iwCLL 2025 | MRD in CLL: technical aspects and clinical significance

MRD generally is a persistence of malignancy below the limit of detection of conventional morphological methods and during this presentation I tried to explain that the concept of MRD, how it can be used for instance for MRD-driven strategies and also to give some technical aspects about the main methods. And these methods are multi-parameter flow cytometry, which is the most accessible method in routine practice, but it has a little less, it is a little less sensitive than other methods; here the threshold is 10 to the minus 4 or MRD4, but it is the best suited now for routine clinical practice. The other two methods are ASO RQ-PCR, allele-specific oligonucleotide RQ-PCR, and next-generation sequencing. ASO RQ-PCR is very labor-intensive and time-consuming, so it is mostly used in the clinical research setting, but NGS is the most sensitive up to MRD6, and it can be used in routine practice, but it’s not universally available at the moment. 

So the main problem with MRD assessment, or one of the problems, is that there is no single universal method for all applications; it needs to be tailored to specific research or clinical objectives. There are other issues like the effect of the CLL compartment; so we measure MRD only in the bone marrow and peripheral blood, while the cells can also reside in the lymph node compartment or spleen. There is an issue of high-risk genetics, so the interpretation is different with different treatments in the patients with mutated and unmutated IGHV status. And most importantly, MRD maybe should be interpreted differently with different CLL therapies. So it is prognostic for past chemoimmunotherapy, and nowadays used fixed-duration venetoclax-based regimen, but unfortunately, it is not prognostic with continuous treatment with Bruton’s tyrosine kinase inhibitors, and it complicates the use in clinical practice. 

So for now, MRD is recognized as an important predictor of such outcomes like progression-free survival, overall survival, by all international guidelines, including iwCLL guidelines. Regulatory agencies provided documents on the use of MRD as a surrogate endpoint in clinical studies, but it is not recommended to be used in clinical practice yet.

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