For venetoclax, MRD is “also a vehicle to allow for discontinuation of therapy,” Dr Mato said. “For example, ven patients who achieve undetectable disease who are treated with a time-limited approach are the ones who tend to have the best outcomes, and so it should be our goal.”

With the advent of BTK inhibitors, though, undetectable MRD may not always be the goal when it comes to CLL management, Dr Mato said.

“Prior to BTK inhibitors, a general rule of thumb was deeper remissions with chemotherapy or chemoimmunotherapy, or even stem cell transplantation, translates into more durable remissions for patients,” Dr Mato said. “The same is also true for venetoclax-based therapies. The exception to the rules appears to be [with] the BTK inhibitor monotherapies, which are able to control disease for long periods of time with a very low expectation of attaining undetectable residual disease.”

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Traditionally, MRD has been assessed with bone marrow. But “liquid biopsies” are increasingly in use, measuring peripheral blood samples instead. 

“Current methodologies show concordance between the peripheral blood bone marrow compartments leading to situations where patients don’t have to undergo procedures that they don’t necessarily want to undergo to obtain this information,” Dr Mato said. “And what patient really wants to have a bone marrow biopsy?”

Importantly, traditional flow cytometry is not the same as MRD, Dr Mato emphasized. “Sending flow cytometry on a peripheral blood or a bone marrow sample that doesn’t achieve a sensitivity of least 10-4 or greater is actually doing a patient a disservice because you may make decisions based on a sample that’s not adequately sensitive, for example, at 10-2. And it is very easy for that to happen if one is not familiar with the sensitivity of the flow cytometry assay. Particularly if in-house flow cytometry may not be geared towards MRD assessment. So [it’s] very important to know what you’re ordering — that it truly is an MRD assay — before ordering that test.”

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As methodologies advance and proliferate, standardization can also become an issue, Dr Mato cautioned. “Flow cytometry and the clonoSEQ® assay are often used on studies and sometimes in clinical practice. Flow is already standardized as per ERIC consensus criteria; clonoSEQ is analyzed centrally and is therefore standardized, but in general, we do not have consensus on standards for NGS,” he explained. “I think there needs to be more of a debate about the specifics on methodology requirements for depth of remission and which compartment needs to be used as a standardization across clinical practice in clinical trials.”

There is not yet “absolute consensus” about the answers, Dr Mato acknowledged. “And that can sometimes lead to some confusion.” Nor do commercial labs necessarily offer better MRD tests using flow cytometry than in house labs, he added.