Measurable Residual Disease (MRD)

Role of MRD

Measurable residual disease (MRD) is a sensitivity test that refers to the small number of cancer cells that can remain after treatment is completed. These residual cancer cells may remain undetected (not found) in the body using the original tests that diagnosed the disease (like looking at the cells under a microscope) without causing any signs or symptoms. However, they can reactivate (start to multiply) and cause the cancer to relapse (come back after treatment). MRD testing uses very sensitive laboratory methods (tests run in the laboratory) to look for these residual cancer cells hiding among healthy blood cells. If MRD is detected (MRD-positive result), this means there are residual cancer cells in the body. If no MRD is detected (MRD-negative result), it means there are either no residual cancer cells or the amount is below the sensitivity of the test.

Lymphoma/CLL and MRD

In lymphoma and chronic lymphocytic leukemia (CLL), MRD tests look for residual cancer cells in the patient’s blood or bone marrow (the spongy tissue inside the bones). These tests can detect one cancer cell in at least 10,000 healthy blood cells (depending on the method) and is mainly used as a prognostic marker (predicts how well the patient will do). This means that doctors use MRD to evaluate how effective the treatment was, to predict the risk of relapse, and to monitor patients in remission (no signs and symptoms of cancer).

While MRD testing is not currently part of the daily clinical practice in patients with lymphoma/CLL, it is often investigated in clinical trials (see “Clinical Trials” section below). Doctors can use different tests to look for MRD in patients with lymphoma or CLL/SLL. One important example is called circulating tumor DNA (ctDNA), in which doctors look for DNA released from cancer cells into the patient’s bloodstream. Monitoring ctDNA in the blood is a highly sensitive and minimally invasive procedure that may help doctors detect traces of residual cancer.

Patients who are MRD-negative may be more likely to have a longer remission. However, it is important to highlight that having detectable MRD does not necessarily mean the disease has relapsed or become refractory (does not respond to treatment). For example, patients with CLL receiving treatment with Bruton’s tyrosine kinase (BTK) inhibitors may not reach a negative MRD status but can still maintain disease control for many years.

When and why to test for MRD

The timing for MRD testing depends on the patient’s type of lymphoma and the treatment plan. Patients may be tested before, during, or after treatment. For instance, MRD can be used prior to stem cell transplantation (a procedure that replaces the patient’s immune system with healthy blood-forming cells and restores the bone marrow’s ability to make new blood cells) to select the patients who are more likely to benefit from this treatment. It can also be conducted during treatment to evaluate treatment response, or at selected time points after treatment to monitor remission or predict the risk of relapse.

MRD and Potential Impact on Treatment

Testing for MRD mainly helps doctors understand how well the patient will do after treatment. In some cases, MRD can also be used to evaluate if patients need additional courses of treatment, or if they should receive a different type of treatment.

Methods to Detect MRD

The most widely used methods for MRD testing in lymphoma/ CLL are described in the table below. These tests use samples of the patient’s peripheral blood (by drawing blood from a vein) and/ or bone marrow (by performing a bone marrow biopsy, in which doctors collect a small piece of the spongy tissue inside the bones).

It is important to note that MRD testing may not be used in daily clinical practice in lymphoma/CLL at this time. Hoewever, several MRD tests have been developed for used in blood cancers, and some examples for lymphoma/CLL are included below.

• clonoSEQ® Assay: MRD test detects ctDNA in patients with DLBCL, CLL, and MCL.
• PhaseEd-Seq MRD: MRD test detects ctDNA in patients with large B-cell lymphomas.

Method	Description
FlowCytometry	Cells from the biopsy sample are placed in a liquid solution and mixed with sets of antibodies that recognize antigens (markers) found in different types of lymphoma cells. The cell-antibody mixture is injected into an instrument called a flow cytometer. This machine uses laser beams to detect the different colors of light the cells emit (produce) from the antibodies attached to them. This information is measured and analyzed by a computer and interpreted by a hematopathologist (a doctor who specializes in the diagnosis of blood diseases) or another specialist. Sensitivity: 1 in 10,000 or 1 in 100,000 (depending on the test conditions).
PolymeraseChainReaction(PCR)	A method to amplify (create several copies) DNA pieces (genetic material inside the cells) to detect genetic abnormalities like mutations (permanent changes in the DNA). The presence of specific genetic abnormalities helps doctors tell apart cancer cells from healthy cells. Sensitivity: 1 in 100,000.
Next-GenerationSequencing(NGS)	Genetic sequencing determines the order of the four building blocks (called bases) that form the DNA. The order of DNA bases (genetic sequence) in genes determines which proteins the body makes and what they do. The information in that specific gene may be relevant to the patient’s cancer. NGS is a fast sequencing of many genes at the same time and helps doctors identify thousands or even hundreds of thousands of variants (genetic changes) in a single test. Sensitivity: 1 in 1,000,000.

Questions to Ask Your Healthcare Provider

• What is the goal of MRD testing?
• Is MRD testing appropriate for my type of lymphoma?
• How is MRD testing done?
• How would I benefit from MRD testing?
• Does my treatment center offer MRD testing?
• Is MRD testing covered by my insurance plan?
• How can I access MRD testing if MRD testing is not covered by my insurance plan?
• Are clinical trials available that are studying MRD testing in patients with my type of lymphoma?
• How long does it take to get results for MRD testing?
• What do the MRD testing results mean and will they affect my treatment plan?

Clinical Trials

Testing for MRD is often done in clinical trials of patients with CLL, follicular, mantle cell, Burkitt and diffuse large B-cell lymphoma. Studies are underway to investigate whether MRD testing may be used to shorten the course of treatment for patients with undetectable levels of cancer cells in their blood before they have completed a full course of therapy. For more information about ongoing clinical trials in lymphoma, please visit the Foundation’s Clinical Trials Information Service on the Foundation’s website (visit lymphoma.org/resources/supportservices/ctis/) or talk to your health care team.

Lymphoma Care Plan

Keeping your information in one location can help you feel more organized and in control. This also makes it easier to find information pertaining to your care and saves valuable time. The Foundation’s Lymphoma Care Plan document organizes information on your health care team, treatment regimen, and follow-up care. You can also keep track of health screenings and any symptoms you experience to discuss with your health care provider during future appointments. The Lymphoma Care Plan document can be accessed by visiting lymphoma.org/publications.

MRD Terms to Know

Term	Definition
Antigen	Molecules found on the surface of cells.
CirculatingtumorDNA(ctDNA)	A test in which doctors look for cancer cell DNA released in the patient’s bloodstream.
Flowcytometry	A test that uses a laser to detect and count the different types of blood cells, according to their size, presence of markers on their surface (antigens), and number of small particles (granularity).
Geneticsequencing	A test that determines the order of the four building blocks (called bases) that form the DNA. The order of DNA bases (genetic sequence) in genes determines which proteins the body makes and what they do.
Measurableresidualdisease(MRD)	A sensitivity test that detects small numbers of cancer cells that can remain in the body after treatment is completed.
MRD-negativeresult	There are either no residual cancer cells or the amount of cancer cells is below the sensitivity of the test (the smallest number of cells that can be detected by a given test).
MRD-positiveresult	There are residual cancer cells in the body.
Mutation	Permanent changes in the cell’s genetic material.
Nextgenerationsequencing(NGS)	Fast sequencing of many genes at the same time which helps doctors identify thousands or even hundreds of thousands of variants (genetic changes) in a single test.
Polymerasechainreaction(PCR)	A method to amplify (create several copies) DNA pieces (genetic material inside the cells) to detect genetic abnormalities like mutations.
Prognosticmarker	A measurement that helps doctors determine how well the patient will do.
Refractorydisease	Cancer that no longer responds to treatment.
Diseaserelapse	Cancer comes back after treatment.
Remission	No signs and symptoms of cancer.

Patient Education Programs

The Foundation also offers a variety of educational activities, including live meetings and webinars for individuals looking to learn directly from lymphoma experts. These programs provide the lymphoma community with important information about the diagnosis and treatment of lymphoma, as well as information about clinical trials, research advances and how to manage/cope with the disease. These programs are designed to meet the needs of a lymphoma patient from the point of diagnosis through long-term survivorship. To view our schedule of upcoming programs, please visit lymphoma.org/programs.

Lymphoma Resource Center

The Foundation’s Lymphoma Resource Center staff are available to answer your general questions about lymphoma and treatment information, as well as provide individual support and referrals to you and your loved ones. Callers may request the services of a language interpreter. The Foundation also offers a one-to-one peer support program called the Lymphoma Support Network and clinical trials information through our Clinical Trials Information Service. For more information about any of these resources, visit our website at lymphoma.org, or contact the Lymphoma Resource Center at (800) 500-9976 or [email protected].

Para información en Español, por favor visite lymphoma.org/es. (For Information in Spanish please visit lymphoma.org/es).