A Viewpoints article published in The Lancet Haematology, calls for further research into the use of measurable residual disease (MRD) in hematologic malignancies. The authors specifically noted that in addition to measuring the number of cells remaining after treatment, it is also important to assess which cells remain and their potential impact on relapse.
“Although achieving the eradication of cancer cells in the form of undetectable MRD seems an attractive goal in hematology-oncology, we highlight the epistemic limitations of this biomarker and need for more clinical evidence to guide its effective use,” the authors, led by by Benjamin Chin-Yee, MD, of Western University in Canada, explained in the abstract.
Current MRD assays adopt two main strategies for detecting cancer cells. The first detects atypical immunophenotype expressed by cancer cells through the use of highly sensitive multiparameter flow cytometry; the second detects somatic anomalies found in cancer cells with more sensitive quantitative polymerase chain reaction or assays based on next-generation sequencing. The authors noted, however, that cells harboring driver somatic mutations are not necessarily cancer cells.
Combining immunophenotyping and molecular analysis is a promising option to address this concern but may still be “imperfect,” as only functional assays that measure cells’ ability to recapitulate disease can evaluate their potential to drive relapse, they wrote.
A second limitation of MRD is that it does not account for the heterogeneity of residual cancer cells, not all of which might result in relapse.
Finally, use of MRD as a predictive biomarker is largely based on a cell-centered view of cancer that could be improved by accounting for the role of nontumor cells (eg, those from the microenvironment or immune system) in disease progression.
More evidence is needed
The authors indicated that more evidence is needed to support the use of MRD for treatment decision-making. In some cancers, disease control, rather than undetectable MRD, might result in improved overall survival.
Currently, no prospective data support the benefit of early treatment of MRD-positive hematologic malignancies in terms of overall survival and quality of life, the authors noted, calling for prospective trials to randomize a strategy of MRD-adapted therapy with predefined interventions based on precise MRD thresholds versus standard of care.
“Single cell technologies (eg, DNA-seq, ATAC-seq, and RNA-seq) have the potential to track such cells in patients, and novel models (eg, organoids, or xenograft in humanized NSG mice or chicken embryos) offer future opportunities to study their functional properties,” the authors wrote.
They said MRD-based therapy would be most promising for “curative treatment” such as allogeneic hematopoietic cell transplant or chimeric antigen receptor T-cell therapy.
“When it comes to using MRD to guide treatment decisions, hematologists should remain wary of the often unquestioned assumption that accompanies MRD—that achieving deeper responses is always better, and that eradication of all detectable cancer cells should be the goal of treatment,” the authors concluded. “As we have argued, such a strategy could come with unacceptable trade-offs in terms of toxicity; harming more than helping patients.”
Reference
Chin-Yee B, Laplane L, Sujobert P. Epistemic limitations of measurable residual disease in haematological malignancies. Lancet Haematol. 2025;12(3):e224-e229. doi:10.1016/S2352-3026(25)00002-X
