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Immunoglobulin and T-cell receptor gene rearrangements as PCR-based targets are stable markers for monitoring minimal residual disease in acute lymphoblastic leukemia after stem cell transplantation

Leukemia volume 23, pages 1355–1358 (2009)Cite this article

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Alterations of phenotypic or genotypic markers because of clonal development or selection between disease episodes interfere with the detection of minimal residual disease (MRD) in acute leukemia. This issue has been investigated extensively for relapses after induction and reinduction therapy in acute lymphoblastic leukemia (ALL), in which the usage of rearranged immunogenes is well established (Szczepanski et al.1 and Guggemos et al.,2 and references therein). Currently, allogeneic hematopoietic stem cell transplantation (SCT) is the only curative treatment for many high-risk patients with ALL, but relapse is still the most frequent reason for treatment failure. MRD studies after SCT have shown significant associations between MRD positivity and relapse,3, 4, 5, 6 and, therefore, these studies could form the basis for further interventional preemptive immunotherapy strategies to prevent relapse. With regard to marker stability, however, these studies either did not compare junctional region sequences or limited their investigations to particular gene loci.

Detailed sequencing analysis of immunoglobulin and T-cell receptor (Ig/TCR) rearrangements is the most reliable way to understand how rearrangements persist or evolve during the course of the disease. To assess the extent of marker changes after allogeneic SCT, we performed a retrospective analysis by characterizing currently used IgH, IgK-deletion (IgK-Kde), TCR-γ, TCR-δ and TCR-β gene rearrangements with BIOMED-1 and BIOMED-2 primers7, 8 for target identification and subsequent sequence analyses according to the European Study group on MRD detection in ALL (ESG-MRD-ALL).9 We compared leukemia blast samples from the initial or relapse diagnosis with samples from a subsequent relapse after allogeneic SCT. The cases included 40 pediatric and adolescent ALL patients who suffered a relapse after undergoing allogeneic SCT in the first (CR1, n=8) and either the second (CR2, n=25) or the third (CR3, n=7) complete remissions between 1997 and 2006. Of these patients, 38 were diagnosed for precursor B-ALL and 2 for T-ALL. All patients were pretreated according to the protocols ALL-BFM (n=7), ALL-REZ-BFM (n=32) of the Berlin-Frankfurt-Münster Group and CoALL (n=1) of the German Cooperative Study Group for Childhood ALL. The median age at transplantation was 10.2 years, ranging from 1.5 to 22.2 years. Relapse occurred between 54 and 1188 days (3.3 years) after transplantation (median: 0.61 years), without significant differences between patients transplanted in the CR1 (median 0.47 years), CR2 (median 0.93 years) and CR3 (median 0.49 years). The inclusion of the patients was based on the availability of paired samples at the time of the primary or relapse diagnosis as well as at relapse after allogeneic SCT. For all patients involved in this study, protocols were approved by the local ethical committees. Written informed consent was obtained from the patients or their guardians for sample collection following diagnosis according to the Declaration of Helsinki.

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References

  1. Szczepanski T, Willemse MJ, Brinkhof B, van Wering ER, van der Burg M, van Dongen JJ . Comparative analysis of Ig and TCR gene rearrangements at diagnosis and at relapse of childhood precursor-B-ALL provides improved strategies for selection of stable PCR targets for monitoring of minimal residual disease. Blood 2002; 99: 2315–2323.

    Article  CAS  Google Scholar 

  2. Guggemos A, Eckert C, Szczepanski T, Hanel C, Taube T, van der Velden VH et al. Assessment of clonal stability of minimal residual disease targets between 1st and 2nd relapse of childhood precursor B-cell acute lymphoblastic leukemia. Haematologica 2003; 88: 736–746.

    Google Scholar 

  3. Knechtli CJ, Goulden NJ, Hancock JP, Harris EL, Garland RJ, Jones CG et al. Minimal residual disease status as a predictor of relapse after allogeneic bone marrow transplantation for children with acute lymphoblastic leukaemia. Br J Haematol 1998; 102: 860–871.

    Article  CAS  Google Scholar 

  4. Sanchez J, Serrano J, Gomez P, Martinez F, Martin C, Madero L et al. Clinical value of immunological monitoring of minimal residual disease in acute lymphoblastic leukaemia after allogeneic transplantation. Br J Haematol 2002; 116: 686–694.

    Article  Google Scholar 

  5. Uzunel M, Jaksch M, Mattsson J, Ringden O . Minimal residual disease detection after allogeneic stem cell transplantation is correlated to relapse in patients with acute lymphoblastic leukaemia. Br J Haematol 2003; 122: 788–794.

    Article  Google Scholar 

  6. Spinelli O, Peruta B, Tosi M, Guerini V, Salvi A, Zanotti MC et al. Clearance of minimal residual disease after allogeneic stem cell transplantation and the prediction of the clinical outcome of adult patients with high-risk acute lymphoblastic leukemia. Haematologica 2007; 92: 612–618.

    Article  Google Scholar 

  7. Pongers-Willemse MJ, Seriu T, Stolz F, d’Aniello E, Gameiro P, Pisa P et al. Primers and protocols for standardized detection of minimal residual disease in acute lymphoblastic leukemia using immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets: report of the BIOMED-1 CONCERTED ACTION: investigation of minimal residual disease in acute leukemia. Leukemia 1999; 13: 110–118.

    Article  CAS  Google Scholar 

  8. van Dongen JJ, Langerak AW, Bruggemann M, Evans PA, Hummel M, Lavender FL et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003; 17: 2257–2317.

    Article  CAS  Google Scholar 

  9. van der Velden V, Cazzaniga G, Schrauder A, Hancock J, Bader P, Panzer-Grumayer ER et al. Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia 2007; 21: 604–611.

    Article  CAS  Google Scholar 

  10. Flohr T, Schrauder A, Cazzaniga G, Panzer-Grumayer R, van der Velden V, Fischer S et al. Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia 2008; 22: 771–782.

    Article  CAS  Google Scholar 

  11. Germano G, del Giudice L, Palatron S, Giarin E, Cazzaniga G, Biondi A et al. Clonality profile in relapsed precursor-B-ALL children by GeneScan and sequencing analyses. Consequences on minimal residual disease monitoring. Leukemia 2003; 17: 1573–1582.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by the Wilhelm-Sander-Siftung, Munich. We thank all participating hospitals and colleagues who supported this study: C Niemeyer, MD, University Children's Hospital Freiburg, DW Friedrich, MD, University Children's Hospital Ulm, A Borkhardt, MD, University Children's Hospital Düsseldorf, PG Schlegel, MD, University Children's Hospital Würzburg; W Holter, MD, Children's University Hospital Erlangen-Nuremberg, D Körholz, MD, University Children's Hospital Halle (Saale).

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Authors and Affiliations

  1. Department of Paediatric Oncology, Haematology, and Haemostaseology, Children's Hospital of the JW Goethe University, Frankfurt, Germany

    H Kreyenberg, M Reising, A Willasch, T Klingebiel & P Bader

  2. Department of Paediatric Oncology/Haematology, Charité Hospital, Humboldt University Berlin, Berlin, Germany

    C Eckert, A von Stackelberg & G Henze

  3. Department of Haematology/Oncology, Children's University Hospital, University of Tuebingen, Tuebingen, Germany

    Y Yarkin & R Handgretinger

  4. Department of Pediatric Haematology, Oncology and Endocrinology, University of Essen, Essen, Germany. E-mail: hermann.kreyenberg@kgu.de,

    B Kremens

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  1. H Kreyenberg
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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Kreyenberg, H., Eckert, C., Yarkin, Y. et al. Immunoglobulin and T-cell receptor gene rearrangements as PCR-based targets are stable markers for monitoring minimal residual disease in acute lymphoblastic leukemia after stem cell transplantation. Leukemia 23, 1355–1358 (2009). https://doi.org/10.1038/leu.2009.72

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