Skip to main content
SpringerLink
Log in

Current Management of Childhood Acute Myeloid Leukemia

  • Therapy in Practice
  • Published:
Pediatric Drugs Aims and scope Submit manuscript

Abstract

The outcome for children with acute myeloid leukemia (AML) has improved significantly over the past 30 years, with complete remission and overall survival rates exceeding 90 and 60%, respectively, in recent clinical trials. However, these improvements have not been achieved by the introduction of new agents. Instead, intensification of standard chemotherapy, more precise risk classification, improvements in supportive care, and the use of minimal residual disease to monitor response to therapy have all contributed to this success. Nevertheless, novel therapies are needed, as the cure rates for many subtypes of childhood AML remain unacceptably low. Here, we briefly review advances in our understanding of the biology and genetics of AML, the results of recent clinical trials, and current recommendations for the treatment of children with AML.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Grimwade D, Ivey A, Huntly BJ. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood. 2016;127:29–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52.

    Article  PubMed  Google Scholar 

  4. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    Article  PubMed  Google Scholar 

  5. Sandahl JD, Kjeldsen E, Abrahamsson J, et al. The applicability of the WHO classification in paediatric AML. A NOPHO-AML study. Br J Haematol. 2015;169:859–67.

    Article  PubMed  Google Scholar 

  6. Klco JM, Spencer DH, Miller CA, et al. Functional heterogeneity of genetically defined subclones in acute myeloid leukemia. Cancer Cell. 2014;25:379–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Klco JM, Miller CA, Griffith M, et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. J Am Med Assoc. 2015;314:811–22.

    Article  CAS  Google Scholar 

  8. Faulk K, Gore L, Cooper T. Overview of therapy and strategies for optimizing outcomes in de novo pediatric acute myeloid leukemia. Paediatr Drugs. 2014;16:213–27.

    Article  PubMed  Google Scholar 

  9. Harrison C, HIlls R, Moorman AV, et al. Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council Treatment trials AML 10 and 12. J Clin Oncol. 2010;28:2674–81.

    Article  PubMed  Google Scholar 

  10. von Neuhoff C, Reinhardt D, Sander B, et al. Prognostic impact of specific chromosomal aberrations in a large group of pediatric patients with acute myeloid leukemia treated uniformly according to trial AML-BFM 98. J Clin Oncol. 2010;28:2682–9.

    Article  Google Scholar 

  11. Rubnitz JE, Inaba H, Dahl G, et al. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol. 2010;11:543–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Klein K, Kaspers G, Harrison CJ, et al. Clinical impact of additional cytogenetic aberrations, cKIT and RAS mutations, and treatment elements in pediatric t(8;21)-AML: results from an international retrospective study by the International Berlin–Frankfurt–Munster Study Group. J Clin Oncol. 2015;33:4247–58.

    Article  PubMed  Google Scholar 

  13. Ho PA, Alonzo TA, Gerbing RB, et al. Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children’s Oncology Group. Blood. 2009;113:6558–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hollink IH, Zwaan CM, Zimmermann M, et al. Favorable prognostic impact of NPM1 gene mutations in childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML. Leukemia. 2009;23:262–70.

    Article  CAS  PubMed  Google Scholar 

  15. Hasle H, Alonzo TA, Auvrignon A, et al. Monosomy 7 and deletion 7q in children and adolescents with acute myeloid leukemia: an international retrospective study. Blood. 2007;109:4641–7.

    Article  CAS  PubMed  Google Scholar 

  16. Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. 2006;108:3654–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Staffas A, Kanduri M, Hovland R, et al. Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia. Blood. 2011;118:5905–13.

    Article  CAS  PubMed  Google Scholar 

  18. Hollink IH, van den Heuvel-Eibrink MM, rentsen-Peters ST, et al: NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. Blood. 2011;118:3645-3656.

  19. Ostronoff F, Othus M, Gerbing RB, et al. NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: a COG and SWOG report. Blood. 2014;124:2400–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sandahl JD, Coenen EA, Forestier E, et al. t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients. Haematologica. 2014;99:865–72.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tarlock K, Alonzo TA, Moraleda PP, et al. Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is associated with poor outcome in childhood AML regardless of FLT3-ITD status: a report from the Children’s Oncology Group. Br J Haematol. 2014;166:254–9.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Coenen EA, Zwaan CM, Reinhardt D, et al. Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin–Frankfurt–Munster AML-study group. Blood. 2013;122:2704–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Park IJ, Park JE, Kim HJ, et al. Acute myeloid leukemia with t(16;21)(q24;q22) and eosinophilia: case report and review of the literature. Cancer Genet Cytogenet. 2010;196:105–8.

    Article  CAS  PubMed  Google Scholar 

  24. Gruber TA, Downing JR. The biology of pediatric acute megakaryoblastic leukemia. Blood. 2015;126:943–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gruber TA, Larson GA, Zhang J, et al. An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer Cell. 2012;22:683–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Balgobind BV, Raimondi SC, Harbott J, et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood. 2009;114:2489–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Balgobind BV, Zwaan CM, Pieters R, et al. The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia. Leukemia. 2011;25:1239–48.

    Article  CAS  PubMed  Google Scholar 

  28. Rubnitz JE, Raimondi SC, Tong X, et al. Favorable impact of the t(9;11) in childhood acute myeloid leukemia. J Clin Oncol. 2002;20:2302–9.

    Article  CAS  PubMed  Google Scholar 

  29. Inaba H, Zhou Y, Abla O, et al. Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study. Blood. 2015;126:1575–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zwaan CM, Kolb EA, Reinhardt D, et al. Collaborative efforts driving progress in pediatric acute myeloid leukemia. J Clin Oncol. 2015;33:2949–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pession A, Masetti R, Rizzari C, et al. Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia. Blood. 2013;122:170–8.

    Article  CAS  PubMed  Google Scholar 

  32. Creutzig U, Zimmermann M, Bourquin JP, et al. Randomized trial comparing liposomal daunorubicin with idarubicin in induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004. Blood. 2013;122:37–43.

    Article  CAS  PubMed  Google Scholar 

  33. Gamis AS, Alonzo TA, Meshinchi S, et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014;32:3021–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tsukimoto I, Tawa A, Horibe K, et al. Risk-stratified therapy and the intensive use of cytarabine improves the outcome in childhood acute myeloid leukemia: the AML99 trial from the Japanese Childhood AML Cooperative Study Group. J Clin Oncol. 2009;27:4007–13.

    Article  CAS  PubMed  Google Scholar 

  35. Imamura T, Iwamoto S, Kanai R, et al. Outcome in 146 patients with paediatric acute myeloid leukaemia treated according to the AML99 protocol in the period 2003-06 from the Japan Association of Childhood Leukaemia Study. Br J Haematol. 2012;159:204–10.

    Article  PubMed  Google Scholar 

  36. Gibson BE, Webb DK, Howman AJ, et al. Results of a randomized trial in children with acute myeloid leukaemia: medical research council AML12 trial. Br J Haematol. 2011;155:366–76.

    Article  CAS  PubMed  Google Scholar 

  37. Abrahamsson J, Forestier E, Heldrup J, et al. Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate. J Clin Oncol. 2011;29:310–5.

    Article  PubMed  Google Scholar 

  38. Yates J, Glidewell O, Wiernik P, et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood. 1982;60:454–62.

    CAS  PubMed  Google Scholar 

  39. Creutzig U, Ritter J, Zimmermann M, et al. Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93. AML-BFM Study Group. Leukemia. 2001;15:348–54.

    Article  CAS  PubMed  Google Scholar 

  40. O’Brien TA, Russell SJ, Vowels MR, et al. Results of consecutive trials for children newly diagnosed with acute myeloid leukemia from the Australian and New Zealand Children’s Cancer Study Group. Blood. 2002;100:2708–16.

    Article  PubMed  Google Scholar 

  41. Tierens A, Bjorklund E, Siitonen S, et al. Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study. Br J Haematol. 2016;174:600–9.

    Article  PubMed  Google Scholar 

  42. Hasle H. A critical review of which children with acute myeloid leukaemia need stem cell procedures. Br J Haematol. 2014;166:23–33.

    Article  PubMed  Google Scholar 

  43. Niewerth D, Creutzig U, Bierings MB, et al. A review on allogeneic stem cell transplantation for newly diagnosed pediatric acute myeloid leukemia. Blood. 2010;116:2205–14.

    Article  CAS  PubMed  Google Scholar 

  44. Horan JT, Alonzo TA, Lyman GH, et al. Impact of disease risk on efficacy of matched related bone marrow transplantation for pediatric acute myeloid leukemia: the Children’s Oncology Group. J Clin Oncol. 2008;26:5797–801.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363:2091–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Horan JT, Logan BR, Agovi-Johnson MA, et al. Reducing the risk for transplantation-related mortality after allogeneic hematopoietic cell transplantation: how much progress has been made? J Clin Oncol. 2011;29:805–13.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Leung W, Campana D, Yang J, et al. High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood. 2011;118:223–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Saber W, Opie S, Rizzo JD, et al. Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia. Blood. 2012;119:3908–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374:422–33.

    Article  CAS  PubMed  Google Scholar 

  50. Sung L, Aplenc R, Alonzo TA, et al. Effectiveness of supportive care measures to reduce infections in pediatric AML: a report from the Children’s Oncology Group. Blood. 2013;121:3573–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Inaba H, Fan Y, Pounds S, et al. Clinical and biologic features and treatment outcome of children with newly diagnosed acute myeloid leukemia and hyperleukocytosis. Cancer. 2008;113:522–9.

    Article  PubMed  Google Scholar 

  52. Chen KH, Liu HC, Liang DC, et al. Minimally early morbidity in children with acute myeloid leukemia and hyperleukocytosis treated with prompt chemotherapy without leukapheresis. J Formos Med Assoc. 2014;113:833–8.

    Article  PubMed  Google Scholar 

  53. Sung L, Lange BJ, Gerbing RB, et al. Microbiologically documented infections and infection-related mortality in children with acute myeloid leukemia. Blood. 2007;110:3532–9.

    Article  CAS  PubMed  Google Scholar 

  54. Alexander S, Nieder M, Zerr DM, et al. Prevention of bacterial infection in pediatric oncology: What do we know, what can we learn? Pediatr Blood Cancer. 2012;59:16–20.

    Article  PubMed  Google Scholar 

  55. Dvorak CC, Fisher BT, Sung L, et al. Antifungal prophylaxis in pediatric hematology/oncology: new choices and new data. Pediatr Blood Cancer. 2012;59:21–6.

    Article  PubMed  Google Scholar 

  56. Kurt B, Flynn P, Shenep JL, et al. Prophylactic antibiotics reduce morbidity due to septicemia during intensive treatment for pediatric acute myeloid leukemia. Cancer. 2008;113:376–82.

    Article  PubMed  Google Scholar 

  57. Inaba H, Gaur AH, Cao X, et al. Feasibility, efficacy, and adverse effects of outpatient antibacterial prophylaxis in children with acute myeloid leukemia. Cancer. 2014;120:1985–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Spellberg B, Bartlett JG, Gilbert DN. The future of antibiotics and resistance. N Engl J Med. 2013;368:299–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Taga T, Shimomura Y, Horikoshi Y, et al. Continuous and high-dose cytarabine combined chemotherapy in children with down syndrome and acute myeloid leukemia: report from the Japanese children’s cancer and leukemia study group (JCCLSG) AML 9805 down study. Pediatr Blood Cancer. 2011;57:36–40.

    Article  PubMed  Google Scholar 

  60. Sorrell AD, Alonzo TA, Hilden JM, et al. Favorable survival maintained in children who have myeloid leukemia associated with Down syndrome using reduced-dose chemotherapy on Children’s Oncology Group trial A2971: a report from the Children’s Oncology Group. Cancer. 2012;118:4806–14.

    Article  CAS  PubMed  Google Scholar 

  61. Testi AM, Biondi A, Lo CF, et al. GIMEMA-AIEOP AIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood. 2005;106:447–53.

    Article  CAS  PubMed  Google Scholar 

  62. Bally C, Fadlallah J, Leverger G, et al. Outcome of acute promyelocytic leukemia (APL) in children and adolescents: an analysis in two consecutive trials of the European APL Group. J Clin Oncol. 2012;30:1641–6.

    Article  CAS  PubMed  Google Scholar 

  63. Zhou J, Zhang Y, Li J, et al. Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia. Blood. 2010;115:1697–702.

    Article  CAS  PubMed  Google Scholar 

  64. Ghavamzadeh A, Alimoghaddam K, Rostami S, et al. Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol. 2011;29:2753–7.

    Article  CAS  PubMed  Google Scholar 

  65. Mathews V, George B, Chendamarai E, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010;28:3866–71.

    Article  CAS  PubMed  Google Scholar 

  66. Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116:3751–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111–21.

    Article  CAS  PubMed  Google Scholar 

  68. Tasian SK, Pollard JA, Aplenc R. Molecular therapeutic approaches for pediatric acute myeloid leukemia. Front Oncol. 2014;4:1–11.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA

    Jeffrey E. Rubnitz

  2. Department of Pediatrics, University of Tennessee Health Science Center, College of Medicine, Memphis, TN, USA

    Jeffrey E. Rubnitz

Authors
  1. Jeffrey E. Rubnitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey E. Rubnitz.

Ethics declarations

Conflict of interest

The author has no conflicts of interest.

Funding

This work was supported, in part, by the American Lebanese Syrian Associated Charities (ALSAC).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rubnitz, J.E. Current Management of Childhood Acute Myeloid Leukemia. Pediatr Drugs 19, 1–10 (2017). https://doi.org/10.1007/s40272-016-0200-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40272-016-0200-6

Keywords

Search

Navigation