Immunosuppressive therapy combining anti-thymocyte globulin and cyclosporine A in childhood acquired aplastic anaemia - long term-outcomes and risks
Abstract
In patients with acquired aplastic anaemia (AA), autoimmunity has been shown to play an important role in the pathogenesis. Therefore immunosuppressive therapy combining cyclosporine A (CsA) and antithymocyte globulin (ATG) is currently a standard treatment regimen for paediatric patients with AA, if a matched sibling donor is not available.
Response rate approximately 70% and a 10-20% risk of clonal evolution (paroxysmal nocturnal haemoglobinuria, myelodysplastic syndrome, acute myeloid leukaemia) are the main limitations of IST compared to allogeneic stem cell transplantation (MSD-SCT). Long-term experience with AA management is presented through a cohort of paediatric patients diagnosed with aplastic anaemia between 1996 and 2009 in the Czech Republic.
A total of 72 children with a median age of 10.5 yrs (1.6-17.9 yrs) met the criteria of aplastic anaemia. First-line therapy followed HLA-identical sibling donor availability - 18 patients underwent MSD-SCT and 54 were given immunosuppressive therapy (IST).
Overall survival (OS) at a median follow-up of 7 years was 96±3.5% in the SCT group and 92±3.8% in the IST group. There was a significant difference between 7-year EFS in the SCT group (92.3±7.4%) and in the IST group (58±7.1%).
Overall response to IST was 76%. Cummulative relapse rate 22%, with 75% probability of response to repeated courses of IST.
First-line IST failure and relapse treatment non-response in 12 patients was managed by stem cell transplantation from an alternative donor (MUD-SCT) followed by 5-year OS 80%. No MDS/AML clonal transformation was registered within a 7-year median follow-up after IST.
PNH clonal evolution was registered in 7 out of 37 evaluated patients (19%) at a median interval of 108 months from start of IST. Five of these patients presented with clinical or laboratory symptoms of PNH including two thrombotic events.
Only two patients were asymptomatic, with a subclinical course typical of PNH/AA syndrome. The cumulative risk of PNH evolution following immunosuppressive treatment for aplastic anaemia is 2.2%⋯4.6% ⋯7.2%⋯19.8% 2, 4, 6 and 10 years from start of treatment.
IST should be considered an effective alternative first-line therapy for paediatric aplastic anaemia, with acceptable toxicity facilitating at least temporary disease control in patients lacking a matched sibling donor. From a long-term perspective not relapses, but PNH clonal evolution including symptomatic haemolytic and thrombotic forms are of a major concern in therapy consequencies.