Bone Marrow Transplantation and Immunosuppressive Therapy in Children with Aplastic Anemia: Data from a Prospective Multinational Trial in Germany, Austria and Switzerland.
Authors: Fuehrer Monika M. , Rampf Udo , Niemeyer Charlotte M. , Faldum Andreas , Baumann Irith , Friedrich Wilhelm , Ebell Wolfram , Borkhardt Arndt , Bender-Goetze Christine 
Published: October 2019

Abstract
In children severe aplastic anemia is a rare, lifethreatening disease. Patients present with peripheral pancytopenia and hypoplastic bone marrow. The disease is sub-classified into a severe (PMNs >200/μl: SAA) and a very severe (PMNs <200/μl: vSAA) form. Children with vSAA are especially prone to die from infectious complications. Bone marrow transplantation (BMT) and immunosuppressive therapy (IST) are the two treatment options. However, most of the affected children lack a compatible sibling donor (MSD) and BMT from a matched unrelated donor (MUD) is still complicated by a high risk of graft rejection and graft-versus-host disease. A retrospective analysis based on the EBMT registry data showed in 1990 that in children with vSAA IST with anti-thymocyte-globulin (ATG) +/− androgens resulted in an inferior survival rate (37%) compared to SAA (56%), and BMT, even from MUD, was recommended for this group.
We report the results of a prospective multicentre trial with a combined IST regimen of cyclosporin A (CSA) and ATG for treatment of SAA in children. By biological selection depending on the availability of a MSD, patients were assigned to either the BMT (n=67) or the IST group (n=146). 62 patients received BMT (except 5 patients whose parents refused) after a conditioning treatment with ATG and cyclophosphamide. 151 children (146 without a MSD, 5 with a MSD) were treated with combined IST with ATG (horse 0,75ml/kg BW for 8 days), CSA (5mg/kg BW, adjusted to blood levels), prednisolone (1–2mg/kg tapered until day 28) and in cases with PMN <500/μl with G-CSF (5μg/kg BW) in addition. Response to IST and survival was evaluated on day 112, at 6 months and every 6 months afterwards. Complete response (CR) was registered when haemoglobin reached normal values, platelets >100,000/μl and PMN >1,500/μl. The median follow-up at time of analysis was 50 months (range 0.85–116 months).
97 vSAA patients received IST. In this formerly high-risk group the 5-year survival rate could be improved to 93% (95%-Confidence Interval (CI): 88%–98%). Surprisingly, SAA patients showed a significantly lower 5-year survival rate of 81% (95%-CI: 69%–93%%; p-value: 0.0266). Similarly, vSAA patients reached CR in 68% (95%-CI: 58% – 77%) of cases, compared to 45% in SAA patients (95%-CI: 31% – 59%, p-value: 0.009)(best response after one year). When treated with BMT, both the vSAA and the SAA patients reached comparable survival rates (vSAA 89%; 95%-CI: 80%–99% and SAA 96%; 95%-CI: 89%–100%).
We conclude that in children without a MSD treatment with combined IST and G-CSF converts the former bad prognosis factor severe granulocytopenia into an indicator of better response and survival. Our findings strongly suggest that especially in children with vSAA the immune system plays the key role, and the per se healthy stem-cell compartment is able to compensate for the loss of stem cells as soon as the T-cell-mediated destruction is stopped. Therefore severe granulocytopenia may serve as a surrogate marker for an immune-mediated disease instead of a stem-cell disorder.