Child's Nervous System

, Volume 25, Issue 5, pp 619–626 | Cite as

Poor-risk high-grade gliomas in three survivors of childhood acute lymphoblastic leukaemia—an overview of causative factors and possible therapeutic options

  • Ewa Bien
  • Teresa Stachowicz-Stencel
  • Magdalena Szalewska
  • Malgorzata Krawczyk
  • Anna Synakiewicz
  • Miroslawa Dubaniewicz-Wybieralska
  • Piotr Zielinski
  • Elzbieta Adamkiewicz-Drozynska
  • Anna Balcerska
Case Report



Malignant high-grade gliomas are the most common secondary neoplasms in children cured of acute lymphoblastic leukaemia (ALL). Although many predisposing factors exist (including systemic or intrathecal chemotherapy, young age, brain infiltration and genetic predispositions), cranial irradiation appears to be the strongest one.


Three cases of secondary high-grade gliomas (two multiform glioblastomas, grade IV; one anaplastic astrocytoma, grade III) developed in ALL survivors (F–M, 1:2) 3 to 6.3 years after stopping ALL therapy according to BFM-90 trial.


All tumours were supratentorial, contrast-enhancing, space-occupying, highly advanced and aggressive. Possible risk factors and current therapeutic options for paediatric ALL and malignant gliomas are reviewed and discussed.


Prognosis in secondary malignant gliomas in children is poor (overall survival of 5, 10 and 19 months) despite intense therapy. Thus, protocols for paediatric ALL reduce prophylactic cranial irradiation in favour of intrathecal and intravenous high-dose MTX. Nevertheless, ALL survivors must undergo systematic, long-term surveillance for early detection of intracranial neoplasms.


Acute lymphoblastic leukaemia Secondary neoplasia High-grade glioma Cranial radiotherapy complications Intrathecal methotrexate Children 


  1. 1.
    Bhatia S, Sather HR, Pabustan OB et al (2002) Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983. Blood 99:4257–4264PubMedCrossRefGoogle Scholar
  2. 2.
    Bhatia S (2003) Late effects among survivors of leukemia during childhood and adolescence. Blood Cells Mol Dis 31:84–92PubMedCrossRefGoogle Scholar
  3. 3.
    Bokstein F, Shpigel S, Blumenthal DT (2008) Treatment with bevacizumab and irinotecan for recurrent high-grade glial tumors. Cancer 112:2267–2273PubMedCrossRefGoogle Scholar
  4. 4.
    Borgmann A, Zinn C, Hartmann R et al (2008) Secondary malignant neoplasms after intensive treatment of relapsed acute lymphoblastic leukaemia in childhood. Eur J Cancer 44:257–268PubMedCrossRefGoogle Scholar
  5. 5.
    Bucci MK, Maity A, Janss AJ et al (2004) Near complete surgical resection predictsa favorable outcome in pediatric patients with nonbrainstem, malignant gliomas: results from a single center in the magnetic resonance imaging era. Cancer 101:817–824PubMedCrossRefGoogle Scholar
  6. 6.
    Clarke M, Gaynon P, Hann I et al (2003) CNS-directed therapy for childhood acute lymphoblastic leukemia: Childhood ALL Collaborative Group overview of 43 randomized trials. J Clin Oncol 21:1798–1809PubMedCrossRefGoogle Scholar
  7. 7.
    Combs SE, Gutwein S, Schulz-Ertner D et al (2005) Temozolomide combined with irradiation as postoperative treatment of primary glioblastoma multiforme. Phase I/II study. Strahlenther Onkol 181:372–377PubMedCrossRefGoogle Scholar
  8. 8.
    Conter V, Aricò M, Valsecchi MG et al (1995) Extended intrathecal methotrexate may replace cranial irradiation for prevention of CNS relapse in children with intermediate-risk acute lymphoblastic leukemia treated with Berlin–Frankfurt–Münster-based intensive chemotherapy. The Associazione Italiana di Ematologia ed Oncologia Pediatrica. J Clin Oncol 13:2497–2502PubMedGoogle Scholar
  9. 9.
    Elexpuru-Camiruaga J, Buxton N, Kandula V et al (1995) Susceptibility to astrocytoma and meningioma: influence of allelism at glutathione S-transferase (GSTT1 and GSTM1) and cytochrome P450 (CYP2D6) loci. Cancer Res 55:4237–4239PubMedGoogle Scholar
  10. 10.
    Evans WE, Horner M, Chu YQ et al (1991) Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 119:985–989PubMedCrossRefGoogle Scholar
  11. 11.
    Felix CA, Nau MM, Takahashi T et al (1992) Hereditary and acquired p53 mutations in childhood acute lymphoblastic leukemia. J Clin Invest 89:640–647PubMedCrossRefGoogle Scholar
  12. 12.
    Hijiya N, Hudson MM, Lensing S et al (2007) Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA 297:1207–1215PubMedCrossRefGoogle Scholar
  13. 13.
    Löning L, Zimmermann M, Reiter A et al (2000) Secondary neoplasms subsequent to Berlin–Frnakfurt–Munster therapy of acute lymphoblastic leukemia in childhood: significantly lower risk without cranial radiotherapy. Blood 95:2770–2775PubMedGoogle Scholar
  14. 14.
    Martino R, Giralt S, Caballero MD et al (2003) Allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning in acute lymphoblastic leukemia: a feasibility study. Haematologica 88:555–560PubMedGoogle Scholar
  15. 15.
    Nathan PC, Maze R, Spiegler B et al (2004) CNS-directed therapy in young children with T-lineage acute lymphoblastic leukemia: high-dose methotrexate versus cranial irradiation. Pediatr Blood Cancer 42:24–29PubMedCrossRefGoogle Scholar
  16. 16.
    Pettorini BL, Park YS, Caldarelli M, Massimi L, Tamburrini G, Di Rocco C (2008) Radiation-induced brain tumours after central nervous system irradiation in childhood: a review. Childs Nerv Syst 24(7):793–805 Epub 2008 Apr 8PubMedCrossRefGoogle Scholar
  17. 17.
    Pui C-H (2006) Central nervous system disease in acute lymphoblastic leukemia: prophylaxis and treatment. Hematology 2006:142–146CrossRefGoogle Scholar
  18. 18.
    Pui C-H, Pei D, Sandlund JT et al (2005) Risk of adverse events after completion of therapy for childhood acute lymphoblastic leukemia. J Clin. Oncol 23:7936–7941PubMedCrossRefGoogle Scholar
  19. 19.
    Qin D, Ma J, Xiao J et al (1997) Effect of brain irradiation on blood–CSF barrier permeability of chemotherapeutic agents. Am J Clin Oncol 20:263–265PubMedCrossRefGoogle Scholar
  20. 20.
    Reddick WE, Glass JO, Helton KJ et al (2005) Prevalence of leukoencephalopathy in children treated for acute lymphoblastic leukemia with high-dose methotrexate. AJNR Am J Neuroradiol 26:1263–1269PubMedGoogle Scholar
  21. 21.
    Relling MV, Rubnitz JE, Rivera GK et al (1999) High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet 354:34–39PubMedCrossRefGoogle Scholar
  22. 22.
    Romeike BF, Kim YJ, Steudel WI, Graf N (2007) Diffuse high-grade gliomas as second malignant neoplasms after radio-chemotherapy for pediatric malignancies. Childs Nerv Syst 23(2):185–193 Epub 2006 Oct 5PubMedCrossRefGoogle Scholar
  23. 23.
    Rosso P, Terracini B, Fears TR et al (1994) Second malignant tumors after elective end of therapy for a first cancer in childhood: a multicenter study in Italy. Int J Cancer 59:451–456PubMedCrossRefGoogle Scholar
  24. 24.
    Shah KC, Rajshekhar V (2004) Glioblastoma multiforme in a child with acute lymphoblastic leukemia: case report and review of literature. Neurol India 52:375–377PubMedGoogle Scholar
  25. 25.
    Silverman LB, Sallan SE (2003) Newly diagnosed childhood acute lymphoblastic leukemia: update on prognostic factors and treatment. Curr Opin Hematol 10:290–296PubMedCrossRefGoogle Scholar
  26. 26.
    Spiegler BJ, Kennedy K, Maze R et al (2006) Comparison of long-term neurocognitive outcomes in young children with acute lymphoblastic leukemia treated with cranial radiation or high-dose or very high-dose intravenous methotrexate. J Clin Oncol 24:3858–3864PubMedCrossRefGoogle Scholar
  27. 27.
    Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011–1018PubMedCrossRefGoogle Scholar
  28. 28.
    Vilmer E, Suciu S, Ferster A et al (2000) Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report. Children Leukemia Cooperative Group. Leukemia 14:2257–2266PubMedCrossRefGoogle Scholar
  29. 29.
    Waber DP, Silverman LB, Catania L et al (2004) Outcomes of a randomized trial of hyperfractionated cranial radiation therapy for treatment of high-risk acute lymphoblastic leukemia: therapeutic efficacy and neurotoxicity. J Clin Oncol 22:2701–2707PubMedCrossRefGoogle Scholar
  30. 30.
    Walter AW, Hancock ML, Pui C-H et al (1998) Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children’s Research Hospital. J Clin Oncol 16:3761–3767PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Ewa Bien
    • 1
  • Teresa Stachowicz-Stencel
    • 1
  • Magdalena Szalewska
    • 1
  • Malgorzata Krawczyk
    • 1
  • Anna Synakiewicz
    • 1
  • Miroslawa Dubaniewicz-Wybieralska
    • 2
  • Piotr Zielinski
    • 3
  • Elzbieta Adamkiewicz-Drozynska
    • 1
  • Anna Balcerska
    • 1
  1. 1.Department of Paediatrics, Haematology, Oncology and EndocrinologyMedical University of GdanskGdanskPoland
  2. 2.Department of RadiologyMedical University of GdanskGdanskPoland
  3. 3.Department of NeurosurgeryMedical University of GdanskGdanskPoland

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