prescriptions and transfusions, organ damage, and early death. Unfortunately, they are also likely to be infertile, and they have an undefined risk of a chemotherapy-induced malignant condition or other late complication of transplantation. In four of the patients (18 percent), the marrow allograft was rejected and sickle cell disease recurred. Two of the 22 children died after transplantation.

From this experience, one might ask whether bone marrow transplantation is worthwhile in sickle cell disease. The 15 cured patients (and their families and doctors) would undoubtedly answer "yes." This response is particularly unequivocal, because all the patients in this study had enough clinical experiences to classify them as the type depicted by Patient 2 or Patient 3, described above. The small group of patients who survived but were not cured by transplantation will add the long-term effects of busulfan and cyclophosphamide to their already long list of potential medical problems related to sickle cell disease.

Given the current state of transplantation technology, deaths are unavoidable. Without a major breakthrough, it is unlikely that the death rate will fall substantially below 10 percent, the current rate among children who undergo bone marrow transplantation for nonmalignant diseases in many centers. The problem is that predictions of the clinical course of sickle cell disease are imprecise, and the temptation is to intervene early, when the risks attending transplantation may be relatively low. However, a liberal selection policy would increase the chance that patients who would otherwise have a relatively benign clinical course (such as patients 4 and 5) would be exposed to the risks of infertility, graft-versus-host disease, exacerbation of sickle vascular disease, complications related to the conditioning regimen, and even death. Ongoing studies involving transcranial Doppler and magnetic resonance brain imaging may identify high-risk patients for whom transplantation early in the course of the disease would be appropriate.

The reasonable and relatively strict entry criteria used by Walters et al. for their investigation of bone marrow transplantation parallel the criteria for enrolling patients in studies of the treatment of sickle cell disease with hydroxyurea. Clinicians must now weigh the pros and cons of these two approaches. The irrefutable advantage of transplantation is that a successful outcome is definitive, and unless severe, chronic graft-versus-host disease occurs, the procedure is curative. But the potential for cure comes at a considerable risk, most of which is incurred at the time of the procedure.

The question of how ambitious and aggressive physicians should be in treating sickle cell disease will need to be resolved through a careful examination of the risks and benefits. Fortunately, we are now in the position of studying therapeutic options for a disease that until very recently had no options.