Clinical Applications of ctDNA MRD Testing in Lymphoma

As lymphoma care becomes increasingly personalized, clinicians are being asked to make more nuanced decisions—particularly after frontline therapy. The question is no longer just whether a patient has responded, but how confidently we can define remission and predict what comes next. 

Circulating tumor DNA (ctDNA)–based molecular residual disease (MRD) testing is emerging as a practical tool to help answer those questions. While initially studied as a prognostic biomarker, its role is rapidly expanding into everyday clinical decision-making.¹   

Why ctDNA MRD Testing Is Clinically Relevant 

The clinical rationale for MRD testing is straightforward: a subset of patients who achieve complete response on imaging still relapse, reflecting disease that remains below the threshold of detection.² ctDNA MRD testing addresses this gap by providing a tumor-specific, molecular readout of residual disease.¹  

Importantly, MRD status offers risk-stratification insight that is independent of traditional PET imaging results.² Studies have shown that ctDNA detection after therapy is strongly associated with inferior outcomes, even when accounting for clinical indices such as stage or IPI.³ This makes MRD a valuable tool for refining risk beyond what is currently captured in routine practice. 

Evidence Supporting Clinical Use 

A growing body of data supports the clinical utility of ctDNA MRD testing across key decision points. 

At end of treatment (EOT), MRD status has demonstrated strong prognostic value.² Patients with detectable ctDNA have significantly worse progression-free survival compared with those who achieve molecular clearance.² Multiple studies have shown that ctDNA has outperformed conventional imaging in predicting outcomes, highlighting its ability to more accurately reflect underlying disease biology.^4,5  

Real-world data further reinforce these findings. ctDNA dynamics—particularly early clearance during therapy—have been associated with improved outcomes, while persistent detection signals a higher risk of relapse.⁴ Additionally, ctDNA monitoring has been shown to detect relapse earlier than imaging, often by several months, providing a potential window for intervention before clinical deterioration.⁵ 

Taken together, these data support ctDNA MRD as both a prognostic and predictive biomarker, with increasing relevance for guiding clinical decisions. 

Building Confidence in Clinical Use 

For clinicians, the key value of ctDNA MRD testing lies in its ability to provide actionable clarity.¹ It complements imaging by adding a biologically specific signal, helping to distinguish true residual disease from treatment-related effects.  

While ongoing studies will continue to refine how best to act on MRD results, current evidence supports its role in: 

• Improving risk stratification¹  

• Informing treatment decisions¹  

• Enabling earlier intervention⁶  

Guidelines and Practical Considerations 

The shift toward MRD-informed care is already reflected in clinical guidance. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-cell lymphomas recommend consideration of ctDNA MRD testing as an alternative to biopsy in patients with PET-positive findings at the end of treatment.⁷ NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.  

This recommendation underscores a broader transition: MRD testing is no longer viewed solely as a research tool, but as a clinically relevant adjunct that can enhance existing workflows. 

From a practical standpoint, ctDNA testing offers several advantages—it is minimally invasive, repeatable, and adaptable to longitudinal monitoring.¹ These features make it particularly well-suited for integration into routine practice without adding significant burden to patients or providers. 

ctDNA MRD testing is moving beyond research and into clinical practice. By providing a more precise, real-time assessment of disease, it offers clinicians a powerful tool to guide decisions with greater confidence. 

As adoption increases, the focus will shift from whether to use MRD testing to how best to integrate it into routine care—ultimately advancing a more personalized approach to lymphoma management. 

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. Roschewski M, Kurtz DM, Westin JR, et al. Remission assessment by circulating tumor DNA in large B-cell lymphoma. J Clin Oncol. 2025;43(34):3652-3661. doi:10.1200/JCO-25-01534  

3. Goldstein JS, Roschewski M, Kim WS, et al. Baseline prognostic factors do not predict end of treatment ctDNA MRD status and have limited impact on MRD prognostic performance in DLBCL. Presented at: American Society of Hematology (ASH) Annual Meeting; 2024. 

4. Galanina N, Iqbal M, Nousome D, et al. Real-world evaluation of ctDNA for risk stratification across the spectrum of both aggressive and indolent lymphomas. Presented at: American Society of Hematology (ASH) Annual Meeting; December 2025; Orlando, FL. 

5. Narkhede M, Tomassetti S, Iqbal M, et al. Tumor-informed ctDNA assessment as a valuable prognostic and predictive biomarker in diffuse large B-cell lymphoma. Front Oncol. 2024;14:1407003. doi:10.3389/fonc.2024.1407003  

6. 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  

7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer v.5.2026 © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed April 14, 2026. To view the most recent and complete version of the guideline, go online to NCCN.org