Measurable residual disease (MRD; also known as minimal residual disease) assessment and status currently has no clear role in routine clinical practice but watch this space.

Writing in Hematology and Oncology Clinics of North America, Melbourne’s Professor John Seymour and international colleagues questioned whether undetectable MRD (U-MRD) should be the goal of CLL therapy.

They noted MRD outcomes vary depending on the therapy – having high prognostic value with chemotherapy, chemoimmunotherapy, ASCT and CAR T-cell therapy but more limited value with targeted agents.

“Currently, there is no consensus on how to use MRD as a tool for clinical decision-making,” they said.

However some of the challenges are being gradually dealt with.

An international, multidisciplinary, 174-member panel of experts – including Sydney haematologists Professor Stephen Mulligan and Dr Xavier Badoux – has achieved consensus on many issues regarding the use of MRD in CLL.

Their review and consensus, published in Leukemia, includes preferred nomenclature for reporting MRD and validated methods of MRD detection which underpins globally reproducible results.

Some of their other recommendations include:

• MRD status should be assessed in both peripheral blood (PB) and bone marrow (BM) in clinical trials aimed at disease eradication. If MRD is detected in blood, no BM aspiration is needed. However unmeasurable-MRD in the PB calls for BM aspiration for confirmatory purposes in regimens where a relevant discrepancy between PB and BM exists.
• For fixed-duration therapies, MRD testing should be aligned with response assessment, at least 2 months after completion of the last treatment. For continuous treatment, MRD status should be tested when best clinical response has been achieved.
• The relationship between clinical response (i.e., iwCLL response) and end-of-treatment MRD status requires clarification and should be evaluated in a treatment-specific context.
• Clinical trials of defined-duration CLL treatments should assess MRD at least 2 months after the last treatment cycle is completed for correlation with PFS and OS.
• Factors associated with achieving U-MRD should be identified for each agent/regimen. Collaborative efforts are important for elucidating MRD biology for emerging therapies and correlations with outcomes.
• Serial MRD testing is not indicated in routine practice; MRD relapse currently has no impact on treatment decisions for standard of care. We propose that it be defined as detectable MRD (>10−4) on at least two consecutive timepoints in PB.
• In clinical trials, MRD may be explored for modifying treatment duration or for determining whether switching treatment strategies may be beneficial. To transition MRD assessment from trials into routine clinical practice, however, data demonstrating that such modifications lead to improved outcomes are needed.

Professor Seymour and colleagues said MRD is a highly informative surrogate that has allowed better understanding of the disease characteristics and kinetics of CLL.

The goal of individual optimisation of treatment strategies such as duration or intensity of treatment was already being demonstrated in clinical trials, they said.

“Further research is necessary to identify which patients not only have the deepest, but also the most stable remissions, and which patients are at risk of either not achieving uMRD or losing MRD response. This knowledge will eventually translate into more individualised and effective treatment algorithms for patients with CLL,” they concluded.

Professor Mulligan, from the Royal North Shore Hospital, told the limbic MRD was clearly important but there were different ways of looking at it.

“Basically should it be an aim of therapy or is it basically just an outcome for the lucky people who have got genetically favourable disease? My overwhelming opinion is that it is the latter.”

“It’s a marker and a monitorable manifestation of the disease that confirms that a patient has got a very good outcome with their disease.”

He said most patients with mutated IgHV and FCR treatment want to know if they are relapsing early.

“The ones that are often still take 3, 4, 5, 6 even out to 8 years before they actually need retreatment. But if you get out to 8 years of MRD negativity, then your chances of relapsing are essentially approaching zero.”

“It’s a kind of similar formula with venetoclax. If you relatively quickly get into MRD negativity then the evidence we have got at the moment is those patients are going to do really well.”

“And with ibrutinib MRD is completely irrelevant. Essentially what is critically important with ibrutinib and B cell receptor antagonists is clinical disease control and absence of adenopathy, absence of hepatosplenomegaly, absence of symptoms, a near normal bone marrow, and essentially a stable lymphocyte count and a stable low-ish clone.”

“At the end of the day in CLL it is still predominantly clinical manifestations that tend to dictate disease progression and most certainly time to implementation of second and next line therapy.”