“There are nuances associated with MRD about knowing what the original clone looked like in terms of cell surface markers, making sure that you’re following the appropriate markers, so it’s not just commercial,” he said. “But there are certainly, in all the regions of the country, commercial labs that do offer MRD testing by flow cytometry for patients.”

When asked why prospective validation studies of MRD haven’t already been undertaken to translate assessment strategies into clinical practice, Dr Mato replied that clinical advances happen incrementally — but also that such studies are now under way, such as the international, multicohort, phase 2 CAPTIVATE trial (ClinicalTrials.gov Identifier: NCT02910583).

The CAPTIVATE study, which is ongoing but has stopped recruiting new patients, is assessing ibrutinib plus venetoclax in treatment-naive patients with CLL and small lymphocytic lymphoma.


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Previous research rarely included MRD as a patient-randomization criterion or decision point. “CAPTIVATE is one of the most heavily accrued trials where there’s a decision point based on MRD,” Dr Mato noted.

“The first step was learning that the novel agents can produce undetectable MRD,” Dr Mato explained. “And then the second is trying to understand if MRD predicts for better outcomes. The third is trying to decide whether or not patients can stop a treatment based on depth of remission.”

These incremental steps in translation to the clinic can be frustrating, Dr Mato acknowledged. “But it probably would be irresponsible to conduct trials just assuming MRD is the appropriate surrogate endpoint before that’s actually validated. So now that validation really has been under way across many novel agents and, previously, chemotherapy-based clinical trials, there is a reasonable research question to now explore MRD as a primary endpoint for studies in CLL.”

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And, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) both appear to support that approach, he said.

Most current-era studies use all of the available MRD assessment methodologies, which might prove helpful in sorting out which tests are most predictive of patient outcomes with different treatment regimens, he noted.

Regardless of the test used, MRD assessment is likely to become a routine component of clinical decision making in the next few years, Dr Mato predicted.

“I would argue, while it’s not yet the standard of care, it certainly has a very important prognostic value to consider at the end of therapy,” he explained. “It may have particular importance for younger patients where you’re thinking about consolidation instead of other therapies.”

*Editor’s note: This article was updated on 2/28/20 to correct some of Dr Mato’s statements and to clarify some of the supporting copy.

Disclosure: Dr Mato recently reported the receipt of personal grants and fees from Adaptive Biotechnologies, the maker of the ClonoSEQ assay, and Pharmacyclics LLC, which is the sponsor of the trial he mentioned.

References

  1. Lew TE, Anderson MA, Lin VS, et al. Undetectable peripheral blood MRD should be the goal of venetoclax in CLL, but attainment plateaus after 24 months. Blood Adv. 2020;4(1):165-173.
  2. Thompson M, Brander D, Nabhan C, Mato A. Minimal residual disease in chronic lymphocytic leukemia in the era of novel agents: a review. JAMA Oncol. 2018;4(3):394-400.
  3. Del Giudice I, Raponi S, Starza ID, et al. Minimal Residual Disease in Chronic Lymphocytic Leukemia: A New Goal? Front Oncol. 2019;9:689.
  4. Thompson PA, Srivastava J, Peterson C, et al. Minimal residual disease undetectable by next-generation sequencing predicts improved outcome in CLL after chemoimmunotherapy. Blood. 2019;134(22):1951-1959.