MRD Testing in Chronic Lymphocytic Leukemia

The purpose of measurable residual disease (MRD) testing is to help determine the amount of tumor cells remaining in the body after cancer treatment. This measurement is important because residual tumor cells can cause the cancer to spread or return. MRD testing has been used in hematologic cancers for some time now and is strongly correlated with long-term outcomes. The ideal result of MRD testing is to have “undetectable MRD,” meaning that less than one cancer cell has been detected per a certain threshold of normal bone marrow cells, ranging from 10,000 to 1,000,000, depending on the disease state. In chronic lymphocytic leukemia (CLL), undetectable MRD is defined as less than one CLL cell per 10,000 normal white blood cells. Recent studies show that undetectable MRD after CLL treatment is associated with a longer duration of progression-free survival.¹

The role of MRD testing in CLL is expanding, with active discussion on how best to implement guideline-concordant testing in cancer programs and how to optimally interpret the data. One major way that MRD testing can be used for patients with CLL is with venetoclax-inclusive fixed-duration regimens. Experts recommend that MRD testing be conducted after one or two years of treatment, and patients who have undetectable MRD at those points can likely come off therapy.^1,2 This can be beneficial for patients who want to reduce their time on medications or want to reduce their medication load overall. Options for patients with persistent disease continue to be investigated and may include continuing single-agent venetoclax or switching to other therapies. It is important to note that MRD testing in CLL may not be relevant in all treatment settings, as single-agent BTK inhibitors (i.e., ibrutinib) do not induce undetectable MRD but are effective treatments nonetheless.³

With data already demonstrating the role of MRD for CLL response assessment and prognosis, cancer programs should prepare themselves for implementation of MRD testing for appropriate patients. Dr. Tara Graff, an oncologist at a large community practice in Iowa, notes that an important factor to consider when initiating MRD testing is identifying the type of patients who are most likely to benefit from testing.⁴ For example, high-risk patients with poor prognostic factors are more likely to have disease progression and would therefore be good candidates for routine monitoring with MRD. Dr. Graff suggests obtaining a baseline test (required to enable next-generation sequencing MRD monitoring), followed by testing every three to six months after starting treatment to trend the response.

To successfully implement MRD testing in the community setting, cancer care teams should designate a physician champion to lead the initiative and develop a work group that establishes not only the types of patients who would be considered for testing, but also the method of testing, the timing of testing, and which providers would order the test. One example of a best practice that encourages appropriate use of MRD testing is to incorporate it into clinical pathways that would help community providers determine when to conduct testing. Furthermore, Dr. Graff provides the example of developing an order set in her practice for the diagnostic work-up of CLL, which includes testing for various genomic aberrations, including IGHV mutational status, TP53, and chromosome 17p, among others, as well as a potential add-on for MRD.

For measurement of MRD, some oncologists prefer the clonoSEQ^® assay due to its ease of use and high sensitivity. The clonoSEQ uses next-generation sequencing to determine MRD with a typical turnaround time of 7 to 14 days for results.⁵ The test is the only FDA-cleared MRD test for CLL and other hematological cancers, and it is covered by Medicare and many private insurances. The MRD work group should help train the rest of the care team on how to implement testing, including all the logistics of performing the test, preparing the sample, and properly storing and shipping the sample. Moreover, the physician champion should educate other providers on proper interpretation of the results. With strong guidance and diligent efforts, community cancer programs can successfully integrate MRD testing into their workflow to optimize patient care.

Learn more about MRD testing in CLL by listening to Dr. Graff’s CANCER BUZZ podcast. The podcast and this blog are part of the MRD Testing Implementation Roadmaps education project funded by Adaptive Biotechnologies.

References

1. Cheson BD, Mato AR. The evolving use of minimal residual disease assessment in chronic lymphocytic leukemia. Clin Adv Hem Onc. 2020;supp 10(6):1-20. https://pubmed.ncbi.nlm.nih.gov/33843867/

2. Wierda WG, Rawstron A, Cymbalista F, et al. Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations. Leukemia. 2021;35: 3059-3072. https://www.nature.com/articles/s41375-021-01241-1

3. Pharmacy Times. Limited-duration therapy based on MRD testing. Published May 29, 2020. Accessed May 29, 2022. pharmacytimes.com/view/limited-duration-therapy-based-on-mrd-testing

4. Association of Community Cancer Centers. [PODCAST] ep 80: the promise of MRD testing in multiple myeloma & CLL. Published March 29, 2022. Accessed May 29, 2022. accc-cancer.org/home/learn/resource-detail/mini-podcast-ep-80-the-promise-of-mrd-testing-in-multiple-myeloma-cll

5. Adaptive Biotechnologies. ClonoSEQ by Adaptive. Accessed May 30, 2022. clonoseq.com