Tortoise and hare win for SCD

Sickle cell anemia is a severe recessive genetic disorder resulting from a single nucleotide substitution in codon 6 of the β-globin gene, which, in the homozygous state, produces an abnormal hemoglobin that is prone to polymer formation under deoxygenated conditions. The polymerized hemoglobin leads to decreased red blood cell deformability and sickling within end arterioles, resulting in repeated vasoocclusive crises. Worldwide, sickle cell disease and the related β-thalassemias affect hundreds of thousands of individuals, causing severe morbidity and shortened life expectancy. Palliative therapies have been developed that extend life beyond childhood; however, conventional treatment remains unsatisfactory.

Strategies that aim to correct sickle cell disease permanently through the hematopoietic stem-cell compartment have long been sought, and bone marrow transplantation from a human leukocyte antigen (HLA)–matched sibling has previously been demonstrated to be curative in a select group of pediatric patients.¹  Indeed, these results have also set the stage for therapeutic strategies that aim to correct autologous hematopoietic stem cells through gene-transfer approaches, and progress has been sufficient to offer promise over the coming decade. Selecting patients with demonstrated severe disease, Walters et al¹  reported, in their landmark multicenter study, an EFS of 73% among 22 patients undergoing allogeneic stem-cell transplantation; overall survival (OS) was 91%. Incremental changes to the protocol over time also had the effect of improving upon their pioneering results, as disease-specific complications required adjustments of supportive care guidelines. Four of the first 7 patients experienced neurologic events, including central nervous hemorrhaging in 2, which prompted anticonvulsant prophylaxis, strict control of hypertension, swift magnesium replacement, and an increase in the red blood cell and platelet transfusion thresholds to 9 g/dL and 50 000/mm³, respectively. A recent analysis utilizing data reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR) between 1989 and 2002 confirmed these earlier results, with disease-free survival at 85% and OS at 97% among 67 SCD patients, each of whom had received transplants at one of 30 centers.² 

In the current issue of Blood, Bernaudin and colleagues report for the Société Française de Greffe de Moelle et de Thérapie Cellulaire the long-term results of related myeloablative stem-cell transplantation for sickle cell disease in 87 consecutive patients who underwent transplantation between 1988 and 2004. Patients were initially conditioned with varying doses of busulfan and cyclophosphamide, but due to unstable mixed chimerism in several, busulfan dosing was adjusted to body area, and ATG was added. Rejection rates fell from 22.6% before the addition of ATG to 2.9% thereafter. Transplant-related mortality was 6.9% overall; however, no deaths occurred after the 40th patient. EFS at 5 years was 86.1% overall, similar to the previously reported studies. Importantly, multivariate ana-lysis identified date of transplantation as the only variable that significantly affected EFS; the 5-year EFS was 95.3% for the 44 patients who underwent transplantation after January 2000. Although there has been recent enthusiasm for the development of nonmyeloablative regimens for transplantation in sickle cell anemia, an EFS of 95.3% will prove a high bar to overcome, especially given the high rejection rates observed in studies reported thus far,^3,4  and further supports the exploration of these regimens in older patients at high risk for conventional myeloablative transplantation due to comorbidities. These results represent a significant advance in the treatment of sickle cell anemia, and although the investigators argue that myeloablative stem-cell transplantation should be considered the standard of care for children at high risk for stroke, they might further argue that it should be considered standard of care for children with other disabling complications who have a suitable sibling-matched donor.