Immunosuppressive therapy for aplastic anemia in children: a more severe disease predicts better survival

Abstract

IntroductionA more severe form of a given disease negatively affects outcome in almost all human diseases. This seemed likely to apply to severe acquired aplastic anaemia (SAA), the pathophysiology of which is characterized by immune-mediated bone marrow failure. 1 A predominant oligoclonal immune response 2 by autologous T lymphocytes was shown to cause excessive apoptosis in stem and progenitor cells. 3,4 The molecular target of this T-cell response is still unknown, although in vitro a T-cell-mediated inhibition of aneuploid hematopoietic cells was demonstrated in patients with myelodysplastic syndrome. 5 Immunosuppressive therapy (IST) 6 seems to be the appropriate treatment for an autoimmune disease, but tissue replacement by bone marrow transplantation (BMT) is still the treatment of first choice 7,8 because there have been 20% to 30% IST nonresponders, a significant proportion of patients with subnormal blood counts 9 and a high risk of relapse 10,11 and clonal disease. 12,13 Because of the long latency of response to IST, identification of predictors of response and survival would be helpful to assign patients to the appropriate regimen.In children very SAA (vSAA) is predominant (Ͼ 60%). Patients with vSAA are especially prone to develop life-threatening infections. As most of those high-risk patients lack an HLA-identical sibling donor (matched sibling donor; MSD), searching for a matched unrelated donor (MUD) was recommended, despite that BMT from a MUD is still complicated by a high risk of graft rejection and graft-versus-host disease. This recommendation was well founded on the basis of a previous retrospective analysis 14 in which the outcome for children with vSAA was the worst with IST consisting of antithymocyte-globulin (ATG) plus androgens and/or steroids (probability of survival: vSAA, 37%; SAA, 56%).Combined IST with ATG and cyclosporin A (CSA) has been shown to be superior to ATG alone or in combination with androgens in adults, 15,16 and the addition of granulocyte colonystimulating factor (G-CSF) to the treatment regimen was able to improve granulocyte recovery. 17,18 We conducted a prospective multicenter trial comparing combined IST plus G-CSF and BMT 19 to identify prognostic factors for response to therapy and survival. Study designTwo hundred and thirteen patients newly diagnosed with SAA younger than the age of 17 years in 53 centers in Germany and Austria were included in A complete list of the members of the German/Austrian Aplastic Anemia Working Group appears in the "Appendix."Supported by the Friedrich-Baur-Stiftung (43/98), the Wilhelm-Sander-Stiftung (97.080.1), the Dr Sepp und Hanne Sturm Gedä chtnisstiftung, and AMGEN Germany.M.F., U.R., C.N., G.J.-S., W.F., A.B., and C.B.-G. conceived the study, designed the approach, and interpreted the data. M.F. wrote the paper. A.F. performed and interpreted the statistical analysis. I.B. reviewed the bone marrow biopsies to establish the correct diagnosis. 20 Zytogenetics and/or fluorescence in situ hybridization (FISH) analysis for...

Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade: a report from the European Group for Blood and Marrow Transplantation

“…21 The message is that while improvements have not been seen with immunosuppression in the 1990s, we are doing better than in the 1980s. As to the second point, we found a strong effect of age of outcome, confirming the results of numerous previous studies: 12,20,21,22,23,24,25 this effect was present in patients treated with transplantation (79% survival in children versus 68% in adults) as well as for those receiving immunosuppressive therapy (81% vs 70%), and could be demonstrated in univariate and multivariate analyses. The explanation of the different outcome in children and adults is relatively straightforward for BMT: children tolerate the conditioning regimen, associated toxicity, and GvHD better graft and have faster immune reconstitution, possibly also as a consequence of having younger donors.…”

“…Similar outcomes were recently reported in two large cooperative pediatric studies by Kojima and Fuhrer. 25,20 Also among patients treated with immunosuppression, we found that infectious deaths, together with hemorrhages and other toxicities, were more frequent in adults. Furthermore, the adult group had a higher rate of second tumors.…”

“…17 The addition of granulocyte colonystimulating factor (G-CSF) has been reported to accelerate neutrophil recovery and improve failure-free survival, but has failed to reduce early mortality or increase response rates and survival. [18][19][20] A more accurate screening at diagnosis aimed at excluding hypoplastic myelodysplasia with specific chromosomal disorders, such as monosomy 7, may further improve the long term outcome of patients treated with immunosuppressive therapy. Several important issues in the treatment of severe AA are still unsettled.…”

Hematopoietic growth factors in aplastic anemia patients treated with immunosuppressive therapy-systematic review and meta-analysis

“…Of them, 19 trials were excluded for various reasons 3,7,[10][11][12]14,15,18,19,[22][23][24][25][26][27][28][29][30][31] (Figure 1). Six trials performed between 1991-2007 and randomizing 414 patients fulfilled inclusion criteria.…”

Model-Based Determination of Effective Blood Concentrations of Cyclosporine for Neutrophil Response in the Treatment of Severe Aplastic Anemia in Children

“…However, in two thirds of cases, no suitable donor is available and IST becomes necessary. The response rate to IST varies from 60 to 80% with a survival rate at 5 years ranging from 55 to 80% (7,9). Hematological response rarely occurs before 4 months.…”