Minimal Residual Disease Testing for Patients with Chronic Lymphocytic Leukemia

John M Pagel, MD, PhD

What is minimal residual disease (MRD) and why is it important to measure?

MRD is a term used to describe the highly sensitive estimate of the remaining number of cancer cells in blood and tissues (such as the bone marrow) during and after cancer treatment that may eventually cause recurrence of the disease. Measuring MRD helps us understand disease burden at a very low level for blood cancers like leukemias. Assessment of MRD status has been shown to be valuable for prognostic purposes for relapse and survival, and has been rapidly expanding as a tool to help us make informed decisions around therapy to help guide day-to-day patient management.¹

What types of tools are used to measure MRD?

There are several methods to measure MRD, each with its own limit of detection. Imaging with CT or PET scans are crude measurements of disease burden, whereas conventional flow cytometry (cell assay) is more sensitive and can detect one malignant cell in 10,000 lymphocytes (sensitivity of 10^-4).² Using next generation sequencing (NGS), clonoSEQ® is a molecular test that sequences a patient's unique immunoglobulin (Ig), with a sensitivity of one malignant cell in a million lymphocytes (10^-6), provided there is sufficient sample material.^1,3 The more sensitive the test, the more accurately we can predict treatment response, and assess and understand relapse with the hope of ultimately improving survival.^4,5

What is undetectable MRD and what can it show?

Getting to an “undetectable MRD” (uMRD) disease status (i.e., presence of less than 1 cancer cell in 10,000 leukocytes (<10⁻⁴)), with sensitive testing measures such as NGS gives us not only prognostic value but important information with regards to duration of remission and time to next treatment, which are often more prolonged in the setting of uMRD, as opposed to those who have “detectable MRD” (i.e., >10⁻⁴).⁴

What are the benefits of measuring MRD with clonoSEQ and what do oncologists need to understand about MRD testing?

The clonoSEQ Assay is powered by NGS technology that reads the DNA sequence of malignant B cells, such as chronic lymphocytic leukemia (CLL) cells.¹ Much like a snowflake, each B cell has a specific antibody structure which makes it different from other B cells.⁶ These differences stem from rearrangements that occur in the DNA within a specific region of the B-cell receptor called the CDR3 region. When the B cell becomes malignant, the DNA that encodes the CDR3 region of that lymphocyte serves as a precise and unique marker of the malignancy.

It is the most powerful tool we currently have to predict treatment response.⁷ As an example, a patient who is in partial remission based on CT scan criteria, yet with evidence of uMRD by molecular testing, is going to have a better outcome than a patient that has a complete remission upon imaging but still has evidence of circulating disease or evidence of MRD.⁸

Testing for MRD helps the oncologist to really understand follow-up frequency and appointments. If a patient is in a deep remission (or uMRD), an oncologist may not require that patient to come in for an appointment quite as often as someone who has significantly increasing evidence of MRD. Additionally, MRD testing may allow an oncologist to recommend that a patient receive treatment for only a finite period of time rather than ongoing treatment. After current treatments, those patients with CLL who have the deepest remissions have the most likelihood of being able to stop selected treatment.

The most important aspect for oncologists to understand about testing is the most sensitive MRD tests are likely the most valuable, reliable, and reproducible, with extremely high levels of sensitivity, as well as specificity.

What benefits does MRD testing provide for patients and what is the most important aspect for patients to understand when it comes to MRD and MRD testing?

For patients, there is tremendous value in knowing disease burden if it helps them understand their current status and may help them plan their lives around their treatment plans. It is important for patients to know that tools such as clonoSEQ are available, and can be valuable regarding treatment decisions, follow up, or assessing for potential relapse.

In certain situations, measuring MRD may not change treatment or monitoring approaches; this should be discussed with each individual patients’ physician and provider team.

What research have you been involved in regarding making treatment decisions based on MRD testing?

The recent CAPTIVATE trial, using ibrutinib and venetoclax as a novel frontline combination for patients with CLL, resulted in deep remissions, allowing patients to eventually stop treatment. Investigators determined the majority of patients became uMRD using flow cytometry after about one year of treatment with this combination therapy; furthermore, it was found that ongoing maintenance therapy, with someone who has uMRD, was not particularly helpful or beneficial.⁹

How do you use MRD testing in your clinical practice today?

I use MRD testing to provide valuable information to chronic lymphocytic leukemia, acute lymphoblastic leukemia and diffuse large B-cell lymphoma patients. In many cases, the results help to make treatment decisions around therapy discontinuation. The testing in our practice has also been used to monitor for relapse and to allow for the early detection and therefore, the potential for early intervention in a high-risk patient.

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John M Pagel, MD, PhD

Dr. Pagel is the Chief of Hematologic Malignancies Program at the Swedish Cancer Institute. He earned his Medical Degree from Boston University School of Medicine in Boston, Massachusetts, where he graduated magna cum laude, and his Doctor of Philosophy in Microbiology and Molecular Genetics from the University of California in Irvine, CA. Prior to his current position, he was a Member and Professor at Fred Hutchinson Cancer Research Center and University of Washington, respectively.

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About clonoSEQ

clonoSEQ^® is available as an FDA-cleared in vitro diagnostic (IVD) test service provided by Adaptive Biotechnologies to detect minimal residual disease (MRD) in bone marrow from patients with multiple myeloma or B-cell acute lymphoblastic leukemia (B-ALL) and blood or bone marrow from patients with chronic lymphocytic leukemia (CLL). clonoSEQ is also available for use in other lymphoid cancers and specimen types as a CLIA-validated laboratory developed test (LDT). For important information about the FDA-cleared uses of clonoSEQ including test limitations, please visit clonoSEQ.com/technical-summary.

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About Adaptive Biotechnologies

Adaptive Biotechnologies is a commercial-stage biotechnology company focused on harnessing the inherent biology of the adaptive immune system to transform the diagnosis and treatment of disease. Adaptive’s proprietary immune medicine platform reveals and translates the massive genetics of the adaptive immune system with scale, precision and speed to develop products in life sciences research, clinical diagnostics and drug discovery.

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References

1. clonoSEQ®. [technical summary]. Seattle, WA: Adaptive Biotechnologies Corporation; 2020.
2. Thompson P, et al. Blood. 2019;134(22):1951-1959.
3. Ching T, et al. BMC Cancer. 2020;20:612.
4. Seymour JF, et al. N Engl J Med. 2018;378(12):1107-1120.
5. Cheson BD, Mato AR. Clin Adv Hematol Oncol. 2020;18 Suppl 10(6):1-20.
6. Kirsch I, et al. Molec Oncol. 2015;9(10):2063-70.
7. Molica S, et al. Clin Lymphoma Myeloma Leuk. 2019;19(7):423-430.
8. Fischer K et al. ASH 2019; Abstract 36.
9. Jain N, et al. N Engl J Med. 2019;380(22):2095-2103.