Liquid Biopsy in Lymphoma

Liquid Biopsy in Hematological Malignancies: A Growing Opportunity

Liquid biopsy refers to the detection of tumor-derived genetic material—primarily ctDNA—in body fluids, most commonly blood. In hematological malignancies, this technique holds promise for disease characterization, monitoring, and therapeutic decision-making without the need for repeated invasive procedures.

Compared to standard methods such as lymph node excision or bone marrow aspiration, liquid biopsy is less burdensome for patients and allows for serial sampling over time. This opens the door to dynamic disease tracking, which is critical in fast-evolving conditions like lymphoma. Furthermore, ctDNA levels have been shown to correlate with tumor burden and treatment response, and in some subtypes, offer earlier signals of relapse than imaging alone ^(1,2).

As technologies improve and data accumulates, liquid biopsy is increasingly being positioned not just as a research tool but as a clinically actionable adjunct in lymphoma care.

Clinical Applications in Lymphoma

In clinical practice, liquid biopsy is being increasingly explored in the management of B-cell lymphomas, particularly diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. In addition, ctDNA assays are in use in clinical practice for both response assessment and disease surveillance in these subtypes, where they complement—but do not replace—conventional imaging.

Studies have demonstrated that ctDNA dynamics—such as early molecular response or persistent ctDNA after initial therapy—can offer prognostic value beyond conventional imaging ^(2,3). In particular, liquid biopsy may aid in distinguishing true progression from post-treatment inflammation, reducing the risk of overtreatment or unnecessary biopsies.

In DLBCL, ctDNA clearance within the first few treatment cycles has been associated with superior progression-free survival, suggesting its potential use as an early surrogate marker ⁽²⁾. Similarly, in follicular lymphoma, ctDNA levels can help monitor transformation risk and detect molecular relapse before clinical symptoms emerge ⁽³⁾.

Serial monitoring is particularly valuable. Liquid biopsy is being used to track disease evolution across cycles, offering clinicians a dynamic view of response over time. This supports timely decision-making and enhances confidence in treatment continuation or escalation when imaging is ambiguous.

There is also growing interest in applying liquid biopsy to peripheral T-cell lymphoma (PTCL), a rare and clinically challenging group of lymphomas with limited treatment options and poor outcomes. Recognizing the urgent need for better monitoring tools in PTCL, a dedicated project is currently underway at START Madrid-FJD to develop and validate ctDNA panels specific to T-cell subtypes. These efforts aim to improve early response assessment and disease surveillance in a patient population that often lacks reliable biomarkers. By tailoring liquid biopsy applications to the molecular characteristics of PTCL, clinicians hope to enable earlier interventions and more precise treatment adaptation.

Although laboratory workflows sometimes result in delayed reporting due to sample batching, the clinical value of liquid biopsy remains clear—especially when paired with imaging for a more comprehensive assessment. As experience builds, these insights are shaping a more refined and proactive approach to lymphoma care across both B-cell and T-cell subtypes.

Use in Clinical Trials

While liquid biopsy is gaining traction in clinical practice, its integration into clinical trial design has lagged behind its potential. Many ongoing lymphoma trials include liquid biopsy as an exploratory endpoint, but ctDNA results are often used retrospectively rather than to guide real-time decision-making.

In most clinical trials, ctDNA data is typically collected, processed centrally, and reported back weeks later—well after key therapeutic decisions have already been made. This time lag limits the clinical utility of liquid biopsy within the trial context and misses opportunities to adapt treatment based on early molecular response. Nevertheless, its use in late-phase clinical trials is steadily increasing, with ctDNA beginning to inform treatment-driven decisions, marking a shift from retrospective analysis toward prospective clinical relevance.

An ideal trial design would incorporate liquid biopsy into predefined decision points—such as escalation or de-escalation of therapy based on ctDNA clearance. Adaptive trial frameworks that integrate molecular response as a trigger for randomisation or treatment change could improve precision and accelerate outcomes ⁽²⁾.

Moreover, liquid biopsy could aid in patient stratification, identifying high-risk molecular signatures that warrant alternative therapeutic approaches from the outset ⁽¹⁾. Used this way, ctDNA would not only be a tool for monitoring but a lever for real-time personalisation.

These possibilities are increasingly supported by emerging trial data, yet adoption remains slow. For broader implementation, sponsors must be willing to invest in faster laboratory workflows, decentralised testing models, and standardised interpretation protocols ⁽³⁾. As feedback from trial centers accumulates, there is growing recognition that liquid biopsy should evolve from a passive data collector to an active driver of trial decisions.

Clinical Decision-Making and the Case for Broader Adoption

Liquid biopsy has the potential to transform how clinicians evaluate remission, progression, and therapeutic response in lymphoma. One area of particular interest is its role in guiding treatment de-escalation. For patients who achieve ctDNA-negative remission, there may be an opportunity to reduce or avoid further cycles of chemotherapy or radiation, thereby minimising toxicity without compromising outcomes.

This concept mirrors the use of MRD as a decision-making tool in multiple myeloma and other hematologic malignancies. In lymphoma, especially for patients with deep metabolic responses on PET, ctDNA negativity could serve as an added layer of reassurance before scaling back therapy. Conversely, rising ctDNA levels may signal molecular relapse ahead of radiological evidence, enabling earlier intervention.

Clinicians are already exploring such scenarios, using liquid biopsy results to support or challenge treatment continuation in ambiguous cases. These insights help refine decisions in real-time, especially when imaging alone leaves clinical uncertainty. Importantly, liquid biopsy does not replace standard modalities but adds molecular precision to existing tools.

Broader adoption will likely depend on further validation of ctDNA thresholds, greater availability of rapid testing workflows, and integration into clinical guidelines. As use cases expand across lymphoma subtypes, liquid biopsy may evolve from an adjunct into a routine decision-support tool in frontline and relapsed/refractory settings alike.

Challenges to Implementation

Despite promising clinical applications, several barriers continue to limit the widespread integration of liquid biopsy into routine lymphoma care.

One major challenge is the lack of standardised gene panels and reporting thresholds. Currently, most hospitals and institutions develop in-house assays, leading to variability in test design and interpretation. This lack of harmonisation complicates data comparison across centers and hampers efforts to generate universally accepted clinical guidelines ⁽¹⁾.

In addition, operational logistics remain a hurdle. Due to batching requirements for cost-efficiency, turnaround times are often delayed, reducing the value of liquid biopsy for real-time clinical decision-making. This issue is particularly relevant in public health systems where reimbursement policies may not yet accommodate regular testing required for serial monitoring.

There is also a need for more consensus on what constitutes a clinically meaningful ctDNA signal. Without agreed-upon cutoffs for positivity, clinicians are left to interpret results in relative terms, which introduces subjectivity into treatment decisions.

Addressing these barriers will require multi-institutional collaboration, technical standardisation, and policy engagement. Initiatives such as the development of standardised panels for broader use (e.g., EuroClonality-NDC), which aim to align assay design, validation, and reporting practices across institutions, represent critical steps toward widespread clinical implementation.

Outlook and Conclusion

The promise of liquid biopsy in lymphoma is no longer theoretical. Its applications—from molecular monitoring and risk stratification to clinical trial design—are already demonstrating value in real-world settings. Ongoing work is helping to define best practices and uncover use cases that go beyond conventional endpoints.

Looking ahead, broader adoption will depend on standardisation, accessibility, and scale. As assay technology matures and costs decline, ctDNA testing could become a routine part of lymphoma management and in clinical trials to determine treatment endpoints, much like PET imaging or lymph node biopsies today. However, realising this vision will require coordinated efforts across oncologists, pathologists, regulators, and payers.

Crucially, liquid biopsy must be viewed not as a replacement but as a complementary layer of decision-making—one that brings molecular precision to the art of oncology. With the right infrastructure and frameworks, it has the potential to redefine remission, personalise therapy, and ultimately improve outcomes for patients with lymphoma.

References

1. Talotta D, Almasri M, Cosentino C, Gaidano G and Moia R (2023). Liquid biopsy in hematological malignancies: current and future applications. Front. Oncol. 13:1164517. doi: 10.3389/fonc.2023.1164517
2.  Jacqueline V. Aredo et al. Liquid Biopsy Approaches for Cancer Characterisation, Residual Disease Detection, and Therapy Monitoring. Am Soc Clin Oncol Educ Book 45, e481114(2025). doi:10.1200/EDBK-25-481114
3. Jamal E, Poynton E, Elbogdady M, Shamaa S, Okosun J. Prospects for liquid biopsy approaches in lymphomas. Leuk Lymphoma. 2024;65(13):1923-1933. doi:10.1080/10428194.2024.2389210

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