ctDNA Testing Joins NCCN Guidelines for MRD Assessment in DLBCL

Maris– stock.adobe.com

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for B-Cell Lymphomas were updated to include circulating tumor DNA (ctDNA) testing for minimal residual disease (MRD) assessment for patients with PET-positive diffuse large B-cell lymphoma (DLBCL) at end of first-line treatment.^1,2

This decision marks the first inclusion of ctDNA MRD testing in these guidelines.¹ In the guidelines, ctDNA MRD assessment is indicated as an alternative to biopsy for evaluating positive PET imaging results for patients who have achieved partial response or progressive disease at the conclusion of frontline DLBCL therapy. Patients with PET-positive, ctDNA MRD–negative test results can follow the PET-negative pathway, which involves imaging and clinical follow-ups. According to the guidelines, only ctDNA MRD tests with an assay detection limit of less than 1 ppm are permitted for use.

“Until now, [treatment] of patients with a positive or equivocal PET scan at the end of [first-line] therapy has been a challenging issue, particularly when biopsy is not possible. Furthermore, PET scans have a false positive rate, where 50% of positive scans or more are not due to residual lymphoma,” Mark Roschewski, MD, senior clinician and clinical director of the Lymphoid Malignancies Branch of the Center for Cancer Research, stated in a news release. “The inclusion of ctDNA testing in the NCCN Guidelines gives us a powerful tool to address both challenges—providing guidance when biopsy isn’t possible and helping us more accurately determine which patients truly need additional therapy.”

The update to the NCCN Guidelines follows the August 2024 submission of clinical recommendations by Foresight Diagnostics for the inclusion of ctDNA testing in the guidelines. Evidence for this submission was obtained by the Foresight CLARITY MRD test, a noninvasive test that uses Phased Variant Enrichment and Detection Sequencing to improve the error profile and sensitivity of ctDNA detection.³ A study investigating the analytical validation of CLARITY for detecting MRD in B-cell malignancies used clinical (n = 76) and clinical-contrived (n = 2) DLBCL samples compared with healthy donor plasma samples from non-cancer controls (n = 169) to assess the specificity of the assay.

Analytical specificity findings were assessed using cell-free DNA from 60 cancer-free donors and tumor-derived phased variant (PV) lists from 35 patients with DLBCL. CLARITY showed an overall false positive rate of 0.24% and a background error rate of 1.95 x 10⁸, which translated to 1.95 mutant molecules in 100 million informative molecules.

Probit models showed that the mutant molecules and PV allele frequency (PVAF) corresponded to a 95% detection rate for CLARITY. The limit of detection was 3.11 mutant molecules and 6.61 x 10⁷ PVAF, translating to 0.7 ppm.

The assay’s repeatability and reproducibility rate was greater than 96%. The assay’s clinical accuracy was measured at 90.62% (95% CI, 74.98%-98.02%) positive percent agreement (PPA) and 77.78% (95% CI, 52.73%-93.59%) negative percent agreement (NPA) compared with a previously established single-nucleotide variant–based MRD detection method. Seven discordant calls were observed between the 2 detection methods. In all discordant cases, the CLARITY results agreed with the clinical outcomes (PPA, 100%; NPA, 100%), and the comparator assay had lower clinical outcome concordance rates (PPA, 0%; NPA, 60%).

“These updated guidelines also represent a significant step forward in reducing unnecessary procedures and treatment burden for lymphoma patients,” Ash Alizadeh, MD, PhD, co-founder of Foresight Diagnostics and a professor of medicine, oncology, and hematology at Stanford University in California, added in the news release.¹ “When PET scans are positive, patients often undergo invasive procedures to confirm the result. Or, if results are not confirmed and the scan reflects a false positive, patients are exposed to additional treatment that they don’t actually need. By using ctDNA MRD testing to adjudicate these cases, we can now better identify which patients can safely avoid further treatment, sparing them from significant toxicities and the physical, emotional, and financial burden of unnecessary interventions.”

References

1. NCCN Guidelines updated to include ctDNA-MRD testing recommendation for B-cell lymphoma. Foresight Diagnostics. January 10, 2025. Accessed January 10, 2025. https://foresight-dx.com/press_releases/nccn-guidelines-updated-to-include-ctdna-mrd-testing-recommendation-for-b-cell-lymphoma/
2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) B-Cell Lymphomas Version 1.2025. December 20, 2024. Accessed January 10, 2025. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
3. Boehm N, Close S, Kurtz DM, Hockett Jr RD, Hyland L. Analytical validation of a circulating tumor DNA assay using PhasED-seq technology for detecting residual disease in B-cell malignancies. medRvix. Published online August 9, 2024. doi:10.1101/2024.08.09.24311742