Currently, no diagnostic tests exist that can determine the genetic profile of a tumor in diffuse large B-cell lymphoma (DLBCL) before treatment, a critical factor for choosing the appropriate therapy. Now, new research indicates that circulating tumor DNA (ctDNA) is becoming a valuable tool in the initial treatment of DLBCL. Its emerging applications include identifying genetic subtypes and informing decisions on whether to intensify or reduce chemotherapy.

The findings, from the preliminary results of the phase 2 SAKK 38/19 trial presented by researchers from the Oncology Institute of Southern Switzerland (IOSI, Bellinzona, Switzerland), demonstrated that a PET/ctDNA-guided approach in frontline DLBCL is feasible in a multicenter setting. Patient stratification and therapy assignment based on combined PET and ctDNA outcomes were effectively implemented. The SAKK 38/19 trial aims to identify patients carrying the MCD genetic subtype—known for poor response to standard R-CHOP chemotherapy (rituximab + cyclophosphamide, doxorubicin hydrochloride [hydroxydaunomycin], vincristine [Oncovin], prednisone)—who might respond better when a Bruton tyrosine kinase inhibitor like acalabrutinib is added to the regimen.

The study, conducted across 16 locations in Switzerland and 3 in Italy, utilized ctDNA to pinpoint individuals with the MCD subtype by detecting the MYD88 and CD79B mutations associated with it. Out of 230 treatment-naive patients with CD20-positive DLBCL screened for participation, ctDNA was found in 194 patients (88.2%), and 35 (15.9%) carried one or both of the target mutations. Notably, the turnaround time for ctDNA genetic profiling in the 124 patients included in the full analysis set—after accounting for screening failures and other exclusions—was just 9 days, with the median time to treatment initiation recorded at 15 days.

“We have demonstrated that a PET/ctDNA-guided approach in frontline DLBCL is feasible in a multicenter setting,” said first author Anastasios Stathis, MD, of the IOSI, in presenting the findings at the 18th International Conference on Malignant Lymphoma (ICML) 2025. “The allocation of patients and treatment based on the combined results of PET and ctDNA is operationally successful.”

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