The impact of immunological and biomolecular investigations on the outcome of children with acute lymphoblastic leukemia - experience of IIIrd Paediatric Clinic Timisoara

Open access


Introduction. The unsatisfactory results of the survival in patients with acute lymphoblastic leukemia (ALL) until 2000 in our center have led us to improve the approach of diagnosis and therapy. Since 2003 in all patients the following have been performed: flow cytometry, conventional genetic diagnosis, FISH (fluorescent in situ hybridization), and molecular biology. Objectives. Our aims were to identify solutions to increase patients’ survival. Patients and method. It is a single-center, retrospective study of 136 patients with ALL treated at 3rd Pediatric Clinic of Timisoara, over a period of 10 years (2003-2012), where survival was assessed. Results. Morphologically, 86% of the patients were L1 type, 13% L2 type and 1% L3 type. Flow citometry revealed that 68% were ALL with B precursors, and 19% with T immunophenotype. Acute leukemia with mixed phenotype (biphenotypic) was identified in 2.3% of patients and 10.7% of the forms were acute leukemia with myeloid markers. In 27.7% of patients, mutations were detected by the RT-PCR method, the most commonly identified was TEL-AML1 (ETV6- RUNX1) accounting for 12.7% of the cases. Relapse-free survival at 5 years for the entire group was 59%, and for the group treated between 2008 and 2012 it was 72%. Conclusion. Our analysis confirms the decisive value of laboratory investigations for the prognosis and improvement of supportive therapy.

1. Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. The Lancet. 2013 Jun;381(9881):1943-55. DOI: 10.1016/S0140-6736(12)62187-4

2. Bartram CR, Schrauder A, Köhler R, Schrappe M. Acute lymphoblastic leukemia in children: treatment planning via minimal residual disease assessment. Dtsch Arzteblatt Int. 2012 Oct;109(40):652-8.

3. Harrison CJ. Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia. Br J Haematol. 2009 Jan;144(2):147-56. DOI: 10.1111/j.1365-2141.2008.07417.x

4. Pui C-H, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet Lond Engl. 2008 Mar 22;371(9617):1030-43. DOI: 10.1016/S0140-6736(08)60457-2

5. Mullighan CG, Collins-Underwood JR, Phillips LAA, Loudin MG, Liu W, Zhang J, et al. Rearrangement of CRLF2 in B-progenitor and Down syndrome associated acute lymphoblastic leukemia. Nat Genet. 2009 Nov;41(11):1243-6. DOI: 10.1038/ng.469

6. Kamariah Ibrahim, Siti Sarah Daud, Yeow-Liang Seah, Allen E. Yeoh, Hany Ariffin. Rapid Detection of Prognostically Important Childhood Acute Lymphoblastic Leukemia Chimeric Transcripts Using Multiplex SYBR Green Real-Time Reverse Transcription PCR. Ann Clin Lab Sci. 2008;38(4):338-43.

7. Harrison CJ. Acute lymphoblastic leukemia. Clin Lab Med. 2011 Dec;31(4):631-647, ix. DOI: 10.1016/j.cll.2011.08.016

8. Brüggemann M, Schrauder A, Raff T, Pfeifer H, Dworzak M, Ottmann OG, et al. Standardized MRD quantification in European ALL trials: proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. Leukemia. 2010 Mar;24(3):521-35. DOI: 10.1038/leu.2009.268

9. Ivanov IC, Jitaru D, Grigore GE, Zlei M, Ivanov A, Dumitraș S, et al. Infant acute leukemia with lineage switch at relapse expressing a novel t(4;11)(q21;q23) MLL-AF4 fusion transcript. Rev Romana Med Lab. 2013;21(1):47-58. DOI:10.2478/rrlm-2013-0017 DOI: 10.2478/rrlm-2013-0017

10. Boldeanu FM, Gruia AT, Ordodi VL, Serban M, Bader P, Kreyenberg H. Childhood Acute Lymphoblastic Leukemia: Detection of Minimal Residual Disease after Allogeneic Transplantation. Rev Romana Med Lab. 2012;20(3):245-53

11. Jardan D, Talmaci R, Jardan C, Coriu D, Colita A, Colita A, et al. Real-time qPCR for assessment of minimal residual disease in acute myeloid and lymphoid leukemia. Rev Romana Med Lab. 2011;19(4):349-57

12. 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(6):497-505. DOI: 10.1002/mpo.2950200603

13. Gabert J, Beillard E, van der Velden VHJ, Bi W, Grimwade D, Pallisgaard N, et al. Standardization and quality control studies of “real-time” quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - A Europe Against Cancer Program. Leukemia. 2003 Dec;17(12):2318-57. DOI: 10.1038/sj.leu.2403135

14. R Core Team. R: A Language and Environment for Statistical Computing [Internet]. R Foundation for Statistical Computing; 2014. Available from:

15. Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group. J Clin Oncol Off J Am Soc Clin Oncol. 2012 May 10;30(14):1663-9. DOI: 10.1200/JCO.2011.37.8018

16. Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2011 Feb 10;29(5):532-43. DOI: 10.1200/JCO.2010.30.1382

17. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012 Feb;62(1):10-29. DOI: 10.3322/caac.20138

18. Roganovic J. Acute Lymphoblastic Leukemia in Children. In: Guenova M, editor. Leukemia [Internet]. In- Tech; 2013 [cited 2017 Apr 19]. Available from:

19. Lustosa de Sousa DW, de Almeida Ferreira FV, Cavalcante Félix FH, de Oliveira Lopes MV. Acute lymphoblastic leukemia in children and adolescents: prognostic factors and analysis of survival. Rev Bras Hematol E Hemoter. 2015 Jul; 37(4):223-9. DOI: 10.1016/j.bjhh.2015.03.009

20. Pui C-H, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009 Jun 25; 360(26):2730-41. DOI: 10.1056/NEJMoa0900386

21. Gökbuget N, Kneba M, Raff T, Trautmann H, Bartram C-R, Arnold R, et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012 Aug 30;120(9):1868-76.DOI: 10.1182/blood-2011-09-377713

22. Liang D-C, Shih L-Y, Yang C-P, Hung I-J, Liu H-C, Jaing T-H, et al. Frequencies of ETV6-RUNX1 fusion and hyperdiploidy in pediatric acute lymphoblastic leukemia are lower in far east than west. Pediatr Blood Cancer. 2010 Sep;55(3):430-3. DOI: 10.1002/pbc.22628

23. Weltgesundheitsorganisation, Swerdlow SH, International Agency for Research on Cancer, editors. WHO classification of tumours of haematopoietic and lymphoid tissues: [... reflects the views of a working group that convened for an Editorial and Consensus Conference at the International Agency for Research on Cancer (IARC), Lyon, October 25 - 27, 2007]. 4. ed. Lyon: Internat. Agency for Research on Cancer; 2008. 439 p. (World Health Organization classification of tumours).

24. Maurer J, Janssen JW, Thiel E, van Denderen J, Ludwig WD, Aydemir U, et al. Detection of chimeric BCR-ABL genes in acute lymphoblastic leukaemia by the polymerase chain reaction. Lancet Lond Engl.1991 May 4;337(8749):1055-8. DOI: 10.1016/0140-6736(91)91706-Z

25. Sazawal S, Bhatia K, Gutierrez MI, Saxena R, Arya LS, Bhargava M. Paucity of TEL-AML 1 translocation, by multiplex RT-PCR, in B-lineage acute lymphoblastic leukemia (ALL) in Indian patients. Am J Hematol. 2004 May;76(1):80-2. DOI: 10.1002/ajh.20000

26. Oyekunle A, Haferlach T, Kröger N, Klyuchnikov E, Zander AR, Schnittger S, et al. Molecular Diagnostics, Targeted Therapy, and the Indication for Allogeneic Stem Cell Transplantation in Acute Lymphoblastic Leukemia. Adv Hematol. 2011;2011:1-8. DOI: 10.1155/2011/154745

27. Diakos C, Xiao Y, Zheng S, Kager L, Dworzak M, Wiemels JL. Direct and indirect targets of the E2APBX1 leukemia-specific fusion protein. PloS One. 2014;9(2):e87602. DOI: 10.1371/journal.pone.0087602

28. Hu Y, He H, Lu J, Wang Y, Xiao P, Li J, et al. E2APBX1 exhibited a promising prognosis in pediatric acute lymphoblastic leukemia treated with the CCLGALL2008 protocol. OncoTargets Ther. 2016 Nov;Volume 9:7219-25. DOI: 10.2147/OTT.S115257

29. Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, et al. Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/ E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. DOI: 10.1038/sj.leu.2404420

30. Ballerini P, Landman-Parker J, Cayuela JM, Asnafi V, Labopin M, Gandemer V, et al. Impact of genotype on survival of children with T-cell acute lymphoblastic leukemia treated according to the French protocol FRALLE- 93: the effect of TLX3/HOX11L2 gene expression on outcome. Haematologica. 2008 Nov;93(11):1658-65. DOI: 10.3324/haematol.13291

31. Mansur MB, Emerenciano M, Brewer L, Sant’Ana M, Mendonça N, Thuler LCS, et al. SIL-TAL1 fusion gene negative impact in T-cell acute lymphoblastic leukemia outcome. Leuk Lymphoma. 2009 Aug;50(8):1318-25. DOI: 10.1080/10428190903040014

32. D’Angio M, Valsecchi MG, Testi AM, Conter V, Nunes V, Parasole R, et al. Clinical features and outcome of SIL/TAL1-positive T-cell acute lymphoblastic leukemia in children and adolescents: a 10-year experience of the AIEOP group. Haematologica. 2015 Jan 1;100(1):e10-3.DOI: 10.3324/haematol.2014.112151

33. Matutes E, Pickl WF, van’t Veer M, Morilla R, Swansbury J, Strobl H et al. Mixed- phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood. 2011;117:3163-71 DOI: 10.1182/ blood-2010-10-314682

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

Journal Information

IMPACT FACTOR 2018: 0,800
5-year IMPACT FACTOR: 0,655

CiteScore 2017: 0.31

SCImago Journal Rank (SJR) 2018: 0.194
Source Normalized Impact per Paper (SNIP) 2018: 0.306


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 291 214 20
PDF Downloads 135 121 6