Advertisement

Bone Marrow Failure in Children: Approach to Diagnosis and Treatment

  • Hannah Fassel
  • Sujit ShethEmail author
Review Article
  • 72 Downloads

Abstract

Bone marrow failure has many different etiologies, including genetic defects which manifest with specific syndromes, as well as acquired conditions as a result of insults to the bone marrow leading to aplasia. The clinical picture is varied and clues for the underlying cause may or may not be evident at the time of presentation, frequently leading to a complex workup with a battery of tests often done to rule out genetic defects. The treatment approach for bone marrow failure is very dependent on the underlying cause, which makes it all the more critical to have an accurate diagnosis. First line management essentially consists of either hematopoietic stem cell transplant or immunosuppressive therapy. In this review authors will provide a broad look at the causes of bone marrow failure, the stepwise diagnostic algorithm and the approach to decision making for treatment. Fine details of each cause, and of each treatment modality are beyond the scope of this review which aims to provide an overview.

Keywords

Inherited bone marrow failure syndromes Secondary aplastic anemia Immunosuppression Hematopoietic stem cell transplantation 

Notes

Compliance with Ethical Standards

Conflict of Interest

None.

References

  1. 1.
    Höchsmann B, Moicean A, Risitano A, Ljungman P, Schrezenmeier H. Supportive care in severe and very severe aplastic anemia. Bone Marrow Transplant. 2013;48:168–73.CrossRefGoogle Scholar
  2. 2.
    Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011;365:430–8.CrossRefGoogle Scholar
  3. 3.
    Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood. 2012;120:1185–96.CrossRefGoogle Scholar
  4. 4.
    Scheinberg P, Nunez O, Weinstein B, Wu CO, Young NS. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia. Blood. 2012;119:345–54.CrossRefGoogle Scholar
  5. 5.
    Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123:1818–25.CrossRefGoogle Scholar
  6. 6.
    Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367:11–9.CrossRefGoogle Scholar
  7. 7.
    Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017;376:1540–50.CrossRefGoogle Scholar
  8. 8.
    Tichelli A, Socié G, Henry-Amar M, et al. Effectiveness of immunosuppressive therapy in older patients with aplastic anemia. European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party. Ann Intern Med. 1999;130:193–201.CrossRefGoogle Scholar
  9. 9.
    Scheinberg P, Wu CO, Nunez O, Young NS. Long-term outcome of pediatric patients with severe aplastic anemia treated with antithymocyte globulin and cyclosporine. J Pediatr. 2008;153:814–9.CrossRefGoogle Scholar
  10. 10.
    Scheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol. 2009;144:206–16.CrossRefGoogle Scholar
  11. 11.
    Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108:2509–19.CrossRefGoogle Scholar
  12. 12.
    Bacigalupo A. How I treat acquired aplastic anemia. Blood. 2017;129:1428–36.CrossRefGoogle Scholar
  13. 13.
    George B, Mathews V, Viswabandya A, Lakshmi KM, Srivastava A, Chandy M. Allogeneic hematopoietic stem cell transplantation is superior to immunosuppressive therapy in Indian children with aplastic anemia--a single-center analysis of 100 patients. Pediatr Hematol Oncol. 2010;27:122–31.CrossRefGoogle Scholar
  14. 14.
    Scheinberg P, Nunez O, Young NS. Retreatment with rabbit anti-thymocyte globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemia. Br J Haematol. 2006;133:622–7.CrossRefGoogle Scholar
  15. 15.
    Di Bona E, Rodeghiero F, Bruno B, et al. Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Br J Haematol. 1999;107:330–4.CrossRefGoogle Scholar
  16. 16.
    Rosenfeld S, Follmann D, Nunez O, Young NS. Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA. 2003;289:1130–5.CrossRefGoogle Scholar
  17. 17.
    Bacigalupo A, Bruno B, Saracco P, et al. Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) working party on severe aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO). Blood. 2000;95:1931–4.CrossRefGoogle Scholar
  18. 18.
    Tichelli A, Marsh JC. Treatment of aplastic anaemia in elderly patients aged >60 years. Bone Marrow Transplant. 2013;48:180–2.CrossRefGoogle Scholar
  19. 19.
    Socié G, Rosenfeld S, Frickhofen N, Gluckman E, Tichelli A. Late clonal diseases of treated aplastic anemia. Semin Hematol. 2000;37:91–101.CrossRefGoogle Scholar
  20. 20.
    Champlin RE, Ho WG, Feig SA, Winston DJ, Lenarsky C, Gale RP. Do androgens enhance the response to antithymocyte globulin in patients with aplastic anemia? A prospective randomized trial. Blood. 1985;66:184–8.CrossRefGoogle Scholar
  21. 21.
    Bacigalupo A, Chaple M, Hows J, et al. Treatment of aplastic anaemia (AA) with antilymphocyte globulin (ALG) and methylprednisolone (MPred) with or without androgens: a randomized trial from the EBMT SAA working party. Br J Haematol. 1993;83:145–51.CrossRefGoogle Scholar
  22. 22.
    Giammarco S, van Lint MT, Lamparelli T, et al. Androgens may boost hematologic response to anti-thymocyte globulin in acquired aplastic anemia. Blood. 2016;128:3900.Google Scholar
  23. 23.
    Leleu X, Terriou L, Duhamel A, et al. Long-term outcome in acquired aplastic anemia treated with an intensified dose schedule of horse antilymphocyte globulin in combination with androgens. Ann Hematol. 2006;85:711–6.CrossRefGoogle Scholar
  24. 24.
    Scheckenbach K, Morgan M, Filger-Brillinger J, et al. Treatment of the bone marrow failure in Fanconi anemia patients with danazol. Blood Cells Mol Dis. 2012;48:128–31.CrossRefGoogle Scholar
  25. 25.
    Paustian L, Chao MM, Hanenberg H, et al. Androgen therapy in Fanconi anemia: a retrospective analysis of 30 years in Germany. Pediatr Hematol Oncol. 2016;33:5–12.CrossRefGoogle Scholar
  26. 26.
    Dufour C. How I manage patients with Fanconi anaemia. Br J Haematol. 2017;178:32–47.CrossRefGoogle Scholar
  27. 27.
    Yoshida N, Kobayashi R, Yabe H, et al. First-line treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy. Haematologica. 2014;99:1784–91.CrossRefGoogle Scholar
  28. 28.
    Gupta V, Eapen M, Brazauskas R, et al. Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. Haematologica. 2010;95:2119–25.CrossRefGoogle Scholar
  29. 29.
    Schrezenmeier H, Passweg JR, Marsh JC, et al. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia. Blood. 2007;110:1397–400.CrossRefGoogle Scholar
  30. 30.
    Bacigalupo A, Socié G, Schrezenmeier H, et al. Bone marrow versus peripheral blood as the stem cell source for sibling transplants in acquired aplastic anemia: survival advantage for bone marrow in all age groups. Haematologica. 2012;97:1142–8.CrossRefGoogle Scholar
  31. 31.
    Bacigalupo A, Socié G, Hamladji RM, et al. Current outcome of HLA identical sibling versus unrelated donor transplants in severe aplastic anemia: an EBMT analysis. Haematologica. 2015;100:696–702.CrossRefGoogle Scholar
  32. 32.
    Eapen M, Le Rademacher J, Antin JH, et al. Effect of stem cell source on outcomes after unrelated donor transplantation in severe aplastic anemia. Blood. 2011;118:2618–21.CrossRefGoogle Scholar
  33. 33.
    Peffault de Latour R, Peters C, Gibson B, et al. Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes. Bone Marrow Transplant. 2015;50:1168–72.CrossRefGoogle Scholar
  34. 34.
    Peffault de Latour R, Porcher R, Dalle JH, et al. Allogeneic hematopoietic stem cell transplantation in Fanconi anemia: the European Group for Blood and Marrow Transplantation experience. Blood. 2013;122:4279–86.CrossRefGoogle Scholar
  35. 35.
    Locatelli F, Bruno B, Zecca M, et al. Cyclosporin a and short-term methotrexate versus cyclosporin a as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: results of a GITMO/EBMT randomized trial. Blood. 2000;96:1690–7.PubMedGoogle Scholar
  36. 36.
    Storb R, Etzioni R, Anasetti C, et al. Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia. Blood. 1994;84:941–9.CrossRefGoogle Scholar
  37. 37.
    Peffault de Latour R. Transplantation for bone marrow failure: current issues. Hematology Am Soc Hematol Educ Program. 2016;2016:90–8.CrossRefGoogle Scholar
  38. 38.
    Killick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016;172:187–207.CrossRefGoogle Scholar
  39. 39.
    Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373:35–47.CrossRefGoogle Scholar

Copyright information

© Dr. K C Chaudhuri Foundation 2019

Authors and Affiliations

  1. 1.Division of Pediatric Hematology and OncologyWeill Cornell Medical CollegeNew YorkUSA

Personalised recommendations