Navigating Decision-Making for Lymphoid Malignancies: How MRD Testing Can Help

MRD testing is incredibly valuable in informing clinical decision-making in the treatment of lymphoid malignancies, and its adoption by all oncologists is crucial in the era of precision medicine.

During my 10 plus years of practicing medicine, I have seen the blood cancer treatment landscape transform, as the development of CAR T-cell therapies and various other immunotherapies have ushered in a new era of precision medicine. In parallel, disease burden assessment technology has continued to advance, providing insights into a patient's response to treatment and informing shared decision-making.

One tool in particular that has changed my approach to treating patients with various lymphoid malignancies is measurable residual disease (MRD) testing. This cutting-edge testing technology provides a powerful and dynamic measure of risk status and real-time insights into disease progression that can help oncologists provide a more personalized approach to treatment.

Role of MRD Testing in Clinical Decision-Making

MRD refers to the number of cancer cells that remain in the body during and after cancer treatment. An MRD test detects, counts, and tracks MRD in a bone marrow or blood sample to provide information into the depth of response to a treatment or detect early signs of relapse in patients with lymphoid malignancies. These results can also provide insight into long-term outcomes, as patients who test MRD positive may be more likely to experience cancer growth or recurrence than those who consistently achieve MRD-negativity; this depends on the testing time point and type of cancer.

Different types of MRD testing methods are available, but I use molecular next-generation sequencing (NGS)–based testing due to its depth of detection—identifying a single cancer cell among a million healthy cells.¹ NGS can accurately process a vast amount of genetic information quickly and inexpensively, which is crucial in situations where prompt treatment decisions are necessary.² During and after treatment, oncologists can utilize MRD testing to accomplish the following:

• help predict patient outcomes;
• monitor and assess response to treatment over time;
• inform potential changes in therapy including stopping or re-initiating treatment;
• monitor disease burden over time, even in the absence of therapy;
• detect potential relapse early, before physical signs and symptoms;
• and complement other monitoring tools with simple blood-based testing.

Incorporating MRD Testing in my own Practice

As a community oncologist practicing in South Florida, I have been using highly sensitive NGS testing, specifically clonoSEQ^®, for approximately 3 years. The test works by identifying the dominant DNA sequences associated with the tumor through a high-disease burden sample taken at the time of diagnosis or relapse. Once identified, these sequences can be tracked over time, allowing me to monitor my patient’s disease status throughout the course of their treatment and during remission.³

I initially began using NGS testing for solid tumors and was curious to see if there was an equivalent test for my patients with chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma. Currently, I use NGS testing for my patients with lymphoid malignancies throughout their entire treatment journey because it allows me to make treatment decisions with confidence. It helps me monitor patients for recurrence, as well as determine if I should end treatment early, re-initiate therapy, put the patient on maintenance therapy, or de-escalate and adjust a patient’s follow-up schedule if they remain MRD-negative.

For example, in CLL, I use MRD testing before the patient starts treatment to get a baseline reading. Once I have initiated treatment, I typically monitor MRD in the peripheral blood in the first 3 to 4 months and then every 3 months thereafter. I continue with that schedule unless the patient has not reached MRD-negativity by 12 months. If they continue to be MRD-positive, I monitor them more frequently. With fixed-duration therapy for CLL, having an MRD test that is very sensitive is key in helping to make decisions about ending treatment early. The test provides insight into the depth of response with a long enough lead time to allow me to adjust the treatment regimen accordingly.

In DLBCL, an especially aggressive type of non-Hodgkin’s lymphoma, I monitor patients very closely using peripheral blood MRD assessments, which measure circulating tumor DNA (ctDNA) to determine if relapse has occurred, as that will determine how I manage the disease. I generally use MRD testing after every 2 cycles if the patient is receiving 6 cycles of therapy. When the treatment is completed, I repeat the test monthly to determine if there are early treatment failures. If the patient remains MRD-negative, I monitor every 2 to 3 months after that during the first year and every 4 months during the second year.

For those with multiple myeloma, using a highly sensitive MRD test allows me to make critical decisions about treatment de-escalation or maintenance. If a patient is MRD-negative, I might be able to de-escalate treatment and see them every 6 months rather than more frequently. For MRD-negative patients who have come off treatment, I might recommend blood-based MRD testing to monitor their disease status, which is less invasive for them. If a patient is MRD-positive, I consider reinitiating therapy and seeing the patient more often.

Barriers to MRD Testing in Community Oncology

Despite the proven benefits of MRD testing, my utilization of the test in a community oncology practice is the exception and not the rule. It is more frequently performed in academic medical centers and in clinical trials than in community oncology programs and practices. This variation in adoption rates can be attributed to multiple factors.

One barrier is limited awareness among community oncologists about NGS testing in hematologic malignancies, its characteristics, and how to interpret the results. In solid tumors, any level of disease is problematic, whereas in certain types of lymphoma, low levels of MRD are not always clinically actionable. To gain information and insight into how to interpret the dynamics of MRD testing, community oncologists might consider partnering with oncologists at academic medical centers who have significant experience using this type of test.

Another barrier to uptake by community oncologists is a desire for more prospective data about how MRD testing has contributed to treatment modification and improved outcomes, as well as its prognostic value. However, clinical guidelines across multiple myeloma, CLL and ALL support MRD monitoring at multiple timepoints. Additionally, there are various clinical studies being published that continue to evaluate the applications and benefits of the test, including IFM 2009, DETERMINATION, and MASTER.^4-6

The perceived cost of the test, a concern that patients occasionally bring up with their oncologist, is another obstacle. Fortunately, clonoSEQ is covered by Medicare and is relatively inexpensive compared to other NGS tests. It is also significantly less expensive than administering unnecessary treatment to patients.

Improving Uptake of MRD Testing in the Community 

MRD testing is incredibly valuable in informing clinical decision-making in the treatment of lymphoid malignancies, and its adoption by all oncologists is crucial in the era of precision medicine. Integrating MRD testing into a community oncology practice is relatively simple, the results are easy to interpret with adequate education, and the prognostic value of the test is well established in the data. To access support and guidance in implementing and interpreting test results, tap into community oncology network resources, like NCODA’s positive quality interventions (PQIs) for multiple myeloma and CLL.^7,8

As MRD testing can provide unparalleled benefits, especially for patients who prefer to receive treatment in the community setting, I encourage other community oncologists to become well informed about this test and its value throughout a patient’s entire treatment journey. The specificity of MRD testing can give oncologists and their patients more confidence in making shared treatment decisions with a more complete picture of their disease.

Editor’s note: Dr. Azzi was compensated by Adaptive for his time working on this article.

Author Bio

Georges Azzi, MD, is a hematologist/oncologist and co-director of the Department of Hematology/Oncology, Prostate Cancer, at Holy Cross Health, in Fort Lauderdale, Florida. Born and raised in Lebanon, he received his medical degree from Saint Joseph University of Beirut. He completed a fellowship in medical oncology with honors from the University of Miami Miller School of Medicine. Dr. Azzi has authored multiple peer-reviewed articles in hematology/oncology. He is a member of the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), the American Association of Cancer Research (AACR), the American College of Physicians (ACP), and the Florida Society of Clinical Oncology. He is board certified in hematology and oncology.

References

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8. NCODA. Positive Quality Intervention: clonoSEQ® Next Generation Sequencing for Minimum Residual Disease Testing in Chronic Lymphocytic Leukemia. Accessed December 18, 2023. https://bit.ly/41qFddj