Blood, 1 October 2007, Vol. 110, No. 7, pp. 2223-2224.
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TRANSPLANTATION
Comment on Bernaudin et al, page 2749
Tortoise and hare win for SCD
John F. Tisdale
NATIONAL INSTITUTES OF HEALTH
Bernaudin and colleagues report, in this issue of Blood, the long-term results of the largest study of related myeloablative stem-cell transplantation for sickle cell disease (SCD). Their results show that slow, steady improvements over time, along with the addition of rabbit anti–thymocyte globulin (ATG) to the conditioning regimen, combine to produce an event-free survival (EFS) of 95.3%. They argue that for children with a suitable sibling-matched donor, myeloablative transplantation should be considered the standard of care in those at high risk for stroke.
Sickle cell anemia is a severe recessive genetic disorder resulting from a single nucleotide substitution in codon 6 of the ß-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 ß-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.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests. 
REFERENCES
- Walters MC, Patience M, Leisenring W, et al. Bone marrow transplantation for sickle cell disease [see comments]. N Engl J Med 1996; 335:369–376.[Abstract/Free Full Text]
- Panepinto JA, Walters MC, Carreras J, et al. Matched-related donor transplantation for sickle cell disease: report from the Center for International Blood and Transplant Research. Br J Haematol 2007; 137:479–485.[CrossRef][Medline]
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- Iannone R, Casella JF, Fuchs EJ, et al. Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. Biol Blood Marrow Transplant 2003; 9:519–528.[CrossRef][Medline]
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- Horan JT, Liesveld JL, Fenton P, Blumberg N, Walters MC. Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin. Bone Marrow Transplant 2005; 35:171–177.[CrossRef][Medline]
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Related Article in Blood Online:
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Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease
- Françoise Bernaudin, Gérard Socie, Mathieu Kuentz, Sylvie Chevret, Michel Duval, Yves Bertrand, Jean-Pierre Vannier, Karima Yakouben, Isabelle Thuret, Pierre Bordigoni, Alain Fischer, Patrick Lutz, Jean-Louis Stephan, Nathalie Dhedin, Emmanuel Plouvier, Geneviève Margueritte, Dominique Bories, Suzanne Verlhac, Hélène Esperou, Lena Coic, Jean-Paul Vernant, and Eliane Gluckman, for the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)
Blood 2007 110: 2749-2756.
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