Challenges in Standardizing Use of MRD Assessment in CLL

Although minimal residual disease (MRD) has emerged as a valuable prognostic marker across several hematological malignancies, its use in chronic lymphocytic leukemia (CLL) is mostly limited to clinical trials.

As minimal residual disease (MRD) continues to play an increasing prognostic role among a variety of cancers, researchers of a new review have outlined several considerations for its growing role in chronic lymphocytic leukemia (CLL).

Although MRD has emerged as a valuable prognostic marker across several hematological malignancies, being used to guide disease management, its use in CLL remains mostly limited to clinical trials, particularly for measuring efficacy in the absence of mature trial end point data.

MRD has carved out a space in CLL trials, as more recent treatments provide prolonged remissions, resulting in delayed readouts of traditional outcomes, such as progression-free and overall survival. With the increase in MRD-directed end points, challenges have arisen in determining how to integrate MRD evaluation into clinical practice, which the researchers of the present study noted will require considerations of both patient benefit and economic impact.

“Patient counseling would be crucial if and when therapeutic decisions are made based on MRD results, as negative results may give false reassurance while positive results may cause undue distress,” explained the researchers in Frontiers in Oncology. “Given that undetectable MRD can occur in the context of partial response or complete remission/incomplete count recovery, as demonstrated in CAPTIVATE (fixed duration and MRD cohorts) and FLAIR, clarification of these terms and the relationship between them need to be addressed.”

Outside of validated assays—multiparameter flow cytometry and real-time quantitative polymerase chain reaction (RQ-PCR)—techniques that have emerged as potential approaches for measuring MRD include digital droplet PCR, mass spectrometry, cell-free DNA, cytometry time-of-flight, and computational techniques.

The variety of options for measuring MRD has created a challenge in standardizing MRD, noted the researchers, with difficulties in making comparisons across trials unless the limit of detection and reporting criteria is indicated. However, even in these cases, challenges arise due to different sensitivities of the methods, explained the researchers. Choice of validated assay—multiparameter flow cytometry or RQ-PCR—typically depends on the reason for MRD monitoring and accessibility, as there are no recommendations guiding choice.

“Emerging data on DNA-based monitoring, particularly the use of next-generation sequencing (high-throughput sequencing [HTS]), suggest that increasing the depth of MRD may be beneficial for trial and clinical outcomes, although a consensus for validation of the technique is yet to be reached,” wrote the researchers. “There will also be a practical limitation of laboratory capacity (in terms of human, bench, financial, and computational resources) if MRD monitoring, particularly HTS, becomes adopted into routine practice. Computational tools could relieve some running and reporting burden for these assays but would require similar robust standardization and validation.”

Other considerations outlined by the researchers included MRD in different genomic and biologic subgroups, MRD by disease compartment, and use of MRD in fixed-duration and continuous therapy regimens. The researchers noted that it is not currently understood whether fixed-duration, continuous therapy, or MRD-based stopping rules or randomizations will be most appropriate for balancing MRD effects that correlate with favorable outcomes with adverse effects.

Questions also remain over when to assess MRD for fixed-duration treatment vs continuous therapy throughout a trial.


Fisher A, Goradia H, Matrinez-Calle N, Patten P, Munir T. The evolving use of measurable residual disease in chronic lymphocytic leukemia clinical trials. Front Oncol. Published online February 22, 2022. doi:10.3389/fonc.2023.1130617

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