Signatera ctDNA Test Shows Superior MRD Assessment in Lymphoma

Data from a prospective, real-world cohort demonstrated that tumor-informed circulating tumor DNA (ctDNA) testing with the Signatera assay was a stronger prognostic and predictive biomarker than standard PET/CT imaging for molecular residual disease (MRD) assessment across B- and T-cell lymphoma subtypes, according to findings published in Blood Neoplasia.¹ The study, reported as the largest to evaluate ctDNA testing, ctDNA-MRD detection, and ctDNA clearance dynamics in newly diagnosed and relapsed/refractory lymphoma, enrolled 144 patients with newly diagnosed or relapsed/refractory lymphoma and analyzed 1142 plasma samples collected serially from baseline through posttreatment surveillance.

What were the key efficacy findings from the Signatera lymphoma study?

Pretreatment ctDNA was detectable in 92% of evaluable patients across aggressive and indolent subtypes. The end-of-treatment (EOT) ctDNA-MRD positivity was strongly prognostic of inferior event-free survival (EFS; adjusted HR [aHR], 28.03; 95% CI, 8.16–96.29; P <.0001). In a multivariate analysis incorporating both ctDNA and PET/CT status, EOT ctDNA-MRD positivity was the strongest independent predictor of inferior EFS (HR, 80.83; 95% CI, 12.07–541.3; P <.001), exceeding the prognostic contribution of EOT PET/CT positivity (HR, 5.18; 95% CI, 1.26–21.4; P = .023).

ctDNA clearance during first-line therapy was associated with significantly improved EFS (aHR, 8.57; 95% CI, 2.55–28.81; P = .005), with early clearance during cycle 1 associated with the most favorable prognosis. A time-varying covariate analysis showed that during posttreatment surveillance, ctDNA positivity was strongly prognostic of inferior EFS (aHR, 33.74; 95% CI, 9.34–121.82; P <.0001); the sensitivity was 91%, specificity was 92%, positive predictive value (PPV) was 87%, and negative predictive value (NPV) was 95%. Among patients who achieved a complete response and later experienced relapse (n = 6), ctDNA-MRD testing identified molecular recurrence a median of 5.3 months (range, 0.7–7.1) before imaging- or biopsy-confirmed relapse.

“Lymphoma is an incredibly diverse group of cancers and this study shows that Signatera delivers consistent and reliable insights across multiple lymphoma subtypes,” stated Natalie Galanina, MD, associate professor of Medicine at the University of Pittsburgh Medical Center Hillman Cancer Center and corresponding author of the study, in a press release on the findings.² “ctDNA/MRD assessment is transforming how we evaluate treatment response, offering the opportunity to move beyond conventional imaging and toward more precise, individualized, and dynamic treatment decisions.”

How did Signatera compare with PET/CT at end of treatment?

Among 59 patients with both EOT ctDNA-MRD and EOT PET/CT results available, Signatera demonstrated significantly stronger prognostic ability for EFS than PET/CT (aHR, 45.33 vs aHR, 9.98 for PET/CT positivity). EOT ctDNA-MRD positivity status showed a 100% PPV for inferior EFS, compared with 62% PPV for PET/CT (P <.0001); NPVs were comparable (91% vs 89%; P > .05). In 85% of divergent instances with imaging, ctDNA-MRD results were corroborated by clinically adjudicated outcomes, yielding an overall agreement rate of 96.8% between ctDNA results and clinical adjudication.

What did ctDNA dynamics reveal after CAR-T therapy in the study?

In a subset of 12 patients with relapsed/refractory lymphoma with both pre- and post–CAR-T ctDNA data, Signatera clearance predicted durable remission. Patients who achieved ctDNA-MRD negativity after CAR-T had a median relapse-free interval of 16.1 months, compared with 1.97 months in patients who remained ctDNA-MRD positive (P = .0091). All 3 patients who were ctDNA-MRD negative before CAR-T infusion remained relapse-free after therapy.

“The ability to reliably detect and monitor molecular residual disease over time has the potential to impact the approach to treatment of lymphoma,” stated Minetta Liu, MD, chief medical officer of oncology and early cancer detection at Natera, in the press release.² “By enabling visibility into recurrence earlier than imaging, Signatera testing creates a window for more timely, risk-adapted interventions that could meaningfully change patient management.”

What is the Signatera assay and how does it detect MRD in lymphoma?

Signatera is a personalized, tumor-informed ctDNA test that uses whole-exome sequencing of formalin-fixed, paraffin-embedded tumor tissue to identify up to 16 patient-specific somatic single-nucleotide variants, which are incorporated into a custom multiplex PCR–based next-generation sequencing panel. Plasma samples with at least 2 variants detected are classified as ctDNA-MRD positive. The approach is histology-agnostic, with the current study demonstrating consistent prognostic utility across aggressive B-cell, aggressive T-cell, and indolent B-cell and T-cell lymphoma subtypes, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and peripheral T-cell lymphoma.

References

1. Galanina N, Iqbal M, Tomassetti S, et al. ctDNA for MRD assessment is prognostic and predictive in newly diagnosed and relapsed/refractory lymphoma. Blood Neoplasia. 2026;3:100250. doi:10.1016/j.bneo.2026.100250
2. New publication establishes strong clinical validation of Signatera for MRD assessment in lymphoma. News release. Natera, Inc. September 1, 2026. Accessed September 1, 2026. https://tinyurl.com/mrx2