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Acute Leukemias

Favorable outcome in infants with AML after intensive first- and second-line treatment: an AML-BFM study group report

Abstract

Infants <1 year of age have a high prevalence of prognostically unfavorable leukemias and a presumed susceptibility to treatment-related toxicities. A total of 125 infants with acute myeloid leukemia (AML) were treated in studies AML-BFM-98 (n=59) and -2004 (n=66). Treatment regimens of both studies were comparable, consisting of intensive induction followed by four courses (mainly high-dose cytarabine and anthracyclines). Allogeneic-hematopoietic stem-cell-transplantation (allo-HSCT) in 1st remission was optional for high-risk (HR) patients. Most infants (120/125=96%) were HR patients according to morphological, cytogenetic/molecular genetic and response criteria. Five-year overall survival was 66±4%, and improved from 61±6% in study-98 to 75±6% in study-2004 (Plogrank 0.14) and event-free survival rates were 44±6% and 51±6% (Plogrank 0.66), respectively. Results in HR infants were similar to those of older HR children (1–<2- or 2–<10-year olds, Plogrank 0.90 for survival). Survival rates of HSCT in 1st remission, initial partial response and after relapse were high (13/14, 2/8 and 20/30 patients, respectively). The latter contributes to excellent 5-year survival after relapse (50±8%). Despite more severe infections and pulmonary toxicities in infants, treatment-related death rate was identical to that of older children (3%). Our data indicate that intensive frontline and relapse AML treatment is feasible in infants, toxicities are manageable, and outcome is favorable.

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References

  1. Sorensen PH, Chen CS, Smith FO, Arthur DC, Domer PH, Bernstein ID et al. Molecular rearrangements of the MLL gene are present in most cases of infant acute myeloid leukemia and are strongly correlated with monocytic or myelomonocytic phenotypes. J Clin Invest 1994; 93: 429–437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pui CH, Raimondi SC, Srivastava DK, Tong X, Behm FG, Razzouk B et al. Prognostic factors in infants with acute myeloid leukemia. Leukemia 2000; 14: 684–687.

    Article  CAS  PubMed  Google Scholar 

  3. Greaves MF, Wiemels J . Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 2003; 3: 639–649.

    Article  CAS  PubMed  Google Scholar 

  4. Sanders JE, Im HJ, Hoffmeister PA, Gooley TA, Woolfrey AE, Carpenter PA et al. Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia. Blood 2005; 105: 3749–3756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pieters R . Infant acute lymphoblastic leukemia: lessons learned and future directions. Curr Hematol Malig Rep 2009; 4: 167–174.

    Article  PubMed  Google Scholar 

  6. Kawasaki H, Isoyama K, Eguchi M, Hibi S, Kinukawa N, Kosaka Y et al. Superior outcome of infant acute myeloid leukemia with intensive chemotherapy: results of the japan infant leukemia study group. Blood 2001; 98: 3589–3594.

    Article  CAS  PubMed  Google Scholar 

  7. Webb DK, Harrison G, Stevens R, Gibson BG, Hann I, Wheatley K . Relationship between age at diagnosis, clinical features, and outcome of therapy in children treated in the medical research concil AML 10 and 12 trials for acute myeloid leukemia. Blood 2001; 98: 1714–1720.

    Article  CAS  PubMed  Google Scholar 

  8. Creutzig U, Zimmermann M, Ritter J, Reinhardt D, Hermann J, Henze G et al. Treatment strategies and long-term results in pediatric patients treated in four consecutive AML-BFM trials. Leukemia 2005; 19: 2030–2042.

    Article  CAS  PubMed  Google Scholar 

  9. von Neuhoff C, Reinhardt D, Sander A, Zimmermann M, Bradtke J, Betts DR 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: 2682–2689.

    Article  CAS  PubMed  Google Scholar 

  10. Creutzig U, Zimmermann M, Lehrnbecher T, Graf N, Hermann J, Niemeyer CM et al. Less toxicity by optimizing chemotherapy, but not by addition of granulocyte colony-stimulating factor in children and adolescents with acute myeloid leukemia: results of AML-BFM 98. J Clin Oncol 2006; 24: 4499–4506.

    Article  CAS  PubMed  Google Scholar 

  11. Creutzig U, Zimmermann M, Bourquin JP, Dworzak MN, Fleischhack G, von Neuhoff C et al. CNS irradiation in pediatric acute myleoid leukemia: equal results by 12 or 18 Gy in studies AML-BFM98 and 2004. Pediatr. Blood Cancer 2011; 57: 986–992.

    Article  PubMed  Google Scholar 

  12. Periclou AP, Avramis VI . NONMEM population pharmacokinetic studies of cytosine arabinoside after high-dose and after loading bolus followed by continuous infusion of the drug in pediatric patients with leukemias. Cancer Chemother Pharmacol 1996; 39: 42–50.

    Article  CAS  PubMed  Google Scholar 

  13. 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  CAS  PubMed  Google Scholar 

  14. Kaspers GJL, Zimmermann M, Reinhardt D, Gibson B, Tamminga R, Aleinikova O et al. Addition of liposomal daunorubicin (DaunoXome®) to FLAG significantly improves treatment response in pediatric relapsed AML: final results from the international randomised phase III study relapsed AML 2001/01 [abstract]. Blood 2009; 114: 13–14.

    Google Scholar 

  15. Sander A, Zimmermann M, Dworzak M, Fleischhack G, von Neuhoff C, Reinhardt D et al. Consequent and intensified relapse therapy improved survival in pediatric AML: results of relapse treatment in 379 patients of three consecutive AML-BFM trials. Leukemia 2010; 24: 1422–1428.

    Article  CAS  PubMed  Google Scholar 

  16. Groll AH, Ritter J, Muller FM . Prevention of fungal infections in children and adolescents with cancer. Klin Padiatr 2001; 213 (Suppl 1): A50–A68.

    Article  PubMed  Google Scholar 

  17. Simon A, Fleischhack G, Marklein G, Ritter J . Antimicrobial prophylaxis of bacterial infections in pediatric oncology patients. Klin Padiatr 2001; 213 (Suppl 1): A22–A37.

    Article  PubMed  Google Scholar 

  18. Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD et al. Report of the national cancer institute-sponsored workshop on definitions and response in acute myeloid leukemia. J Clin Oncol 1990; 8: 813–819.

    Article  CAS  PubMed  Google Scholar 

  19. Kalbfleisch J, Prentice R . The statistical analysis of failure time data. Wiley: New York, NY, 2002.

    Book  Google Scholar 

  20. Vormoor J, Ritter J, Creutzig U, Boos J, Heyen P, Ludwig W-D et al. Acute myelogenous leukaemia in children under 2 years—experiences of the west german AML studies BFM-78, -83 and -87. Br J Cancer 1992; 66 (Suppl XVIII): 63–67.

    Google Scholar 

  21. Balgobind BV, Raimondi SC, Harbott J, Zimmermann M, Alonzo TA, Auvrignon A et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood 2009; 114: 2489–2496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Testi AM, Biondi A, Lo CF, Moleti ML, Giona F, Vignetti M et al. GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood 2005; 106: 447–453.

    Article  CAS  PubMed  Google Scholar 

  23. Creutzig U, Zimmermann M, Dworzak M, Urban C, Henze G, Kremens B et al. Favourable outcome of patients with childhood acute promyelocytic leukaemia after treatment with reduced cumulative anthracycline doses. Br J Haematol 2010; 149: 399–409.

    Article  CAS  PubMed  Google Scholar 

  24. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ . Structure and function of the blood-brain barrier. Neurobiol Dis 2010; 37: 13–25.

    Article  CAS  PubMed  Google Scholar 

  25. Pui CH, Howard SC . Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol 2008; 9: 257–268.

    Article  PubMed  Google Scholar 

  26. Creutzig U, Zimmermann M, Ritter J, Henze G, Graf N, Löffler H et al. Definition of a standard-risk group in children with AML. Br J Haematol 1999; 104: 630–639.

    Article  CAS  PubMed  Google Scholar 

  27. Holm-Knudson RJ, Rasmussen LS . Paediatric airway management:basic aspects. Acta Anaesthesiol Scand 2009; 53: 1–9.

    Article  Google Scholar 

  28. Baker KS, Bresters D, Sande JE . The burden of cure: long-term side effects following hematopoietic stem cell transplantation (HSCT) in children. Pediatr Clin North Am 2010; 57: 323–342.

    Article  PubMed  Google Scholar 

  29. Ishii E, Kawasaki H, Isoyama K, Eguchi-Ishimae M, Eguchi M . Recent advances in the treatment of infant acute myeloid leukemia. Leuk Lymphoma 2003; 44: 741–748.

    Article  CAS  PubMed  Google Scholar 

  30. Reinhardt D, Thiele C, Creutzig U . Neuropsychological sequelae in children with AML treated with or without prophylactic CNS-irradiation. Klin Pädiatr 2002; 214: 22–29.

    Article  CAS  PubMed  Google Scholar 

  31. Duffner PK . Long-term effects of radiation therapy on cognitive and endocrine function in children with leukemia and brain tumors. Neurologist 2004; 10: 293–310.

    Article  PubMed  Google Scholar 

  32. Pui CH, Pei D, Sandlund JT, Ribeiro RC, Rubnitz JE, Raimondi SC et al. Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia 2010; 24: 371–382.

    Article  CAS  PubMed  Google Scholar 

  33. Moricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dordelmann M et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2008; 111: 4477–4489.

    Article  PubMed  Google Scholar 

  34. Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 2007; 370: 240–250.

    Article  CAS  PubMed  Google Scholar 

  35. Woods WG, Neudorf S, Gold S, Sanders J, Buckley JD, Barnard DR et al. A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 2001; 97: 56–62.

    Article  CAS  PubMed  Google Scholar 

  36. Lie SO, Abrahamsson J, Clausen N, Forestier E, Hasle H, Hovi L et al. Treatment stratification based on initial in vivo response in acute myeloid leukaemia in children without Down's syndrome: results of NOPHO-AML trials. Br J Haematol 2003; 122: 217–225.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the colleagues, data managers and technicians of the participating hospitals for their valuable cooperation, Jans-Enno Müller for competent data management and Ursula Bernsmann for her help in preparing the manuscript. The studies were supported by the Deutsche Krebshilfe e.V. and partly by grant from the Czech Ministry of Education (MSM0021620813).

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Correspondence to U Creutzig.

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Creutzig, U., Zimmermann, M., Bourquin, JP. et al. Favorable outcome in infants with AML after intensive first- and second-line treatment: an AML-BFM study group report. Leukemia 26, 654–661 (2012). https://doi.org/10.1038/leu.2011.267

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