Circulating Tumor DNA Utility for Predicting Outcomes for Patients With Aggressive and Indolent Lymphomas: Real-World Analysis
Key Clinical Takeaways
- Population and Design: Retrospective real-world analysis of 148 patients with lymphoma (129 B-cell, 19 T-cell) spanning indolent and aggressive subtypes, including newly diagnosed and R/R individuals treated with CAR-T. Plasma samples were assessed using the Signatera tumor-informed 16-plex mPCR-NGS assay from 2020 to 2025, with ctDNA measured at baseline, during treatment, end-of-treatment, and throughout follow-up.
- Efficacy: Baseline ctDNA detection was high (95.7%), and ctDNA status proved strongly prognostic. Patients who remained ctDNA-positive at EOT had significantly worse event-free survival across all lymphoma subtypes. ctDNA clearance during first-line therapy was associated with markedly improved outcomes, while all patients who failed to clear ctDNA relapsed. In the CAR-T cohort, post-infusion ctDNA clearance correlated with complete responses, whereas persistent positivity predicted rapid relapse or death. A single post-CAR-T ctDNA timepoint showed 100% PPV and NPV for 12-month EFS.
- Clinical Relevance: The findings demonstrate that personalized ctDNA testing provides robust risk stratification and early relapse detection across biologically diverse lymphoma subtypes and treatment settings, including CAR-T therapy. ctDNA dynamics offer actionable prognostic information, supporting its emerging role as a valuable biomarker for disease monitoring and guiding clinical decision-making. Prospective validation is warranted to establish integration into standard lymphoma care.
At the ASH 2025 Annual Meeting & Exposition, real-world data was presented on the prognostic utility of personalized circulating tumor (ct) DNA as biomarker across indolent and aggressive subtypes of lymphoma. Investigators used the Signatera tumor-informed 16-plex mPCR-NGS assay for clinical assessment and found that ctDNA testing demonstrated strong and broad utility for risk stratification and recurrence monitoring for both aggressive and indolent disease.
“Tumor-informed ctDNA testing for detecting molecular residual disease (MRD) is seeing early adoption in this setting, demonstrating technical feasibility and clinical need for personalized monitoring tools,” Natalie Galanina, MD, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, Pennsylvania, and coauthors wrote, “However, the prognostic utility of ctDNA across indolent and aggressive subtypes of lymphoma remains poorly understood.”
Investigators explored real-world data on ctDNA detection and clearance dynamics in patients with various lymphoma subtypes, including patients who are newly diagnosed and those in the relapsed/refractory (R/R) setting receiving CAR T-cell therapy. This analysis is the largest, real-world study evaluating the utility of ctDNA across a broad spectrum of heterogeneous lymphoma subtypes in patients receiving various standard of care therapies.
The study consisted of a retrospective, real-world analysis of ctDNA testing in 148 patients with either B-cell (n=129) or T-cell lymphoma (n = 19) from September 2020 to May 2025. Among the 129 patients with B-cell lymphoma, 113 patients had aggressive subtypes (n=84 with DLBCL; n = 29 with other), and 16 had indolent lymphoma subtypes. ctDNA was analyzed using the Signatera tumor-informed 16-plex mPCR-NGS assay. Plasma samples (n=1,122; median: 7 per patient, range: 1-31) were collected at baseline, during therapy, at end-of-treatment (EOT), and during follow-up per physician’s discretion. ctDNA status at baseline and EOT, and clearance kinetics during first-line (1L) induction therapy were correlated with clinical outcomes.
The median patient age was 61 years, and the median follow-up was 18.7 months (range: 0.6 to 54.4 months). Disease stage at diagnosis was available for 139 patients: stage I (n=15, 11%), stage II (n=31, 22%), stage III (n=16, 12%), and stage IV (n=77, 55%). Stage was unknown in 9 patients. Overall, ctDNA detection at baseline was 95.7% (90/94), including 100% among patients with indolent B-cell (11/11), and T-cell lymphomas (6/6), and 94.8% (73/77) among patients with aggressive B-cell lymphomas. Across all subtypes, EOT ctDNA status was strongly prognostic for event-free survival (EFS).
Patients with ctDNA-positivity at EOT had significantly worse EFS (HR: 7.33, 95%CI, 2.8 to 19.18, P < 0.0001). In aggressive lymphomas, particularly in DLBCL, ctDNA positivity at EOT was associated with a markedly worse prognosis (Aggressive: HR: 7.69, 95% CI, 2.62 to 22.56, p=0.0002; DLBCL only: HR: 5.74, 95% CI, 1.71 to 19.23, P < 0.01). Among patients with evaluable ctDNA time points relative to 1L therapy (N=60), ctDNA clearance at any time point during treatment correlated with improved EFS. (HR, 18.55; 95%CI, 4.82 to 71.32, P < 0.0001).
All patients who did not clear ctDNA relapsed, yielding a positive predictive value of 100% (11/11). The negative predictive value for those who did clear was 88% (43/49). The remaining 6 patients turned positive during surveillance prior to relapse. Of 15 patients treated with CAR-T cell therapy, 11 had pre- and post-infusion timepoints for ctDNA analysis. Of these, 82% (9/11) were ctDNA-positive prior to CAR-T, and 55% (5/9) achieved post-infusion ctDNA clearance and a complete clinical response, though 1 became ctDNA-positive and relapsed (13.3 months post-CAR-T), and another suffered non-disease mortality (22.3 months post-CAR-T). In contrast, all 4 patients remaining ctDNA-positive post-CAR-T relapsed or died within a median of 3.3 months (range: 1.3 to 6.4 months). There were 2 patients who persistently ctDNAnegative remain disease-free. Taken together, the PPV and NPV for 12-month EFS following CAR-T therapy using a single ctDNA timepoint were both 100%.
“ctDNA status at EOT and on-treatment clearance were strong predictors of clinical outcomes across multiple histological subtypes of lymphoma treated with standard-of-care agents including CAR-T cell therapy,” Galanina and coauthors concluded. “The robustness of these findings across biologically distinct subgroups highlight the broad applicability of ctDNA testing for risk stratification and recurrence monitoring for both aggressive and indolent disease.”
“Further prospective studies are needed to validate these findings,” they added.
Source:
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. Dec 6-9, 2025; Orlando, FL. Abstract: 281
