Eltrombopag added to immunosuppression for children with treatment-naïve severe aplastic anaemia

Abstract

Acquired severe aplastic anaemia (SAA) has an immune pathogenesis, and immunosuppressive therapy (IST) with anti-thymocyte globulin and cyclosporine is effective therapy. Eltrombopag (EPAG) added to standard IST was associated with higher overall and complete response rates in patients with treatment-naïve SAA compared to a historical IST cohort. We performed a paediatric subgroup analysis of this trial including all patients aged <18 years who received EPAG plus standard IST (n = 40 patients) compared to a historical cohort (n = 87) who received IST alone. Response, relapse, clonal evolution, event-free survival (EFS), and overall survival were assessed. There was no significant difference in either the overall response rate (ORR) or complete response rate at 6 months (ORR 70% in EPAG group, 72% in historical group, P = 0·78). Adults (≥18 years) had a significantly improved ORR of 82% with EPAG compared to 58% historically (P < 0·001). Younger children had lower response rates than did adolescents. The trend towards relapse was higher and EFS significantly lower in children who received EPAG compared to IST alone. Addition of EPAG added to standard IST did not improve outcomes in children with treatment-naïve SAA. EPAG in the paediatric population should not automatically be considered standard of care. Registration: clinicaltrials.gov (NCT01623167).

Keywords: aplastic anaemia; marrow failure; paediatric aplastic anaemia; paediatric haematology.

Conflict of interest statement

Conflict of interest

Neal S. Young has a cooperative research and development agreement (CRADA) with Novartis that provides research funding. Subsequent to her involvement with this research, Danielle M. Townsley became an employee of AstraZeneca but had no competing financial interests while at NIH. Daniela Baldoni and Annie St. Pierre are employees of Novartis. Novartis provided PK data for this manuscript and reviewed the manuscript prior to submission. All other authors have no conflicts of interest to declare.

© 2020 British Society for Haematology and John Wiley & Sons Ltd.

Figures

Fig 1.

Study design. The study compared two groups: the paediatric EPAG group and the historical paediatric IST group. The paediatric IST group consisted of 87 paediatric patients (aged NCT00061360, NCT00001964, NCT00260689 and (no NCT number available: Rosenfeldet al., 2003) taking place at the NIH from 1989 to 2010. The paediatric EPAG group consisted of 40 patients (aged <18 years) enrolled on NCT01623167 from 2012 to 2019; data of 19 patients were previously published.Analysis was performed using intention to treat. Measured outcomes included: haematological response, relapse, clonal evolution, event-free survival, and overall survival. ATG, anti-thymocyte globulin; CSA, cyclosporine; EPAG, eltrombopag; IST, immunosuppressive therapy; NCT, national clinical trial; NIH, National Institutes of Health; MMF, mycophenolate mofetil.

Fig 2.

Relapse and event-free survival (A) Kaplan–Meier curve comparing relapse in all paediatric responders; the paediatric ISTversuspaediatric EPAG group. The median time to relapse was 349 days in the EPAG group and 585 days in the IST group. Relapse was 43% in the EPAG group and 27% in the IST group. This difference was not significant (likelihood ratioP = 0·0661). (B) Kaplan–Meier curve comparing relapse between children and adults who received EPAG. The median time to relapse was 349 days in children and 277 in adults. There was no significant difference in relapse seen with 41% of adults relapsing compared with 43% of children (likelihood ratioP = 0·56). (C) Kaplan–Meier curve comparing EFS in paediatric responders in the ISTversusEPAG group. At 1432·5 days (median follow-up time in the EPAG group) EFS was significantly lower in the EPAG group (57%) compared with the IST group (69%) (likelihood ratioP = 0·0499). The median follow-up time was 2409 days (6·6 years) in the paediatric IST group and 1432·5 days (3·9 years) in the paediatric EPAG group. EFS, event-free survival; EPAG, eltrombopag; IST, immunosuppressive therapy.