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Minimal Residual Disease Testing

Minimal residual disease (MRD, also called measurable residual disease) is the term for very small numbers of cancer cells that a patient retains after treatment. MRD is a major predictor of relapse in many hematologic malignancies (leukemias and lymphomas) and has important implications for prognosis and treatment decision-making. Recent increases in test sensitivity enable the detection of very small numbers of cancer cells, and thus detection of MRD, in hematologic malignancies. Laboratory techniques used in MRD assessment include polymerase chain reaction (PCR), deep sequencing (a type of next generation sequencing, or NGS), and flow cytometry.

Quick Answers for Clinicians

For which malignancies is minimal residual disease assessment recommended?

The National Comprehensive Cancer Network (NCCN) and European Society for Molecular Oncology (ESMO) recommend minimal residual disease (MRD) assessment for specific hematologic malignancies, including acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and multiple myeloma. -  MRD may also be assessed in some circumstances (such as in the context of clinical trials) in other hematologic malignancies (eg, hairy cell leukemia, some myeloid/lymphoid neoplasms with eosinophilia, follicular lymphoma, and mantle cell lymphoma).    

What is the role of minimal residual disease testing in nonhematologic malignancies?

The role of minimal residual disease (MRD) assessment in patients with solid tumors (eg, melanoma and breast cancer) is currently being researched. There are currently no recommendations for the use of MRD testing in nonhematologic malignancies.

Which factors should be considered when choosing a test for minimal residual disease?

Assays specifically designed for minimal residual disease (MRD) testing are recommended. For flow cytometry tests, a sufficient number of colors should be used, and the validated limit of detection (LOD) should be reported. For example, in multiple myeloma, an LOD of 0.001% is required. An eight-color, two-tube flow cytometry test or a 10-color, one-tube test can meet this requirement and provide high consistency, reliability, and sensitivity. Although the use of flow cytometry and/or polymerase chain reaction (PCR) testing in MRD assessment is established for many hematologic malignancies, the role of next generation sequencing (NGS)-based tests continues to evolve. Regardless of the test selected, a high-quality specimen should be provided for testing (eg, a first or early pull of bone marrow), and the test should be thoroughly validated.

Indications for Testing

MRD testing may be used in hematologic malignancies to:

  • Assess treatment response and inform treatment decisions
  • Determine prognosis
  • Monitor remission and detect recurrence

Laboratory Testing

Testing Methods

A variety of methods are used to detect MRD. The most frequently used methods are deep sequencing (a type of NGS), flow cytometry, and PCR. The choice of which technique to use depends on the phenotype and molecular signature of the disease; for example, PCR may only work for a subset of cases with specific molecular findings. Use of multiple techniques or multiplexed tests that combine techniques may decrease the likelihood of false-negative results, but can be costly. 

Regardless of the technique used, high sensitivity (ie, low limit of detection [LOD] or limit of quantification [LOQ]) is required to ensure detection of very small numbers of leukemic cells. The requisite LOD/LOQ is generally 0.01% of nucleated cells or less, depending on the disease.

Other testing methods, such as fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), have been used for MRD assessment in specific hematologic malignancies.  

MRD Assessment in Specific Hematologic Malignancies

For more information about MRD testing and other laboratory testing in specific hematologic malignancies, see the following ARUP Consult topics and Test Fact Sheets:

ARUP Laboratory Tests

For more information about ARUP MRD test offerings, see Minimal Residual Disease on aruplab.com.

B-ALL

Use to detect MRD in patients of all ages previously diagnosed with B-ALL

LOD/LOQ: 0.0072%

Specimens: bone marrow, whole blood

Order in cases of Philadelphia chromosome-positive (Ph+) lymphoblastic leukemia to quantify the BCR-ABL1 p190 fusion form

LOQ: 0.0004%

Specimen: bone marrow

AML

Use to detect and quantitate PML-RARA fusion transcripts in patients with acute promyelocytic leukemia

Use to monitor MRD and assess the risk of disease relapse

LOQ: 0.01%

Specimens: bone marrow (preferred for maximum sensitivity), whole blood

Use to detect and quantitate NPM1 mutant transcripts (type A, B, and D)

Use to monitor for MRD and assess the risk of disease relapse

LOQ: 0.001%

Specimens: bone marrow, whole blood

Use to detect and quantitate RUNX1-RUNX1T1 fusions arising from t(8;21)

Use to monitor for MRD and assess the risk of disease relapse

LOQ: 0.001%

Specimens: bone marrow (preferred for maximum sensitivity), whole blood

Use to detect and quantitate CBFB-MYH11 inv(16) fusion transcripts

Use to monitor for MRD and assess the risk of disease relapse

LOQ: 0.001%

Specimens: bone marrow (preferred for maximum sensitivity), whole blood

This quantitative test is appropriate for therapeutic monitoring of BCR-ABL1 major (p210)-positive CML or ALL

This test is designed to meet the current National Comprehensive Cancer Network (NCCN) guidelines and is recommended for detection of MRD

For patients with uncertain diagnoses or unknown forms of BCR-ABL1 fusion transcripts, consider ordering Diagnostic Qualitative BCR-ABL1 Assay with Reflex to p190 or p210 Quantitative Assays (3005839)

LOD/LOQ: 0.0032% international scale (IS)

Specimens: bone marrow, whole blood

CLL

Limited phenotyping panel, using peripheral blood or bone marrow, to enumerate and characterize CLL cells (CD5+ monoclonal B cells) in patients with previously established diagnosis of CLL

If no previous flow immunophenotyping has been performed, order Leukemia/Lymphoma Phenotyping Evaluation by Flow Cytometry (3001780)

LOD: 0.0039%

LOQ: 0.01%

Specimens: bone marrow, whole blood

CML

This quantitative test is appropriate for therapeutic monitoring of BCR-ABL1 major (p210)-positive CML or ALL

This test is designed to meet the current NCCN guidelines and is recommended for detection of MRD

For patients with uncertain diagnoses or unknown forms of BCR-ABL1 fusion transcripts, consider ordering Diagnostic Qualitative BCR-ABL1 Assay with Reflex to p190 or p210 Quantitative Assays (3005839)

LOD/LOQ: 0.0032% IS

Specimens: bone marrow, whole blood

This qualitative screening test is appropriate for initial diagnosis of CML or ALL/acute lymphoblastic lymphoma

Use to detect the presence of p210 (major breakpoint), p190 (minor breakpoint), and p230 (micro breakpoint) fusions

If a common p210 or p190 BCR-ABL1 fusion transcript is detected, the appropriate test will be added to provide a quantitative value, which may be used as the diagnostic baseline to further monitor treatment response

For patients with a known history of p210 or p190 fusion transcripts, refer to Quantitative Detection of BCR-ABL1, Major Form (p210) (3005840) or BCR-ABL1, Minor (p190), Quantitative (2005016); these two tests are the appropriate tests to monitor therapeutic response and to detect MRD

Specimens: bone marrow, whole blood

Multiple Myeloma

Limited phenotyping panel to enumerate and characterize plasma cells in patient with previously established diagnosis of plasma cell dyscrasia

If no previous flow immunophenotyping has been performed, order Leukemia/Lymphoma Phenotyping Evaluation by Flow Cytometry (3001780)

LOD/LOQ: 0.001%

References

Educational Videos From ARUP Laboratories

Clinical Flow Cytometry for the Perplexed-Part 5: Minimal (Measurable) Residual Disease Detection (MRD)
37 min

Medical Experts

Contributor

Karner

Kristin Hunt Karner, MD
Kristin Hunt Karner, MD
Associate Professor of Pathology (Clinical), University of Utah
Medical Director, Hematopathology and Molecular Oncology, ARUP Laboratories
Contributor