what is mrdWhat is MRD?

MRD (measurable residual disease) refers to the presence of leukemic cells below the threshold of detection when using conventional morphologic methods.1 Patients who achieve complete remission (CR) according to morphologic assessment alone may harbor some residual cancer cells in the bone marrow. MRD can be detected by various methods with sensitivity thresholds of < 1 × 10-4 (< 0.01%) to < 1 x 10-6 (< 0.0001%).2,3 While there is no consensus on a precise definition of MRD positivity, a sensitivity threshold of 10-4 has been shown to accurately predict patient outcomes.4,5 Recent advancements in testing methods have led to an improved understanding of the impact of MRD on patient prognosis and outcomes.6,7

 

MRD and risk of relapse8,9
mrd and risk of relapse mrd and risk of relapse

why is mrd importantWhy is MRD important?

A recent meta-analysis (Berry et al, 2017) observed patient outcomes when MRD is ≥ 10-4 and concluded that MRD above this threshold is associated with negative outcomes.6

According to the Berry meta-analysis, the presence of MRD is a strong predictor of relapse, which leads to limited treatment options and poor patient outcomes.6,10 Achieving MRD(–) status early in the course of treatment has been shown to give patients a reduced risk of relapse and a stronger chance for longer overall survival. At 10 years, adult patients who achieved MRD negativity had 64% EFS (event-free survival) compared with 21% EFS for patients who were MRD(+).6,*

how do i test for mrdHow do I test for MRD?

Testing for MRD first requires a bone marrow sample. The highest-quality sample comes from the first/early pull.1,11-13 A small (eg, 2–3 mL) sample aspirated after the needle is introduced into the bone marrow is preferred.11-13

The second pull has shown a 50% reduction in leukemic cells.12 The MRD test can then be performed in-house, or the sample can be sent to an outside laboratory if necessary.14-16 Consult with a pathologist prior to testing for considerations that may yield the best results.

There are 3 standard techniques used to test for MRD:

flow cytometry

Flow cytometry is a rapid and quantitative method of identifying cancer cells, with a peak sensitivity of 0.01%, or 1 cancer cell in 10,000 normal cells.2 6-color (or more) flow cytometry assays are the most commonly used to detect abnormal MRD immunophenotypes.1 Adequate sensitivity for MRD quantification requires special calibration and assessment of a large number of cells and may not be available from some labs. In addition, a fresh sample must be used for flow cytometry; however, a baseline sample is not necessary.13

polymerase chain reaction

Polymerase chain reaction is a well-established method in which a specific section of DNA from cancer cells is replicated and amplified. It has a peak sensitivity of 0.001%, or 1 cancer cell in 100,000 normal cells.2 Real-time quantitative polymerase chain reaction assays detect fusion genes (eg, BCR-ABL1).1 A baseline sample or prior sample obtained at diagnosis with detectable disease is required to characterize leukemic clones for MRD analysis.17

next generation sequencing

Next-generation sequencing (NGS) is an extremely sensitive DNA sequencing method, with a peak sensitivity of 0.0001%, or 1 cancer cell in 1,000,000 normal cells.3 NGS assays detect clonal rearrangements in immunoglobulin and/or T cell receptor genes.1 There is an FDA-approved NGS assay to quantify immunoreceptor genes in patients with ALL.18,19 A baseline sample or prior sample obtained at diagnosis with detectable disease is required to characterize leukemic clones for MRD analysis.17

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for ALL recommend MRD characterization of leukemic clones at diagnosis, MRD testing upon completion of initial induction therapy, and continued monitoring every 3–6 months for at least 5 years as clinically indicated.1

nccn guidelines

nccn guidelines
Diagnosis

Baseline characterization of leukemic clones to perform subsequent MRD analysis

End of Induction

CR does not exclude the possible presence of residual leukemic cells in the bone marrow

Surveillance

Every 3–6 months for at least 5 years as clinically indicated

mrd at a glanceMRD at a glance

A resource containing practical and in-depth information on implementing MRD testing in your practice:

download documentDownload MRD at a glance

where do i test for mrdWhere do I test for MRD?

If you are looking for an outside center for MRD testing, download the following resource:

You may want to speak with your pathologist first, as they may have some input or experience with how and where to test.

 

how do i talk to my patient about mrdHow do I talk to my patients about MRD?

Your patients may want to learn more about MRD. When treating patients who have achieved remission, you may explain that a relatively small number of cancer cells can remain in their body. This is called measurable residual disease, or MRD.2

MRD means that, even though they may not have signs or symptoms of cancer, there is a chance the cancer can return, which is called a relapse. If your patients test positive for MRD, you can tell them that there are treatment options that can help them eliminate these small traces of cancer.1,2,20 MRD positivity during treatment may also help inform important decisions such as the role of bone marrow transplantation.2

*According to a meta-analysis of 16 studies evaluating 2065 adult patients with ALL.6
Additional time points should be guided by the regimen used. Serial monitoring frequency may be increased in patients with molecular relapse or persistent low-level disease burden.1
ALL, acute lymphoblastic leukemia; MRD, measurable residual disease.

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia v.2.2019. ©National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed October 16, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 2. Brüggemann M, Gökbuget N, Kneba M. Acute lymphoblastic leukemia: monitoring minimal residual disease as a therapeutic principle. Semin Oncol. 2012;39:47-57. 3. Ladetto M, Brüggemann M, Monitillo L, et al. Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia. 2014;28:1299-1307. 4. Patel B, Rai L, Buck G, et al. Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993. Br J Haematol. 2009;148:80-89. 5. Campana D. Minimal residual disease in acute lymphoblastic leukemia. Semin Hematol. 2009;46:100-106. 6. Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncol. 2017;3:e170580. 7. Gökbuget N, Kneba M, Raff T, 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;120:1868-1876. 8. Gomez-Arteaga A, Guzman ML. Minimal residual disease in acute myeloid leukemia. In: Aguirre-Ghiso JA, ed. Biological Mechanisms of Minimal Residual Disease and Systemic Cancer. Cham, Switzerland: Springer, 2018. 9. Brüggemann M, Raff T, Kneba M. Has MRD monitoring superseded other prognostic factors in adult ALL? Blood. 2012;120:4470-4481. 10. Jain N, Gurbuxani S, Rhee C, et al. Acute lymphoblastic leukemia in adults. In: Hoffman R, Benz EJ Jr, Silberstein LE, et al, eds. Hematology: Basic Principles and Practice. 6th ed. Philadelphia, PA: Saunders-Elsevier; 2013:960-980. 11. Helgestad J, Rosthøj S, Johansen P, et al. Bone marrow aspiration technique may have an impact on therapy stratification in children with acute lymphoblastic leukaemia. Pediatr Blood Cancer. 2011;57:224-226. 12. Paietta E. Immunobiology of acute leukemia. In: Wiernik PH, et al, eds. Neoplastic Diseases of the Blood. Cham, Switzerland: Springer, 2018. 13. van Dongen JJM, van der Velden VHJ, Brüggemann M, et al. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood. 2015;125:3996-4009. 14. Ayala R, Onecha E. Next generation sequencing as the new gold standard for minimal residual disease detection in B-ALL. J Lab Precis Med. 2018. doi:10.21037/jlpm.2018.11.04. 15. Pigneux A, Montesinos P, Cong Z, et al. Testing for minimal residual disease in adults with acute lymphoblastic leukemia in Europe: a clinician survey. BMC Cancer. 2018;18:1-8. 16. Sánchez R, Ayala R, Martínez-López J. Minimal residual disease monitoring with next-generation sequencing methodologies in hematological malignancies. Int J Mol Sci. 2019. doi:10.3390/ijms20112832. 17. Romano A, Palumbo GA, Parrinello NL. Minimal residual disease assessment within the bone marrow of multiple myeloma: a review of caveats, clinical significance and future perspectives. Frontiers Oncol. 2019. doi:10.3389/fonc.2019.00699. 18. Food and Drug Administration. FDA authorizes first next generation sequencing-based test to detect very low levels of remaining cancer cells in patients with acute lymphoblastic leukemia or multiple myeloma. https://www.fda.gov/news-events/press-announcements/fda-authorizes-first-next-generation-sequencing-based-test-detect-very-low-levels-remaining-cancer. Accessed October 16, 2019. 19. clonoSEQ® Assay Technical Information. Adaptive biotechnologies®. 20. National Cancer Institute. NCI Dictionary of Cancer Terms. https://www.cancer.gov/publications/dictionaries/cancer-terms. Accessed October 16, 2019.

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