Monitoring of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia — Preliminary Data from a Prospective Study

  • T. Seriu
  • W.-D. Ludwig
  • M. Schrappe
  • D. Erz
  • Y. Stark
  • C. R. Bartram
Conference paper
Part of the Haematology and Blood Transfusion / Hämatologie und Bluttransfusion book series (HAEMATOLOGY, volume 39)


Minimal residual disease (MRD) was evaluated in bone marrow samples prospectively obtained from children with acute lymphoblastic leukemia (ALL) during complete remission (CR), using allele-specific markers based on junctional regions generated through the recombination of T-cell receptor δ (TCRδ), TCRγ, immunoglobulin K (IgK) chain or sil-tal genes. Suitable TCRδ, TCRγ, IgK and sil-tal recombinations were identified by Southern blot analysis in 27/29 (93%) T-ALL and 152/174 (87%) precursor-B ALL patients. Two or more independent markers were available in 156/203 (77%) cases. Allele-specific oligonucleotides (ASO) were used either as clonospecific probes or primers and reached a detection level between 10−4 to 10−6 in 192/212 (91%) recombined alleles. Six hundred and forty-one remission samples from 112 cases (20 relapsed, 92 in continuous CR) have been analyzed so far. MRD was demonstrated during a period of 6 months after diagnosis in the vast majority of patients who relapsed during the course of treatment. In contrast, 88% of the patients who remained in continuous CR became PCR-negative within 3 months of treatment. Remarkably, 58% of them achieved PCR-negativity within 1 month. Our data suggest that the MRD status at 3 and 6 months after diagnosis may represent a clinically relevant parameter for a second stratification of childhood ALL.


Acute Lymphoblastic Leukemia Minimal Residual Disease Junctional Region Childhood Acute Lymphoblastic Leukemia Continuous Complete Remission 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauer S, Henze G, Zimmermann M, Lampert F, Havers MW, Niethammer D, Odenwald E, Ritter J, Mann G, Welte K, Gadner H, Riehm H (1994) Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86. Blood 84: 3122–3133PubMedGoogle Scholar
  2. 2.
    Childhood ALL Collaborative Group (1996) Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12000 randomised children. Lancet 347: 1783–1788CrossRefGoogle Scholar
  3. 3.
    Yamada M, Hudson S, Tournay D, Bittenbender S, Shane SS, Lange B, Tsujimoto Y, Caton AJ, Roy-era G (1989) Detection of minimal residual disease in hematopoietic malignancies of the B-cell lineage by using third-complementary-determining region (CDR-III)- specific probes. Proc. Natl. Acad. Sci USA 86: 5123–5127PubMedCrossRefGoogle Scholar
  4. 4.
    D’Auriol L, Macintyre E, Galibert F, Sigaux F (1989) In vitro amplification of T cell y gene rearrangements: a new tool for the assessment of minimal residual disease in acute lymphoblastic leukemias. Leukemia 3: 155–158PubMedGoogle Scholar
  5. 5.
    Hansen-Hagge TE,Yokota S, Bartram CR (1989) Detection of minimal residual disease in acute lymphoblastic leukemia by in vitro amplification of rearranged T-cell receptor 8 chain sequences. Blood 74: 1762–1767PubMedGoogle Scholar
  6. 6.
    Bartram CR (1993) Detection of minimal residual leukemia by the polymerase chain reaction: potential implications for therapy. Clin. Chim. Acta 217: 75–83PubMedCrossRefGoogle Scholar
  7. 7.
    Potter MN, Cross NCP, van Dongen JJM, Saglio G, Oakhill A, Bartram CR, Goldman JM (1993) Molecular evidence of minimal residual disease after treatment for leukaemia and lymphoma: an updated meeting report and review. Leukemia 7: 1302–1314PubMedGoogle Scholar
  8. 8.
    Campana D, Pui C-H (1995) Detection of minimal residual disease in acute leukemia: methodologic advances and clinical significance. Blood 85: 1416–1434PubMedGoogle Scholar
  9. 9.
    Ludwig W-D, Bartram CR, Ritter J, Raghavachar A, Hiddemann W, Heil G, Harbott J, Seibt-Jung H, Teichmann JV, Riehm H (1988) Ambiguous phenotypes and genotypes in 16 children with acute leukemia as characterized by multiparameter analysis. Blood 71: 1518–1528PubMedGoogle Scholar
  10. 10.
    van der Does-van der Berg A, Bartram CR, Basso G, Benoit YCM, Biondi A, Debatin KM, Haas OA, Harbott J, Kamps WA, Köller U, Lampert F, Ludwig W-D, Niemeyer CM, van Wering ER (1992) 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. 20: 497–505Google Scholar
  11. 11.
    Yokota S, Hansen-Hagge TE, Ludwig WD, Reiter A, Raghavachar A, Kleihauer E, Bartram CR (1991) Use of polymerase chain reactions to monitor minimal residual disease in acute lymphoblastic leukemia patients. Blood 77: 331–339PubMedGoogle Scholar
  12. 12.
    Breit TM, Wolvers-Tettero ILM, Beishuizen A, Verhoven MAJ, van Wering ER, van Dongen JJM (1993) Southern blot patterns, frequencies and junctional diversity of T-cell receptor-6 gene rearrangements in acute lymphoblastic leukemia. Blood 82: 3063–3074PubMedGoogle Scholar
  13. 13.
    van Dongen JJM, Wolvers-Tettero ILM (1991) Analysis of immunoglobulin and T-cell receptor genes. Part I: basic and technical aspects. Clin. Chim. Acta 198: 1–91PubMedCrossRefGoogle Scholar
  14. 14.
    Quertermous T, Struss WM, van Dongen JJM, Seidman JG (1987) Human T cell g chain joining regions and T cell development. J Immunol. 138: 2687–2690PubMedGoogle Scholar
  15. 15.
    Beishuizen A, Verhoeven MAJ, Mol EJ, van Dongen JJM (1994) Detection of immunoglobulin kappa light-chain gene rearrangement patterns by Southern blot analysis. Leukemia 8: 2228–2236PubMedGoogle Scholar
  16. 16.
    Breit TM, Mol EJ, Wolvers-Tettero ILM, Ludwig WD, van Wering ER, van Dongen JJM (1993) Site-specific deletions involving the tal-1 and sil genes are restricted to cells of the T cell receptor a/13 lineage: T cell receptor S gene deletion mechanism affects multiple genes. J Exp. Med. 177: 965–977PubMedCrossRefGoogle Scholar
  17. 17.
    Seriu T, Yokota S, Nakao M, Misawa S, Takaue Y, Koizumi S, Kawai S, Fujimoto T (1995) Prospective monitoring of minimal residual disease during the course of chemotherapy in patients with acute lymphoblastic leukemia, and detection of contaminating tumor cells in peripheral blood stem cells for autotransplantation. Leukemia 9: 615–623PubMedGoogle Scholar
  18. 18.
    Breit TM, Wolvers-Tettero ILM, Hählen K, van Wering ER, van Dongen JJM (1991) Extensive junctional diversity of y8 T-cell receptors expressed by T-cell acute lymphoblastic leukemia: implications for the detection of minimal residual disease. Leukemia 5: 1076–1086PubMedGoogle Scholar
  19. 19.
    Seriu T, Hansen-Hagge TE, Erz DHR, Bartram CR (1995) Improved detection of minimal residual leukemia through modifications of polymerase chain reaction analyses based on clonospecific T cell receptor junctions. Leukemia 9: 316–320PubMedGoogle Scholar
  20. 20.
    Seriu T, Erz D, Stark Y, Bartram CR. T-cell receptor D62D63 rearrangement: a suitable allele-specific marker for the detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia 1997, in press.Google Scholar
  21. 21.
    Roberts WM, Estrov Z, Ouspenskaia MV, Johnston DA, McClain KL, Zipf TF (1997) Measurement of residual leukemia during remission in childhood acute lymphoblastic leukemia. N Engl. J Med. 336: 317–323PubMedCrossRefGoogle Scholar
  22. 22.
    Brisco MJ, Condon J, Hughes E, Neoh SH, Sykes PJ, Seshardi R, Toogood I, Waters K, Tauro G, Ekert H, Morley AA (1994) Outcome prediction in childhood acute lymphoblastic leukemia by molecular quantification of residual disease at the end of induction. Lancet 343: 196–200PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • T. Seriu
    • 1
  • W.-D. Ludwig
    • 2
  • M. Schrappe
    • 3
  • D. Erz
    • 1
  • Y. Stark
    • 1
  • C. R. Bartram
    • 1
  1. 1.Institute of Human GeneticsUniversity of HeidelbergHeidelbergGermany
  2. 2.Department of Medical Oncology and Applied Molecular Biology, Robert-Rössle Cancer CenterFree University of BerlinGermany
  3. 3.Department of Pediatrics IVHannover Medical SchoolHannoverGermany

Personalised recommendations