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Therapy

Induction death and treatment-related mortality in first remission of children with acute lymphoblastic leukemia: a population-based analysis of the Austrian Berlin-Frankfurt-Münster study group

Leukemia volume 23, pages 1264–1269 (2009)Cite this article

Abstract

In the management of the childhood acute lymphoblastic leukemia (ALL), 5% of failures are due to induction death and treatment-related deaths in first complete remission. We retrospectively analyzed the incidence, pattern and causes of death and its risk factors for 896 children with ALL enrolled into five Austrian (A) Berlin-Frankfurt-Münster (BFM) trials between 1981 and 1999. The estimated 10-year cumulative incidence of death significantly decreased from 6±1% (n=16/268) in trials ALL-BFM-A 81 and ALL-A 84 to 2±1% (n=15/628) in trials ALL-BFM-A 86, 90 and 95 (P=0.006). A significant reduction of death was evident during induction therapy (2.2% in trials ALL-BFM-A 81 and ALL-A 84 and 0.2% in trials ALL-BFM-A 86, 90 and 95, P=0.001). Of 31 patients, 21 (68%) patients died from infectious and 10 (32%) from noninfectious complications. Treatment in trial ALL-BFM-A 81, infant age and female gender were independent predictors of an enhanced risk for death. Conclusively, we found a progressive reduction of death rates that may be explained by the increasing experience in specialized hemato-oncologic centers and improved supportive and intensive care. We also identified a distinct subset of patients who are especially prone to death and may need a special focus when receiving intense chemotherapy.

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References

  1. 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 

  2. Pui CH, Evans WE . Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354: 166–178.

    Article  CAS  PubMed  Google Scholar 

  3. Pui CH, Sandlund JT, Pei D, Campana D, Rivera GK, Ribeiro RC et al. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 2004; 104: 2690–2696.

    Article  CAS  PubMed  Google Scholar 

  4. Silverman LB, Declerck L, Gelber RD, Dalton VK, Asselin BL, Barr RD et al. Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981–1995). Leukemia 2000; 14: 2247–2256.

    Article  CAS  PubMed  Google Scholar 

  5. Atra A, Richards SM, Chessells JM . Remission death in acute lymphoblastic leukaemia: a changing pattern. Arch Dis Child 1993; 69: 550–554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hargrave DR, Hann II, Richards SM, Hill FG, Lilleyman JS, Kinsey S et al. Progressive reduction in treatment-related deaths in Medical Research Council childhood lymphoblastic leukaemia trials from 1980 to 1997 (UKALL VIII, X and XI). Br J Haematol 2001; 112: 293–299.

    Article  CAS  PubMed  Google Scholar 

  7. Rubnitz JE, Lensing S, Zhou Y, Sandlund JT, Razzouk BI, Ribeiro RC et al. Death during induction therapy and first remission of acute leukemia in childhood: the St. Jude experience. Cancer 2004; 101: 1677–1684.

    Article  PubMed  Google Scholar 

  8. Wheeler K, Chessells JM, Bailey CC, Richards SM . Treatment related deaths during induction and in first remission in acute lymphoblastic leukaemia: MRC UKALL X. Arch Dis Child 1996; 74: 101–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hurwitz CA, Silverman LB, Schorin MA, Clavell LA, Dalton VK, Glick KM et al. Substituting dexamethasone for prednisone complicates remission induction in children with acute lymphoblastic leukemia. Cancer 2000; 88: 1964–1969.

    Article  CAS  PubMed  Google Scholar 

  10. Liang DC, Hung IJ, Yang CP, Lin KH, Chen JS, Hsiao TC et al. Unexpected mortality from the use of E. coli L-asparaginase during remission induction therapy for childhood acute lymphoblastic leukemia: a report from the Taiwan Pediatric Oncology Group. Leukemia 1999; 13: 155–160.

    Article  CAS  PubMed  Google Scholar 

  11. Christensen MS, Heyman M, Mottonen M, Zeller B, Jonmundsson G, Hasle H . Treatment-related death in childhood acute lymphoblastic leukaemia in the Nordic countries: 1992–2001. Br J Haematol 2005; 131: 50–58.

    Article  PubMed  Google Scholar 

  12. Slats AM, Egeler RM, van der Does-van den Berg A, Korbijn C, Hahlen K, Kamps WA et al. Causes of death—other than progressive leukemia—in childhood acute lymphoblastic (ALL) and myeloid leukemia (AML): the Dutch Childhood Oncology Group experience. Leukemia 2005; 19: 537–544.

    Article  CAS  PubMed  Google Scholar 

  13. Pui CH, Boyett JM, Rivera GK, Hancock ML, Sandlund JT, Ribeiro RC et al. Long-term results of Total Therapy Studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St Jude Children's Research Hospital. Leukemia 2000; 14: 2286–2294.

    Article  CAS  PubMed  Google Scholar 

  14. Schrappe M . Risk-adapted stratification and treatment of childhood acute lymphoblastic leukemia. Radiat Prot Dosim 2008; 132: 130–133.

    Article  CAS  Google Scholar 

  15. Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig WD, Henze G et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Munster. Leukemia 2000; 14: 2205–2222.

    Article  CAS  PubMed  Google Scholar 

  16. Te Poele EM, de Bont ES, Marike Boezen H, Revesz T, Bokkerink JP, Beishuizen A et al. Dexamethasone in the maintenance phase of acute lymphoblastic leukaemia treatment: is the risk of lethal infections too high? Eur J Cancer 2007; 43: 2532–2536.

    Article  CAS  PubMed  Google Scholar 

  17. Attarbaschi A, Mann G, Dworzak M, Urban C, Fink FM, Dieckmann K et al. Treatment results of childhood acute lymphoblastic leukemia in Austria—a report of 20 years' experience. Wien Klin Wochenschr 2002; 114: 148–157.

    CAS  PubMed  Google Scholar 

  18. van der Does-van den Berg A, Bartram CR, Basso G, Benoit YC, Biondi A, Debatin KM et al. Minimal requirements for the diagnosis, classification, and evaluation of the treatment of childhood acute lymphoblastic leukemia (ALL) in the ‘BFM Family’ Cooperative Group. Med Pediatr Oncol 1992; 20: 497–505.

    Article  CAS  PubMed  Google Scholar 

  19. Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 2000; 95: 3310–3322.

    CAS  PubMed  Google Scholar 

  20. Grigull L, Beier R, Schrauder A, Kirschner P, Loening L, Jack T et al. Invasive fungal infections are responsible for one-fifth of the infectious deaths in children with ALL. Mycoses 2003; 46: 441–446.

    Article  CAS  PubMed  Google Scholar 

  21. Attarbaschi A, Mann G, Panzer-Grumayer R, Rottgers S, Steiner M, Konig M et al. Minimal residual disease values discriminate between low and high relapse risk in children with B-cell precursor acute lymphoblastic leukemia and an intrachromosomal amplification of chromosome 21: the Austrian and German acute lymphoblastic leukemia Berlin-Frankfurt-Munster (ALL-BFM) trials. J Clin Oncol 2008; 26: 3046–3050.

    Article  CAS  PubMed  Google Scholar 

  22. Igarashi S, Manabe A, Ohara A, Kumagai M, Saito T, Okimoto Y et al. No advantage of dexamethasone over prednisolone for the outcome of standard- and intermediate-risk childhood acute lymphoblastic leukemia in the Tokyo Children's Cancer Study Group L95-14 protocol. J Clin Oncol 2005; 23: 6489–6498.

    Article  CAS  PubMed  Google Scholar 

  23. Ito C, Evans WE, McNinch L, Coustan-Smith E, Mahmoud H, Pui CH et al. Comparative cytotoxicity of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. J Clin Oncol 1996; 14: 2370–2376.

    Article  CAS  PubMed  Google Scholar 

  24. Kager L, Lion T, Attarbaschi A, Koenig M, Strehl S, Haas OA et al. Incidence and outcome of TCF3-PBX1-positive acute lymphoblastic leukemia in Austrian children. Haematologica 2007; 92: 1561–1564.

    Article  PubMed  Google Scholar 

  25. Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO . Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol 2005; 129: 734–745.

    Article  CAS  PubMed  Google Scholar 

  26. Pui CH, Relling MV, Downing JR . Acute lymphoblastic leukemia. N Engl J Med 2004; 350: 1535–1548.

    Article  CAS  PubMed  Google Scholar 

  27. Belgaumi AF, Al-Bakrah M, Al-Mahr M, Al-Jefri A, Al-Musa A, Saleh M et al. Dexamethasone-associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin. Cancer 2003; 97: 2898–2903.

    Article  CAS  PubMed  Google Scholar 

  28. Roberts CW, Walker W, Alexander J . Sex-associated hormones and immunity to protozoan parasites. Clin Microbiol Rev 2001; 14: 476–488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dordelmann M, Schrappe M, Reiter A, Zimmermann M, Graf N, Schott G et al. Down's syndrome in childhood acute lymphoblastic leukemia: clinical characteristics and treatment outcome in four consecutive BFM trials. Berlin-Frankfurt-Munster Group. Leukemia 1998; 12: 645–651.

    Article  CAS  PubMed  Google Scholar 

  30. Zwaan CM, Kaspers GJ, Pieters R, Hahlen K, Janka-Schaub GE, van Zantwijk CH et al. Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. Blood 2002; 99: 245–251.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank J Regelsberger, N Mühlegger and D Janousek for documentation and data management.

Author information

Authors and Affiliations

  1. Department of Paediatric Haematology and Oncology, St Anna Children's Hospital, Vienna, Austria

    C Prucker, A Attarbaschi, C Peters, M N Dworzak, O A Haas, H Gadner & G Mann

  2. Children's Cancer Research Institute , St Anna Children's Hospital, Vienna, Austria

    M N Dworzak, U Pötschger & H Gadner

  3. Division of Paediatric Haematology and Oncology, Department of Paediatric and Adolescent Medicine, Medical University of Graz, Graz, Austria

    C Urban

  4. Department of Paediatrics, Innsbruck Medical University, Innsbruck, Austria

    F-M Fink & B Meister

  5. Department of Paediatrics, Landeskinderklinik Linz, Linz, Austria

    K Schmitt

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  1. C Prucker
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  10. O A Haas
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  11. H Gadner
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on behalf of the Austrian Berlin-Frankfurt-Münster (BFM) Study Group

Corresponding author

Correspondence to G Mann.

Additional information

Participating centers and investigators

Krankenhaus (KH) Dornbirn: B Ausserer; Landeskrankenhaus (LKH) Feldkirch: U Busch, G Müller; Universitäts-Kinderklinik Graz: R Kurz, Ch Urban; Universitäts-Kinderklinik Innsbruck: H Berger, F-M Fink, B Meister; LKH Klagenfurt: W Kaulfersch, H Messner; LKH Leoben: I Mutz; Allgemeines öffentliches KH der Barmherzigen Schwestern Linz: O Stöllinger; Landeskinderklinik Linz: W Tulzer, K Schmitt, T Ebetsberger; LKH Salzburg: H Grienberger, N and R Jones, J Rücker; Kardinal Schwarzenberg'sches KH Schwarzach: H Haas; LKH Steyr: R Ploier; St Anna Kinderspital Wien: H Gadner, ER Grümayer-Panzer, P Krepler, G Mann; Universitäts-Kinderklinik Wien: E Pichler, O Jürgenssen, I Slavc; Universitätsklinik für Blutgruppenserologie und Transfusionsmedizin Wien: P Höcker.

Immunophenotyping Institute of Immunology, Centre for Physiology, Pathophysiology and Immunology, Medical University of Vienna, Austria: W Knapp, WF Pickl.

Cytogenetic analyses Children's Cancer Research Institute, St Anna Children's Hospital, Vienna, Austria: OA Haas.

Molecular-genetic analyses Children's Cancer Research Institute, St Anna Children's Hospital, Vienna, Austria: Th Lion

Radiotherapy Department of Radiation Oncology, Medical University of Vienna, Austria: KH Kärcher, R Hawlicek, R Pötter and K Dieckmann.

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Prucker, C., Attarbaschi, A., Peters, C. et al. Induction death and treatment-related mortality in first remission of children with acute lymphoblastic leukemia: a population-based analysis of the Austrian Berlin-Frankfurt-Münster study group. Leukemia 23, 1264–1269 (2009). https://doi.org/10.1038/leu.2009.12

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