The presence of circulating tumor DNA (ctDNA) at end of treatment (EOT) was shown to be prognostic of event-free survival (EFS) outcomes for patients with lymphoma regardless of subtype, according to findings from a retrospective, real-world analysis presented at the 2025 ASH Annual Meeting and Exposition.1
Findings showed that the median EFS was not achieved (NA) in the ctDNA minimal residual disease (MRD)–negative group (n = 49) vs 1.97 months in the ctDNA-MRD-positive group (n = 19; adjusted HR, 22.43; 95% CI, 6.76-74.45; P < .0001). The 12- and 24-month HRs in the ctDNA-MRD-negative population were 0.83 (95% CI, 0.71-0.98) and 0.79 (95% CI, 0.64-0.96), respectively. The respective HRs in the ctDNA-MRD-positive population were 0.05 (95% CI, 0.01-0.35) and 0.00 (95% CI, NA-NA), respectively.
“EOT ctDNA status can clarify ambiguous imaging results and enables earlier relapse detection,” Natalie Galanina, MD, lead study author and clinician investigator at UPMC Hillman Cancer Center in Pittsburgh, Pennsylvania, stated in during the presentation. “ctDNA kinetics offer real-time insights into treatment response during first-line therapy and can further predict response to CAR T-cell treatment,” she added.
Topline Findings From the Real-World Study
- EOT ctDNA-MRD status was a strong prognostic indicator, with MRD negativity linked with significantly longer EFS across lymphoma subtypes.
- ctDNA outperformed PET-CT in detecting residual disease and the likelihood of subsequent relapse.
- Early or delayed ctDNA clearance was associated with improved EFS outcomes, supporting ctDNA’s role in routine management and surveillance.
What served as the foundation for this study?
Personalized, tumor-informed ctDNA assays have shown the ability to capture prognostic and predictive information in diffuse large B-cell lymphoma (DLBCL), but its prognostic capability has been understudied in diverse subsets of lymphoma.2
To bridge that gap, investigators prospectively collected real-world data of MRD detection and ctDNA clearance kinetics in patients with newly diagnosed or relapsed/refractory lymphoma across 14 subtypes.1
“[Signatera is a] personalized tumor-informed assay, where both the tumor and a source of matched normal [tissue] is sequenced, either by whole exome or whole-genome sequencing. Based on the somatic mutation profile of a patient, a custom patient-specific assay is designed to track ctDNA in the plasma. This makes the test ultrasensitive while maintaining extremely high specificity,” Galanina said.
How was the trial designed to answer how ctDNA can be applied in various lymphomas?
The schema was such that 1105 prospectively collected plasma samples from 144 patients with lymphoma were subject to ctDNA assessment. Samples included aggressive (n = 123) T-cell (n = 13) and B-cell (n = 110) lymphomas, as well as indolent (n = 21) follicular (n = 10), marginal zone (n = 5), and cutaneous T-cell lymphoma (n = 6).
The demographics of the patient cohort were representative of the real-world population, Galanina said. The median age was 61 years (range, 18-84) and most patients were male (n = 77; 53%). Most patients had stage IV disease (n = 75; 56%), although those with stage I (n = 15; 11%), II (n = 29; 21%), and III (n = 16; 12%) were also included. ECOG performance status was predominantly 0 (n = 50; 46%), followed by 1 (n = 35; 32%), 2 (n = 16; 15%), 3 (n = 6; 5.6%), and 4 (n = 1; 0.9%). Revised International Prognostic Index score fell between 0 and 2 in 25.2% (n = 31) of patients and between 3 and 5 in 26.8% (n = 33) of patients; 80 scores were not reported.
With respect to therapy, patients reported receiving Pola-R-CHP (n = 6; 4.3%), R-CHOP (n = 72; 51%), R-EPOCH (n = 14; 10%), other rituximab (Rituxan; n = 17; 12%), and other (n = 31; 22%).
The median number of ctDNA MRD timepoints was 7 (range, 1-32). Median follow-up for EFS and overall survival (OS) was 20 (range, 1-108) and 21 (range, 1-108) months, respectively.
Pretreatment ctDNA was detectable in 94% of patients with lymphoma. “The median number of tumor molecules per mL was about 100 in aggressive and about 20 in indolent lymphomas, respectively, which may reflect differences in circulating tumor burden,” Galanina stated.
What else was reported on with respect to ctDNA’s validity as a prognostic tool?
Additional data revealed that ctDNA provided a better indication for treatment response than traditional imaging. Patients who had a negative PET-CT at EOT (n = 35) experienced a median EFS that was NA vs 5.16 months in those whose PET-CT was positive at EOT (n = 25; adjusted HR, 8.68; 95% CI, 2.41-31.29; P = .0010). Conversely, patients who had negative ctDNA-MRD at EOT (n = 44) experienced a median EFS that was NA vs 2.04 months in those who had positive ctDNA-MRD at EOT (n = 16; adjusted HR, 49.77; 95% CI, 9.91-250.02; P < .0001).
Furthermore, PET-negative patients with negative ctDNA-MRD (n = 32) had a median EFS that was NA vs 2.76 months in those with positive ctDNA-MRD (n = 3; HR, 45.29; 95% CI, 4.63-443.27; P = .0011). PET-positive patients with negative ctDNA-MRD (n = 12) had a median EFS that was NA vs 1.97 months in those with positive ctDNA-MRD (n = 13; HR, 12.26; 95% CI, 3.23-46.59; P = .0002).
“The clinical significance of this result is that EOD PET-positive patients present a significant clinical challenge, and most of them ultimately proceed to receive additional therapy. However, although the patient numbers are small, our data clearly show that the majority or 75% of PET-positive MRD-negative patients do not progress, and therefore may not require any additional therapy,” Galanina said. “Based on this, it is reasonable to integrate ctDNA as an adjunct to EOT assessment to help further risk stratify patients who are likely to relapse vs those who remain disease free.”
“For patients who are EOD PET negative, if they are ctDNA positive, this may inform post treatment surveillance, as these patients may need to be monitored more closely, and patients who are PET positive, if they’re MRD negative, may be appropriate candidates for observation only, or at the very least require pathologic confirmation of the PET-positive lesions to rule out the non-etiology of the FDG uptake, as those patients have generally good outcomes,” Galanina added.
In multi-variable analysis investigators demonstrated that ctDNA was the most significant predictor of EFS after correcting for all other factors, including age, tumor histology, and stage (P < .001).
ctDNA clearance during frontline therapy was also shown to be prognostic of outcomes in all lymphoma subtypes. The median EFS was NA in patients who cleared their ctDNA (n = 48) vs 2.05 months in those who did not (n = 12; adjusted HR, 8.57; 95% CI, 2.55-28.81; P = .0005). Moreover, the median EFS was NA, NA, and 2.05 months in patients with cycle 1 clearance (n = 14), delayed clearance (n = 34), and no clearance, respectively. The adjusted HRs for patients without clearance vs those with cycle 1 clearance and delayed clearance were 20.95 (95% CI, 2.09-21.11; P = .0097) and 7.45 (95% CI, 2.22-24.98; P = .0011), respectively.
“Early clearance by cycle 1 may have significant implications for potential de-escalation of therapy, especially for older patients and those with comorbidities,” Galanina explained.
Can ctDNA be used to predict response to CAR T-cell therapy?
“Lastly, we also looked at ctDNA clearance in patients undergoing CAR T-cell therapy [and we found that] ctDNA clearance retains its predictive value in this setting as well. Most MRD-positive patients who cleared ctDNA within 3 months post CAR T attained durable remission at 1 year. There was one patient who became ctDNA negative 1 month post CAR T, but then relapsed more than 1 year after, and this patient turned positive prior to recurrence. This suggests that single time point measurement post CAR T may not be sufficient, and longitudinal testing at various time intervals for several years of follow-up may be more optimal to detect patients who may relapse,” Galanina stated.
“MRD assessment supports the integration of ctDNA testing into routine clinical management and surveillance to personalize lymphoma care,” Galanina said in conclusion.
Disclosures: Galanina had no financial relationships to disclose.
References
- 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. Blood. 2025;146(suppl 1):281. doi:10.1182/blood-2025-281
- 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. Published online July 29, 2024. doi:10.3389/fonc.2024.1407003
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