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G371 Defining transient abnormal myelopoiesis (TAM) and silent tam in neonates with down syndrome
  1. N Bhatnagar1,
  2. L Nizery2,
  3. H Richmond2,
  4. K Perkins3,
  5. A Kennedy3,
  6. M Metzner3,
  7. K Alford3,
  8. J Bonnici2,
  9. A Roy2,
  10. M Anthony4,
  11. R Blumberg5,
  12. A Curley6,
  13. M Gattens7,
  14. S Godambe8,
  15. I Gozar8,
  16. C Halsey9,
  17. J Ho10,
  18. S Jaiswal11,
  19. R Nicholl12,
  20. A Norton13,
  21. S Rasiah14,
  22. A Skinner15,
  23. A Thomas16,
  24. S Uthaya17,
  25. T Watts18,
  26. C Garnett3,
  27. E Louka2,
  28. G Hall2,
  29. P Vyas3,
  30. I Roberts2,3
  1. 1Paediatric Haematology Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  2. 2Department of Paediatrics, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
  3. 3Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
  4. 4Neonatal Medicine Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  5. 5Neontal Unit, The Whittington Hospital, London, UK
  6. 6Neonatal Medicine Unit, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
  7. 7Paediatric Haematology Unit, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
  8. 8Neonatal Medicine Unit, Imperial College Hospital NHS Trust, London, UK
  9. 9Paediatric Haematology Unit, Royal Hospital for Sick Children Glasgow, Glasgow, UK
  10. 10Neonatal Unit, Whipps Cross University Hospital NHS Trust, London, UK
  11. 11Neonatal Unit, Frimley Park Hospital NHS Foundation Trust, Frimley, UK
  12. 12Neonatal Unit, The North West London Hospitals NHS Trust, London, UK
  13. 13Paediatric Haematology Unit, Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK
  14. 14Neonatal Medicine Unit, Birmingham Women’s NHS Foundation Trusti, Birmingham, UK
  15. 15Neonatal Unit, The Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, UK
  16. 16Paediatric Haematology Unit, Royal Hospital for Sick Children Edinburgh, Edinburgh, UK
  17. 17Neonatal Unit, Chelsea & Westminster Hospital NHS Foundation Trust, London, UK
  18. 18Neonatal Medicine Unit, Guy’s and St Thomas' NHS Foundation Trust, London, UK

Abstract

Background and aims Children with Down syndrome (DS) have a 150-fold-increased risk of acute myeloid leukaemia (ML-DS) in the first 5y of life (peak age 12–15 months). ML-DS is preceded by Transient Abnormal Myelopoiesis (TAM), a neonatal pre-leukaemic disorder unique to DS. Recent studies of clinically-diagnosed TAM show acquired mutations in the GATA1 gene in all cases. However, the true clinical spectrum of TAM is unknown since previous retrospective reports have not systematically evaluated blood films or GATA1 mutation status. The purpose of our study was to prospectively determine the clinical, haematological, molecular features and natural history of TAM.

Methods Neonates with karyotypically-confirmed DS were prospectively enrolled to the Oxford-Imperial DS Cohort Study (OIDSCS) from October 2006. Detailed clinical and FBC/blood film data were matched to GATA1 mutational analysis by Sanger sequencing/Direct High Performance Liquid Chromatography (Ss/DHPLC). Targeted next-generation-sequencing (NGS) was used to determine clone size and/or detect small (<5%) mutant GATA1 clones. TAM was prospectively defined as: >10% peripheral blood blasts and GATA1 mutation(s) detected by Ss/DHPLC. Silent TAM was defined as: blasts <10% and GATA1 mutation (s) detected by Ss/DHPLC or NGS.

Results Of 382 neonates recruited to OIDSCS by June 2014, 39 (10.2%) had TAM. Although no clinical features were specific for TAM, hepatosplenomegaly, pericardial/pleural effusion and skin rash were more common in TAM (p < 0.0001, p < 0.01, p < 0.05) than DS neonates without GATA1 mutations. The only haematological features specific for TAM were blasts >20% and WBC >45 × 109/L. Ten neonates with TAM and 8 without TAM had 11–20% blasts. In 163 DS neonates with blasts <10% screened by NGS, 33(20.2%) had small GATA1 clones (Silent TAM); their clinical and haematological features were indistinguishable from 130/163 without mutations. 4 neonates with TAM received low-dose chemotherapy and 1 died. ML-DS has developed in 4/39 TAM, 1/33 Silent TAM and no DS neonates without GATA1 mutations (median follow-up 57 months, range 18- >60).

Conclusion In neonates with DS, acquired mutations in the GATA1 gene are common, often clinically and haematologically silent and confer a risk of ML-DS in TAM and Silent TAM.

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