Skip to main content
Log in

Methods of minimal residual disease (MRD) detection in childhood haematological malignancies

  • Review Article
  • Published:
Journal of Applied Genetics Aims and scope Submit manuscript

Abstract

The appropriate management of haematological disorders must rely on a precise and long-term monitoring of the patient’s response to chemotherapy and radiotherapy. Clinical data are not sufficient and that is why in the last decade it became the most important to improve the knowledge of haematological diseases on the basis of molecular techniques and molecular markers. The presence of residual malignant cells among normal cells is termed minimal residual disease (MRD). Nowadays a great progress has been made in the treatment of malignant diseases and in the development of reliable molecular techniques, which are characterised by high sensitivity (10−3–10−6) and ability to distinguish between normal and malignant cells at diagnosis and during follow-up. Especially, MRD data based on quantitative analysis (RQ-PCR, RT-RQ-PCR) appear to be crucial for appropriate evaluation of treatment response in many haematological malignancies. Implementation of standardized approaches for MRD assessment into routine molecular diagnostics available in all oncohaematological centres should be regarded nowadays a crucial point in further MRD study development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Bader P, Hancock J, Kreyenberg H, Goulden NJ, Niethammer D, Oakhill A, et al. 2002. Minimal residual disease (MRD) status prior to allogeneic stem cell transplantation is a powerful predictor for post-transplant outcome in children with ALL. Leukemia 16: 1668–1672.

    Article  CAS  PubMed  Google Scholar 

  • Boublikova L, Kalinova M, Ryan J, Quinn F, O’Marcaigh A, Smith O, et al. 2006. Wilms’ tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: a wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring. Leukemia 20: 254–263.

    Article  CAS  PubMed  Google Scholar 

  • Campana D, Coustan-Smith E, 1999. Detection of minimal residual disease in acute leukemia by flow cytometry. Cytometry 15; 38: 139–152.

    Article  Google Scholar 

  • Coustan-Smith E, Sancho J, Hancock ML, Razzouk BI, Ribeiro RC, Rivera GK, et al. 2002. Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood 100: 2399–2402.

    Article  CAS  PubMed  Google Scholar 

  • Cross NCP, Lin F, Chase A, Bungey J, Hughes TP, Goldman JM, 1993. Competitive polymerase chain reaction to estimate the number of BCR-ABL transcripts in chronic myeloid leukaemia after bone marrow transplantation. Blood 82: 1929–1936.

    CAS  PubMed  Google Scholar 

  • Dawidowska M, Derwich K, Szczepański T, Jółkowska J, van der Velden VHJ, Wachowiak J, Witt M, 2006. Pattern of immunoglobulin and T-cell receptor (Ig/TCR) gene rearrangements in Polish pediatric acute lymphoblastic leukemia patients implications for RQ-PCR-based assessment of minimal residual disease. Leukemia Res 30: 1119–1125.

    Article  CAS  Google Scholar 

  • De Haas V, Breunis WB, Dee R, Verhagen OJ, Kroes W, van Wering ER, et al. 2002. The TEL-AML1 real-time quantitative polymerase chain reaction (PCR) might replace the antigen receptor-based genomic PCR in clinical minimal residual disease studies in children with acute lymphoblastic leukemia. Br J Haematol 116: 87–93.

    Article  PubMed  Google Scholar 

  • Dibenedetto SP, Lo Nigro L, Mayer SP, Rovera G, Schiliro G, 1997. Detectable molecular residual disease at the beginning of maintenance therapy indicates poor outcome in children with T-cell acute lymphoblastic leukemia. Blood 90: 1226–1232.

    CAS  PubMed  Google Scholar 

  • Faderl S, Kurzrock R, Estrov Z, 1999. Minimal residual disease in hematologic disorders. Arch Pathol Lab Med 123: 1030–1034.

    CAS  PubMed  Google Scholar 

  • Gaiger A, Linnerth B, Mann G, Schmid D, Heinze G, Tisljar K, et al. 1999. Wilms’ tumour gene (WT1) expression at diagnosis has no prognostic relevance in childhood acute lymphoblastic leukaemia treated by an intensive chemotherapy protocol. Eur J Haematol 63: 86–93.

    Article  CAS  PubMed  Google Scholar 

  • Galimberti S, Benedetti E, Morabito F, Papineschi F, Callea V, Fazzi R, et al. 2005. Prognostic role of minimal residual disease in multiple myeloma patients after non-myeloablative allogeneic transplantation. Leukemia Res 29: 961–966.

    Article  CAS  Google Scholar 

  • Gemano G, del Giudice L, Palatron S, Giarin E, Cazzaniga G, Biondi A, Basso G, 2003. Clonality profile in relapsed precursor-B-ALL children by GeneScan and sequencing analyses: consequences on minimal residual disease monitoring. Leukemia 17: 1573–1582.

    Article  CAS  Google Scholar 

  • Goulden N, Virgo P, Grimwade D, 2006. Minimal residual disease directed therapy for childhood acute myeloid leukaemia: the time is now. Br J Haematol 134: 273–282.

    Article  PubMed  Google Scholar 

  • Hardling M, Wei Y, Palmquist L, Swolin B, Stockelberg D, Gustavsson B, et al. 2004. Serial monitoring of BCR-ABL transcripts in chronic myelogenous leukemia (CML) treated with imatinib mesylate. Med Oncol 21: 349–358.

    Article  CAS  PubMed  Google Scholar 

  • Hillmen P, 2006. Beyond detectable minimal residual disease in chronic lymphocytic leukemia. Semin Oncol 33: 23–28.

    Article  CAS  Google Scholar 

  • Huang W, Sun G, Li XS, Cao Q, Lu Y, Jang GS, Zhang FQ, et al. 1993. Acute promyelocytic leukaemia: Clinical relevance of two major PML-RAR-alpha isoforms and detection of minimal residual disease by retrotranscriptase/polymerase chain reaction to predict relapse. Blood 82: 1264–1277.

    CAS  PubMed  Google Scholar 

  • Jilani I, Keating M, Day A, William W, Kantarjian H, O’brien S, et al. 2006. Simplified sensitive method for the detection of B-cell clonality in lymphoid malignancies. Clin Lab Haematol 28: 325–331.

    Article  CAS  PubMed  Google Scholar 

  • Kaeda J, Chase A, Goldman JM, 2002. Cytogenetic and molecular monitoring of residual disease in chronic myeloid leukaemia. Acta Haem 107: 64–75.

    Article  CAS  Google Scholar 

  • Kerst G, Kreyenberg H, Roth C, Well C, Dietz K, Coustan-Smth E, et al. 2005. Concurrent detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukaemia by flow cytometry and real-time PCR. BR J Haematol 128: 774–782.

    Article  CAS  PubMed  Google Scholar 

  • Kletzel M, Olzewski M, Huang W, Chou PM, 2002. Utility of WT1 as a reliable tool for the detection of minimal residual disease in children with leukemia. Pediatr Dev Pathol 5: 269–275.

    Article  PubMed  Google Scholar 

  • Knechtli CJ, Goulden NJ, Hancock JP, Grandage VL, Harris EL, Garland LJ, et al. 1998. Minimal residual disease status before allogeneic bone marrow transplantation is an important determinant of successful outcome for children and adolescents with acute lymphoblastic leukemia. Blood 92: 4072–4079.

    CAS  PubMed  Google Scholar 

  • Lapillonne H, Renneville A, Auvrignon A, Flamant C, Blaise A, Perot C, et al. 2006. High WT1 expression after induction therapy predicts high risk of relapse and death in pediatric acute myeloid leukemia. J Clin Oncol 24: 1507–1515.

    Article  CAS  PubMed  Google Scholar 

  • Li AH, Forestier E, Rosenquist R, Roos G, 2002. Minimal residual disease quantification in childhood acute lymphoblastic leukemia by real-time polymerase chain reaction using the SYBR green dye. Exp Hematol 30: 1170–1177.

    Article  CAS  PubMed  Google Scholar 

  • Li A, Zhou J, Zuckerman D, Rue M, Dalton V, Lyons C, et al. 2003. Sequence analysis of clonal immunoglobulin and T-cell receptor gene rearrangements in children with acute lymphoblastic leukemia at diagnosis and at relapse: implications for pathogenesis and for the clinical utility of PCR-based methods of minimal residual disease detection. Blood 15; 102: 4520–4526.

    Article  CAS  Google Scholar 

  • Liang R, Chan D, Kwong YL, Chan V, 1997. Molecular detection of minimal residual disease for patients with leukaemia and lymphoma. Hong Kong Med J 3: 195–200.

    PubMed  Google Scholar 

  • Ładoń D, Pieczonka A, Jółkowska J, Wachowiak J, Witt M, 2001. Molecular follow up of donor lymphocyte infusion in CML children after allogeneic bone marrow transplantation. J Appl Genet 42: 547–552.

    PubMed  Google Scholar 

  • Malec M, van der Velden VH, Bjorklund E, Wijkhuijs JM, Soderhall S, Mazur J, et al. 2004. Analysis of minimal residual disease in childhood acute lymphoblastic leukemia: comparison between RQ-PCR analysis of Ig/TcR gene rearrangements and multicolor flow cytometric immunophenotyping. Leukemia 18: 1630–1636.

    Article  CAS  PubMed  Google Scholar 

  • Mokany E, Todd AV, Fuery CJ, Applegate TL, 2006. Diagnosis and monitoring of PML-RARalpha-positive acute promyelocytic leukemia by quantitative RT-PCR. Methods Mol Med 125: 127–1247.

    CAS  PubMed  Google Scholar 

  • Munoz L, Lopez O, Martino R, Brunet S, Bellido M, Rubiol E, Sierra J, Nomdedeu JF, 2000. Combined use of reverse transcriptase polymerase chain reaction and flow cytometry to study minimal residual disease in Philadelphia positive acute lymphoblastic leukemia. Haematologica 85: 704–710.

    CAS  PubMed  Google Scholar 

  • Nakao M, Janssen JW, Flohr T, Bartram CR, 2000. Rapid and reliable quantification o minimal residual disease in acute lymphoblastic leukemia using rearranged immunoglobulin and T-cell receptor loci by LightCycler technology. Cancer Res 15; 60: 3281–3289.

    Google Scholar 

  • Raanani P, Ben-Bassat I, 2004. Detection of minimal residual disease in acute myelogenous leukemia. Acta Haematol. 112: 40–54.

    Article  CAS  PubMed  Google Scholar 

  • Robillard N, Cave H, Mechinaud F, Guidal C, Garnache-Ottou F, Rohrlich PS, et al. 2005. Four-color flow cytometry bypasses limitations of IG/TCR polymerase chain reaction for minimal residual disease detection in certain subsets of children with acute lymphoblastic leukemia. Haematologica 90: 1516–1523.

    CAS  PubMed  Google Scholar 

  • Rodrigues PC, Oliveira SN, Viana MB, Matsuda EI, Nowill AE, Brandalise SR, Yunes JA, 2006. Prognostic significance of WT1 gene expression in pediatric acute myeloid leukemia. Pediatr. Blood Cancer (in print).

  • Schuler F, Dolken G, 2006. Detection and monitoring of minimal residual disease by quantitative real-time PCR. Clin Chim Acta 363: 147–156.

    Article  PubMed  CAS  Google Scholar 

  • Steinbach D, Schramm A, Eggert A, Onda M, Dawczynski K, Rump A, et al. 2006. Identification of a set of seven genes for the monitoring of minimal residual disease in pediatric acute myeloid leukemia. Clin Cancer Res 12: 2434–2441.

    Article  CAS  PubMed  Google Scholar 

  • Stock W, Yu D, Karrison T, Sher D, Stone RM, Larson RA, Bloomfield CD, 2006. Quantitative real-time RT-PCR monitoring of BCR-ABL in chronic myelogenous leukemia shows lack of agreement in blood and bone marrow samples. Int J Oncol 28: 1099–1103.

    CAS  PubMed  Google Scholar 

  • Syvanen AC, 1999. From gels to chips: minisequencing primer extension for analysis of point mutations and single nucleotide polymorphisms. Hum Mut 13: 1–10.

    Article  CAS  PubMed  Google Scholar 

  • Szczepański T, Willemse MJ, Brinkhof B, van Wering ER, van der Burg M, van Dongen JJ, 2002. 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 99: 2315–2323.

    Article  PubMed  Google Scholar 

  • Szczepański T, Orfao A, van der Velden VHJ, San Miguel JF, van Dongen JM, 2001. Minimal residual disease in leukaemia patients. The Lancet Oncology 2: 409–417.

    Article  PubMed  Google Scholar 

  • Tamura K, Kanazawa T, Suzuki M, Koitabashi M, Ogawa C, Morikawa A, 2006. Successful rapid discontinuation of immunosuppressive therapy at molecular relapse after allogeneic bone marrow transplantation in apediatric patient with myelodysplastic syndrome. Am J Hematol 81: 139–141.

    Article  PubMed  Google Scholar 

  • Toren A, Rechavi G, Nagler A, 1996. Minimal residual disease post-bone marrow transplantation for hemato-oncological diseases. Stem Cells 14: 300–311.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • van der Velden VHJ, Hochhaus A, Cazzaniga G, Szczepański T, Gabert J, van Dongen JJM, 2003. Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects. Leukemia 17: 1013–1034.

    Article  PubMed  CAS  Google Scholar 

  • van der Velden VH, Hoogeveen PG, Pieters R, van Dongen JJ, 2006. Impact of two independent bone marrow samples on minimal residual disease monitoring in childhood acute lymphoblastic leukaemia. Br J Haematol 133: 382–388.

    Article  PubMed  Google Scholar 

  • Viehmann S, Teigler-Schlegel A, Bruch J, Langebrake C, Reinhardt D, Harbott J, 2003. Monitoring of minimal residual disease (MRD) by real-time quantitative reverse transcription PCR (RQ-RT-PCR) in childhood acute myeloid leukemia with AML1/ETO rearrangements. Leukemia 17: 1130–1136.

    Article  CAS  PubMed  Google Scholar 

  • Willemse MJ, Seriu T, Hettinger K, d’Aniello E, Hop WCJ, Panzer-Grumayer R, et al. 2002. Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL. Blood 99: 4386–4393.

    Article  CAS  PubMed  Google Scholar 

  • Zwick D, Cooley L, Hetherington M, 2006. Minimal residual disease testing of acute leukemia by flow cytometry immunophenotyping: a retrospective comparison of detection rates with flow cytometry DNA ploidy or FISH-based methods. Lab Hematol 12: 75–81.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Justyna Jółkowska.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jółkowska, J., Derwich, K. & Dawidowska, M. Methods of minimal residual disease (MRD) detection in childhood haematological malignancies. J Appl Genet 48, 77–83 (2007). https://doi.org/10.1007/BF03194661

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03194661

Keywords

Navigation