After treatment and remission

Measurable residual disease (MRD)

In remission, an ordinary microscope sees no leukemia cells, but that does not mean not a single one is left in the body. Measurable residual disease (MRD) tests can find the odd leukemia cell among hundreds of thousands, sometimes millions, of normal cells. This topic explains calmly and clearly how MRD is measured, what the results mean and how doctors use them to plan treatment.

Last updated: ~6 min read
A single violet cell highlighted by a fine beam of light among many calm translucent blood cells on a dark navy background.
Figure 1.Concept: an MRD test finds a single leukemia cell among thousands of healthy ones.

01Short answer

MRD (measurable, formerly “minimal”, residual disease) is the small number of leukemia cells left in the blood or bone marrow of a person in remission that cannot be seen under an ordinary microscope. It is measured by flow cytometry, PCR or next-generation sequencing (NGS), and it shows how deeply treatment has worked. An MRD-negative result is linked, on average, with a better outlook, while an MRD-positive result is a timely warning and a reason to discuss additional or different treatment, not a sign that relapse is inevitable. How results change over time matters more than any single result. Your hematology team decides when and how the test is done and what to do with the result.

02Simple explanation

Imagine searching for a few harmful plants hidden in a large forest. From a distance the forest looks clear: that is remission as seen under an ordinary microscope. An MRD test is a precise search that checks every tree up close.

MRD stands for measurable residual disease. It used to be called “minimal residual disease”. It refers to the very small number of leukemia cells left after treatment.

To find these cells, the leukemia’s “fingerprint” is used: special markers on the cell surface (flow cytometry) or genetic changes (PCR, NGS). That is why samples taken at diagnosis matter later too.

An MRD-negative result shows that no trace of leukemia was found within the sensitivity of the test. This is very good news, but it is not a guarantee that “there are no cells at all”.

An MRD-positive result shows that a few cells remain. It gives doctors a chance to act before the problem grows: to intensify or change treatment, or to discuss a transplant or newer medicines.

03Scientific explanation

Measurement methods: according to the 2021 ELN MRD consensus, the threshold for MRD positivity by multiparameter flow cytometry in AML is 0.1%. If a suitable genetic change such as NPM1, CBFB::MYH11 or RUNX1::RUNX1T1 is present at diagnosis, a more sensitive quantitative PCR test is used, and in some cases the sample can be taken from blood. NGS-based methods are also increasingly used.

MRD in ALL: according to the NCI, in childhood ALL flow cytometry or PCR can detect one leukemia cell among 100,000 normal cells, and the MRD level at the end of induction is used to choose how intensive treatment should be. A 2017 meta-analysis (more than 13,000 patients) found that MRD negativity was linked with considerably better event-free survival in both children and adults. In 2018 the FDA approved blinatumomab for people with B-ALL in remission whose bone marrow MRD is at least 1 cell in 1,000.

What MRD means in AML: according to a 2020 meta-analysis, people with MRD-negative AML had, on average, clearly higher overall and disease-free survival than those who were MRD-positive, and this link was seen across age groups and testing methods. The 2022 ELN recommendations list “complete remission without MRD” as a separate response category, and ELN 2021 describes regular MRD monitoring after treatment and early recognition of molecular relapse.

In CML and CLL: according to the 2020 ELN recommendations, in CML the BCR::ABL1 level in blood is usually measured by PCR every 3 months; a deep and lasting molecular response is the key condition for trying treatment-free remission. In the EURO-SKI study, about half of those who stopped their medicine were still in major molecular response two years later. According to iwCLL, undetectable MRD in CLL means fewer than one CLL cell per 10,000 white blood cells.

04What happens in the body?

When is an MRD test done?

Usually at set points: in acute leukemias at the end of induction, after consolidation courses, before and after a transplant, and sometimes during follow-up after treatment ends. The sample is most often taken from the bone marrow; for some tests a blood sample is enough.

Three “lenses”: flow, PCR and NGS

Flow cytometry counts unusual cells by the markers on their surface, and results come back quickly. PCR measures one particular genetic change very sensitively, but only works in leukemias that carry such a change. NGS reads thousands of DNA sequences and can find one cell in a million. Which method is chosen depends on the type of leukemia and what the centre offers.

Three translucent glowing lenses side by side on a dark navy background, each showing the cells behind it larger and sharper.
Figure 2.Flow cytometry, PCR and NGS: three “lenses” of different sensitivity.

A trend, not a single number

An MRD result is judged more like a film than a single photo. A steady fall is a good sign; a rise on repeat tests prompts doctors to look more closely and repeat the test. Because methods differ between laboratories, it is better, where possible, to follow results in the same laboratory.

A row of soft glowing points of light on a dark navy background that gradually descend and fade from left to right.
Figure 3.MRD results are followed over time: the trend gives the clearest picture.

How does the result affect treatment?

In some protocols, MRD results are used to adjust treatment intensity, to judge whether a transplant is needed, or to start additional treatment such as targeted medicines or immunotherapy. But a decision is never based on one test alone: the genetics of the leukemia, your health and your own preferences are taken into account too.

While you wait for the result

Waiting for an MRD result can be very stressful. Ask your doctor in advance when the result will be ready and who will discuss it with you. Do not compare your result with other people’s numbers online: the same number can mean different things in different leukemias and methods.

05How does MRD work?

From the “fingerprint” at diagnosis to treatment decisions.

Fingerprint at diagnosis — The leukemia’s markers and genetic changes are recorded.1Fingerprint at diagnosisThe leukemia’s markers and genetic changes are recorded.
Sample in remission — Bone marrow or blood is taken.2Sample in remissionBone marrow or blood is taken.
Sensitive search — Single cells are sought by flow, PCR or NGS.3Sensitive searchSingle cells are sought by flow, PCR or NGS.
Result and plan — The team decides the next step.4Result and planThe team decides the next step.
MRD-negativeA better outlook on average; the plan continues.
MRD-positiveA chance to act in good time.
TrendRepeat tests give the clearest picture.

06Methods of measuring MRD (simplified)

MethodWhat it looks forApproximate sensitivity
Ordinary microscopeVisible blast cellsAbout 5 cells in 100
Flow cytometryUnusual markers on the cell surface1 cell in 10,000–100,000
Quantitative PCRA specific genetic change (for example NPM1, BCR::ABL1)1 cell in 100,000–1,000,000
NGSDNA sequences unique to the leukemiaDown to 1 cell in 1,000,000

* Sensitivity depends on sample quality, the type of leukemia and the laboratory. Your hematology team decides which test suits you.

07Key terms

MRD
Measurable residual disease: the small number of leukemia cells left in remission.
MRD-negative
No trace of leukemia found within the sensitivity of the test.
MRD-positive
A small number of leukemia cells has been found.
Flow cytometry
A method that counts cells by the markers on their surface.
PCR
A method that copies and measures a specific genetic change.
NGS
Next-generation sequencing: a very sensitive way of reading DNA.
Sensitivity
Among how many normal cells a test can find one leukemia cell.
Molecular relapse
MRD becoming positive again or rising, usually confirmed by a repeat test.
Fingerprint
The set of leukemia-specific markers identified at diagnosis.
Treatment-free remission
In CML, stopping medicine under monitoring after a deep response.

08Key points

  • MRD measures leftover leukemia cells that the microscope cannot see.
  • It is measured by flow cytometry, PCR or NGS.
  • An MRD-negative result is linked with a better outlook on average.
  • An MRD-positive result does not mean relapse is inevitable.
  • The trend matters more than a single number.
  • Where possible, follow your results in the same laboratory.
  • MRD helps with some treatment decisions but is not the only factor.
  • Interpret your result only together with your hematology team.

09Frequently asked questions

I am MRD-negative. Does that mean I am cured?

It is a very good and hopeful result, but on its own it does not guarantee cure. The test can only see down to a certain sensitivity. That is why follow-up and planned treatment continue.

What does an MRD-positive result mean?

It shows that some leukemia cells remain. In some people these cells do not grow for a long time; others need additional treatment. Today there are effective medicines and strategies for an MRD-positive situation.

Is MRD measured in every leukemia?

MRD or molecular response is widely used in ALL, AML, CML and CLL, but the methods and timing differ. In some rare types, the role of MRD testing is still being studied.

Why is it sometimes blood and sometimes marrow?

Marrow usually gives a more sensitive result. But for some genetic changes, such as BCR::ABL1 in CML or NPM1 in AML, regular monitoring with blood samples is possible.

My report says “low-level positive”. What does that mean?

It means a very small amount of leukemia was detected. What it means depends on the type of leukemia, the method and the trend. Often the test is repeated, and the doctor looks at all the information together.

What should I ask my doctor?

Which method is used? How sensitive is the test? When is the next test? How could the result change my treatment? Can I have a copy of the report?

10Questions for your doctor

Take these questions to your appointment. The ones you save are collected on the “My questions” page and stay on this device only.

  1. Which method do you use to measure my MRD, and how sensitive is the test?

  2. What does it mean if my MRD is positive?

  3. How often will we check MRD?

  4. Will the MRD result change my treatment plan?

My questions

12Sources

  1. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms: minimal residual disease
  2. National Cancer Institute (NCI). Adult Acute Lymphoblastic Leukemia Treatment (PDQ®) – Patient Version
  3. National Cancer Institute (NCI). Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®) – Patient Version
  4. National Cancer Institute (NCI). Adult Acute Myeloid Leukemia Treatment (PDQ®) – Patient Version
  5. American Cancer Society. Acute Lymphocytic Leukemia (ALL) Subtypes and Prognostic Factors
  6. U.S. Food and Drug Administration (FDA). FDA expands approval of Blincyto for treatment of a type of leukemia in patients who have a certain risk factor for relapse
  7. Blood, 2021. 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party
  8. Blood, 2022. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN
  9. JAMA Oncology, 2017. Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis
  10. JAMA Oncology, 2020. Association of Measurable Residual Disease With Survival Outcomes in Patients With Acute Myeloid Leukemia: A Systematic Review and Meta-analysis
  11. Leukemia, 2020. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia
  12. Blood, 2018. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL
  13. Lancet Oncology, 2018. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial
Medical disclaimerThis information is for educational purposes only and does not replace medical advice.
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