Skip to main content

Advertisement

Log in

Recent advances in management of acute myeloid leukemia (AML)

  • Symposium on Advances in Therapy
  • Published:
The Indian Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Acute myeloid leukemia (AML) is the most common childhood malignancy. AML has therapentically been difficult to treat. In 2001, the World Health Organization (WHO), in conjunction with the Society for Hematopathology and the European Association of Hematopathology, published a new classification for myeloid neoplasms. A number of chromosomal abnormalities are used to predict outcome and stratify therapeutic risk groups in children with AML. Recently, alterations in receptor tyrosine kinases, tyrosine phosphatases and in oncogenes such as RAS have been implicated in the pathogenesis of AML. This article aims to review the recent development in diagnosis, treatment and monitoring of AML. Better understanding of the molecular pathogenesis of AML has led to the development of target-specific therapies. Some of the new classes of drugs include monoclonal antibody directed against the CD33 antigen, farnesyltransferase inhibitors (FTI), and FMSlike tyrosine kinase 3 (FLT3) inhibitors. The role of allogenic SCT, particularly whether it should be done during first CR or reserved for second remission, remains the most controversial issue in pediatric AML. There is a need of collaboration with international pediatric cooperative oncology groups and definitive clinical trials in order to estabilish use of these newer molecules in pediatric populations.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Chowdhury T, Brady JM. Insights from clinical studies into the role of MLL gene in infant and childhood leukemia. Blood Cell, Molecules Diseases 2008; 40:192–199.

    Article  CAS  Google Scholar 

  2. Ravindranath Y. Recent advances in pediatric acute lymphoblastic and myeloid leukemia. Curr Opin Oncol 2003; 15: 23–25.

    Article  PubMed  CAS  Google Scholar 

  3. GJ Kaspers, U Creutzig, Pediatric acute myeloid leukemia: international progress and future directions. Leukemia 2005; 19: 2025–2029.

    Article  PubMed  CAS  Google Scholar 

  4. James W. Vardiman, Nancy Lee Harris, and Richard D. Brunning, World Health Organization (WHO) classification of myeloid neoplasms. Blood 2002; 100: 2292–2302.

    Article  PubMed  CAS  Google Scholar 

  5. GJL Kaspers, Zwaan CM, Pediatric acute myeloid leukemia: towards high-quality cure of all patients. Hematologica 2007; 92: 1519–1532.

    Article  Google Scholar 

  6. Rubnitz JE, Gibson B, Smith FO, Acute myeloid leukemia. Pediatr Clin North Am 2008; 55: 21–51.

    Article  PubMed  Google Scholar 

  7. Bloomfield CD, Lawrence D, Byrd JC, Carroll A, Pettenati MJ, Tantravahi R et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 1998; 58: 4173–4179.

    PubMed  CAS  Google Scholar 

  8. David G, Helen W, Fiona O, Keith W, Christine H, Georgina H et al. Goldstone on behalf of the Medical Research Council Adult and Children’s Leukaemia Working Parties. The Importance of Diagnostic Cytogenetics on Outcome in AML: Analysis of 1,612 Patients Entered Into the MRC AML 10 Trial. Blood 1998; 92: 2322–2333.

    Google Scholar 

  9. Meshinchi S, Alonzo TA, Stirewalt DL, Zwaan M, Zimmerman M, Reinhardt D et al. Clinical implications of FLT3 mutations in pediatric AML. Blood 2006; 108: 3654–3661.

    Article  PubMed  CAS  Google Scholar 

  10. Brown P, McIntyre E, Meshinchi S, Lacayo N, Dahl G et al. The incidence and clinical significance of nucleophosmin mutations in childhood AML. Blood 2007; 110: 979–985.

    Article  PubMed  CAS  Google Scholar 

  11. Creutzig U, Ritter J, Riehm H, Budde M, Schellong G. The childhood AML studies BFM-78 and-83: treatment results and risk factor analysis. Haematol Blood Transfus 1987; 30: 71–75.

    PubMed  CAS  Google Scholar 

  12. Stevens RF, Hann IM, Wheatley K, Gray RG. Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council’s 10th AML trial. MRC Childhood Leukaemia Working Party. Br J Haematol 1998; 101: 130–140.

    Article  PubMed  CAS  Google Scholar 

  13. Chang M, Raimondi SC, Ravindranath Y, Carroll AJ, Camitta B, Gresik MV et al. Prognostic factors in children and adolescents with acute myeloid leukemia (excluding children with Down syndrome and acute promyelocytic leukemia): univariate and recursive partitioning analysis of patients treated on Pediatric Oncology Group (POG) Study 8821. Leukemia 2000; 14: 1201–1207.

    Article  PubMed  CAS  Google Scholar 

  14. Levitt G, Cardioprotection. Br J Haematol 1999; 106: 860–869

    Article  PubMed  CAS  Google Scholar 

  15. Hempel G, Reinhardt D, Creutzig U, Boos J. Population pharmacokinetics of liposomal daunorubicin in children. Br J Clin Pharmacol 2003; 56: 370–377.

    Article  PubMed  CAS  Google Scholar 

  16. Reinhardt D, Hempel G, Fleischhack G, Schulz A, Boos J, Creutzig U. Liposomal daunorubicine combined with cytarabine in the treatment of relapsed/refractory acute myeloid leukemia in children. Klin Padiatr 2002; 214: 188–194.

    Article  PubMed  CAS  Google Scholar 

  17. Gibson BE, Wheatley K, Hann IM et al. Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia 2005; 19: 2130–2138.

    Article  PubMed  CAS  Google Scholar 

  18. Carella AM, Berman E, Maraone MP et al. Idarubicin in the treatment of acute leukemias.An overview of preclinical and clinical studies. Haematologica 1990; 75: 159–169.

    PubMed  CAS  Google Scholar 

  19. Berman E, McBride M. Comparative cellular pharmacology of daunorubicin and idarubicin in human multidrug-resistant leukemia cells. Blood 1992; 79: 3267–3273.

    PubMed  CAS  Google Scholar 

  20. Reid JM, Pendergrass TW, Krailo MD et al. Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: a Children’s Cancer Study Group report. Cancer Res 1990; 50: 6525–6528.

    PubMed  CAS  Google Scholar 

  21. 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: 348–354.

    Article  PubMed  CAS  Google Scholar 

  22. 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: 2708–2716.

    Article  PubMed  CAS  Google Scholar 

  23. AU Dillman RO, Davis RB Green MR, Weiss RB, Gottlieb AJ, Caplan S et al. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood 1991; 78: 2520–2526.

    Google Scholar 

  24. Tomizawa D, Tabuchi K, Kinoshita A, Hanada R, Kigasawa H, Tsukimoto I et al. Tokyo Children’s Cancer Study Group. Repetitive cycles of high-dose cytarabine are effective for childhood acute myeloid leukemia: long-term outcome of the children with AML treated on two consecutive trials of Tokyo Children’s Cancer Study Group. Pediatr Blood Cancer 2007; 49: 127–132.

    Article  PubMed  Google Scholar 

  25. Crews KR, Gandhi V, Srivastava DK, Razzouk BI, Tong X, Behm FG et al. Interim comparison of a continuous infusion versus a short daily infusion of cytarabine given in combination with cladribine for pediatric acute myeloid leukemia. J Clin Oncol 2002; 20: 4217–4224.

    Article  PubMed  CAS  Google Scholar 

  26. Styczynski J, Wysocki M, Debski R, Juraszewska E, Malinowska I, Stanczak E et al. Ex vivo drug resistance profile in childhood acute myelogenous leukemia: no drug is more effective in comparison to acute lymphoblastic leukemia. Leuk Lymphoma 2002; 43: 1843–1848.

    Article  PubMed  CAS  Google Scholar 

  27. Krance RA, Hurwitz CA, Head DR, Raimondi SC, Behm FG, Crews KR et al. Experience With 2-Chlorodeoxyadenosine in Previously Untreated Children With Newly Diagnosed Acute Myeloid Leukemia and Myelodysplastic Diseases. J Clinical Oncology 2001; 19: 2804–2811.

    CAS  Google Scholar 

  28. Rubnitz JE, Razzouk BI, Srivastava DK, Pui CH, Ribeiro RC, Santana VM. Phase II trial of cladribine and cytarabine in relapsed or refractory myeloid malignancies. Leuk Res 2004; 28: 349–352.

    Article  PubMed  CAS  Google Scholar 

  29. Kornblau SM, Gandhi V, Andreeff HM, Beran M, Kantarjian HM, Roller CA et al. Clinical and laboratory studies of 2-chlorodeoxyadenosine ± cytosine arabinoside for relapsed or refractory acute myelogenous leukemia in adults. Leukemia 1996; 10: 1563–1569.

    PubMed  CAS  Google Scholar 

  30. Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 2001; 7: 1490–1496.

    PubMed  CAS  Google Scholar 

  31. Arceci RJ, Sande J, Lange B, Shannon K, Franklin J, Hutchinson R et al. Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia. Blood 2005; 106: 1183–1188.

    Article  PubMed  CAS  Google Scholar 

  32. Brethon B, Auvrignon A, Cayuela JM, Lapillonne H, Leverger G, Baruchel A. Molecular response in two children with relapsed acute myeloid leukemia treated with a combination of gemtuzumab ozogamicin and cytarabine. Haematologica 2006; 91: 419–421.

    PubMed  Google Scholar 

  33. Reinhardt D, Diekamp S, Fleischhack G, Corbacioglu C, Jürgens H, Dworzak M et al. Gemtuzumab ozogamicin (Mylotarg) in children with refractory or relapsed acute myeloid leukemia. Onkologie 2004; 27: 269–272.

    Article  PubMed  CAS  Google Scholar 

  34. Brown P, Small D. FLT3 Inhibitors: a paradigm for the development of targeted therapeutics for paediatric cancer. Europ JCancer 2004; 40: 707–721.

    Article  CAS  Google Scholar 

  35. Smith BD, Levis M, Beram M, Giles F, Kantarjian H, Berg K et al. Single agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical in patients with refractory acute myeloid leukemia. Blood 2004; 103: 3669–3676.

    Article  PubMed  CAS  Google Scholar 

  36. Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 2005; 105: 54–60.

    Article  PubMed  CAS  Google Scholar 

  37. Giles FJ, Stopeck AT, Silverman LR, Lancet JE, Cooper MA, Hannah AL et al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood 2003; 102: 795–801.

    Article  PubMed  CAS  Google Scholar 

  38. Lancet JE, Gojo I, Gotlib J, Feldman EJ, Greer J, Liesveld JL et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 2007; 109: 1387–1394.

    Article  PubMed  CAS  Google Scholar 

  39. Bleakley M, Lau L, Shaw PJ, Kaufman A. Bone marrow transplantation for pediatric AML in first remission: a systematic review and meta-analysis. Bone Marrow Transplant 2002; 29: 843–852.

    Article  PubMed  CAS  Google Scholar 

  40. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia. NEJM 2008; 358: 1909–1918.

    Article  PubMed  CAS  Google Scholar 

  41. Marcucci G, Radmacher M, Maharry K, Mrozek K, Ruppert A, Paschka P et al. MicroRNA Expression in Cytogenetically Normal Acute Myeloid Leukemia. NEJM 2008; 358: 1919–1928.

    Article  PubMed  CAS  Google Scholar 

  42. Spiekermann K, Dirschinger RJ, Schwab R, Bagrintseva K, Faber F, Buske C et al. The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3. Blood 2003; 101: 1494–1504.

    Article  PubMed  CAS  Google Scholar 

  43. Fiedler W, Serve H, Döhner H, Schwittay M, Ottmann OG, O’Farrell AM et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 2005; 105: 986–993.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Manasi Shah.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shah, M., Agarwal, B. Recent advances in management of acute myeloid leukemia (AML). Indian J Pediatr 75, 831–837 (2008). https://doi.org/10.1007/s12098-008-0155-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12098-008-0155-x

Key words

Navigation