Immune suppression for childhood acquired aplastic anemia and myelodysplastic syndrome: where next?

The childhood bone marrow failure disorders are a heterogeneous group of diseases of which the commonest ones are acquired severe aplastic anemia (SAA) and myelodysplastic syndromes. SAA is characterized by the presence of pancytopenia with a hypocellular marrow in the absence of malignant infiltration or fibrosis. Myelodysplastic syndromes are characterized by ineffective hematopoiesis, dyplasia and cytopenias. The commonest subset of childhood myelodysplastic syndrome is refractory cytopenia of childhood (RCC) accounting for half of all cases of childhood myelodysplastic syndrome. The majority of cases of RCC are hypocellular and distinguishing between SAA and hypocellular RCC can be challenging. Most cases of hypoplastic RCC lack a cytogenetic abnormality and conversely some patients with aplastic anemia have an abnormal cytogenetic clone. Thus careful morphological assessment is required to distinguish between SAA and RCC. Future use of next-generation sequencing to detect acquired somatic mutations typical of myeloid disorders may help to distinguish between the two conditions. It is postulated that, in both hypoplastic myelodysplastic syndrome and SAA, autoimmunity and T-cell-mediated suppression of hematopoiesis contribute to the pathogenesis of these disorders. In both sets of disorders, there is a plethora of data demonstrating oligoclonal T-cell expansion, leading to over-expression of cytokines, such as interferon-γ and tumor necrosis factor-α, which suppress hematopoiesis. In acquired SAA, there is absolute and functional deficiency of regulatory T cells. The best evidence for an immune pathogenesis is provided by the response to immune suppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine. IST with ATG and cyclosporine is currently used as first-line treatment for children with SAA who do not have a matched sibling donor for bone-marrow transplantation. Historically, horse ATG was adopted as first line IST with rabbit ATG being used for relapse or refractory cases. Until 2007, there were two preparations of horse ATG; Lymphoglobulin (Genzyme) and ATGAM (Pfizer). Lymphoglobulin was withdrawn from the market in 2007 and because of the initial unavailability of ATGAM in most European countries, rabbit ATG (Thymoglobulin; Sanofi) was then adopted as first-line therapy. There have been numerous studies (Table 1) comparing the efficacy of rabbit ATG versus horse ATG. As described in this issue of the Journal, Jeong et al. performed a large retrospective comparison between Thymoglobulin and Lymphoglobulin in pediatric acquired SAA. While there was no difference in overall response rate at 6 months, patients in the horse ATG cohort had a superior overall survival and lower relapse rate. Thus so far, none of the seven published studies comparing horse ATG and rabbit ATG has demonstrated superiority of rabbit ATG. In five, rabbit ATG led to inferior overall survival or response rates and in the other two there was no significant difference between the two preparations.