Understanding ctDNA MRD Testing in Lymphoma

As lymphoma care evolves, clinicians are increasingly incorporating new tools to better understand biology. Among these, circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) testing has emerged as a promising approach to assess disease at a molecular level. But how does ctDNA MRD testing actually work, and what does it add to clinical practice?  

From Imaging to Molecular Signals 

Traditional response assessment relies on imaging, which identifies visible or metabolically active disease.¹ In contrast, ctDNA MRD testing detects tumor-derived genetic material circulating in the blood, providing fundamentally different information.² Rather than asking, “Can we see disease?”, ctDNA asks, “Is there molecular evidence that disease is still present?” This distinction is important. ctDNA reflects tumor biology, directly capturing signals that may not yet translate into radiographic findings.¹  

What Is ctDNA and How Does MRD Testing Work? 

ctDNA consists of small fragments of tumor-derived DNA that circulate in the bloodstream, released as tumor cells undergo apoptosis or necrosis.² These fragments carry the same mutations found in the original tumor. Because ctDNA can be measured from a blood sample, it enables noninvasive, repeatable assessment over time, often referred to as a “liquid biopsy.”¹  

Most ctDNA MRD assays are tumor-informed, meaning they are personalized to each patient.³ This approach begins by sequencing a patient’s tumor to identify a unique set of mutations often referred to as a “molecular fingerprint."² A personalized assay is then designed to track these mutations over time. During treatment and follow-up, blood samples are analyzed using high-depth next-generation sequencing (NGS).¹ Detection of tumor-specific variants indicates the presence of residual disease and corresponds to MRD positivity. If not, it suggests a deeper level of response. This approach allows clinicians to move beyond a single snapshot and instead follow how the disease changes over time.¹   

Clinical Relevance Across the Treatment Continuum 

One of the defining features of ctDNA is its dynamic behavior as a biomarker. During treatment, ctDNA levels often decline as tumor burden decreases.¹ Early clearance may signal a favorable response. Persistent or rising levels may indicate residual disease. This dynamic nature provides insight into treatment response kinetics, which can be difficult to capture with imaging alone.^1,4  

ctDNA MRD testing has potential utility at multiple timepoints: 

• Early in treatment: May give an early indication of response by providing insight into treatment response well before imaging changes are apparent.¹  

• End of treatment: Helps interpret depth of remission by distinguishing between patients with true molecular clearance and those with residual disease that may not be apparent on imaging.¹  

• Post-treatment surveillance: May detect molecular relapse before clinical or radiographic progression, creating a potential window for earlier intervention.¹  

These use cases reflect a broader shift toward longitudinal monitoring, in which disease is assessed continuously rather than at isolated time points. 

From Prognostic Tool to Clinical Decision Support 

ctDNA MRD testing is rapidly evolving from a purely prognostic biomarker to a tool with real clinical utility. Increasingly, MRD status is being used to:  

• Refine risk stratification beyond traditional clinical indices¹  

• Identify high-risk patients despite complete metabolic response¹  

• Inform response-adapted treatment strategies¹  

• Guide surveillance and earlier intervention¹  

Despite its promise, ctDNA MRD testing has limitations. Sensitivity can be affected by tumor biology, as some lymphomas shed relatively little DNA into circulation.⁵ Detection may also be challenging at very low disease burdens, highlighting the need for continued improvements in assay sensitivity.³ Additionally, ctDNA levels can vary depending on timing of sample collection relative to treatment, and optimal testing intervals are still being defined.^1,5 

As clinical evidence continues to mature, MRD-guided strategies—including treatment escalation, de-escalation, and early intervention—are likely to play a growing role in patient management. Ultimately, integrating molecular response assessment alongside imaging has the potential to fundamentally reshape how clinicians define remission, monitor disease, and personalize therapy in lymphoma.  

1. Zhang S, Wang X, Yang Z, et al. Minimal residual disease detection in lymphoma: methods, procedures and clinical significance. Front Immunol. 2024;15:1430070. doi:10.3389/fimmu.2024.1430070 

2. Herrera AF, Armand P. Minimal residual disease assessment in lymphoma: methods and applications. J Clin Oncol. 2017;35(34):3877-3887. doi:10.1200/JCO.2017.74.5281  

3. Semenkovich NP, Szymanski JJ, Earland N, et al. Genomic approaches to cancer and minimal residual disease detection using circulating tumor DNA. J Immunother Cancer. 2023;11:e006284. doi:10.1136/jitc-2022-006284 

4. Atout M, Elwaheidi H, Maarouf R, et al. Minimal residual disease testing for diffuse large B cell lymphoma. Clin Lymphoma Myeloma Leuk. 2025;25(10):e750-e755. doi:10.1016/j.clml.2025.05.003 

5. Larribère L, Martens UM. Advantages and challenges of using ctDNA NGS to assess the presence of minimal residual disease (MRD) in solid tumors. Cancers (Basel). 2021;13(22):5698. doi:10.3390/cancers13225698