Minimal Residual Disease (MRD) Diagnostics: Methodology and Prognostic Significance

  • J. J. M. van Dongen
  • V. H. J. van der Velden
  • M. Brüggemann
  • A. Orfao


Monitoring of minimal residual disease (MRD) has become part of routine clinical practice in treatment of childhood acute lymphoblastic leukemia (ALL). MRD measurements have proven to be the strongest independent prognostic factor, allowing for risk-group assignment into different treatment arms, ranging from treatment reduction or intensification. MRD measurements are also guiding treatment decisions in relapsed ALL patients and patients undergoing stem cell transplantation. MRD may also become a surrogate measure of efficacy in new drug studies. And phase III clinical trials, thereby requiring shorter follow-up to answer the study question. MRD techniques need to be sensitive (≤10−4, preferably ≤10−5), broadly applicable, accurate, reliable, fast, and affordable. So far, flow cytometry and PCR analysis of rearranged immunoglobulin and T-cell receptor genes (ASO-PCR) meet these criteria, but standard flow cytometry often does not reliably detect MRD levels below 10−4, whereas ASO-PCR is time-consuming and labor intensive. Therefore two high throughput technologies are being explored; high throughput sequencing and next generation (multidimensional) flow cytometry, both evaluating millions of sequences or cells, respectively. Both have specific advantages and disadvantages, but standardization, external quality assessment, and world-wide availability will become decisive criteria for acceptance.


Acute lymphoblastic leukemia (ALL) Minimal residual disease (MRD) Monitoring Prognostication Flow cytometry Polymerase chain reaction (PCR) Next generation flow cytometry (NGF) High throughput sequencing (HTS) Euro flow Euro MRD Euro clonality 



The authors thank their colleagues of the EuroClonality, EuroMRD, and EuroFlow consortia for their fruitful collaboration and collective actions to innovate, standardize and disseminate the collective achievements in the field of MRD diagnostics. These achievements form the basis for this review. Marieke Bitter is thanked for the design of the figures and Bibi van Bodegom for her secretarial support.


All four authors (JJMvD, VHJvdV, MB, and AO) have contributed to the writing of the invited review and to the design of the figures and the tables.


The authors are members of EuroMRD (JJMvD, VHJvdV, and MB), EuroFlow (JJMvD, AO, and VHJvdV) and EuroClonality (JJMvD and MB). These consortia are scientifically independent organizations, which collectively own intellectual property (IP), including patents. Revenues from licensed IP and patents are collectively owned by the three above mentioned consortia and are fully used for sustainability of these consortia, such as for covering costs for scientific meetings, reagents, and management support as well as for educational materials, which are distributed upon request free-of-charge. BD Biosciences provides support for part of the external EuroFlow educational meetings and workshops, including part of the travelling costs (JJMvD and AO).


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Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • J. J. M. van Dongen
    • 1
    • 2
  • V. H. J. van der Velden
    • 2
  • M. Brüggemann
    • 3
  • A. Orfao
    • 4
  1. 1.Department of Immunohematology and Blood TransfusionLeiden University Medical Center LUMCLeidenThe Netherlands
  2. 2.Department of Immunology, Erasmus MCUniversity Medical Center RotterdamRotterdamThe Netherlands
  3. 3.Department of HematologyUniversity Hospital Schleswig Holstein, Campus Kiel (UNIKIEL)KielGermany
  4. 4.Department of Medicine, Cancer Research Center (IBMCC-CSIC-USAL) and Cytometry Service (NUCLEUS)University of Salamanca (USAL) and IBSALSalamancaSpain

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