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Circulating tumor DNA (ctDNA) is gaining ground as an important multitasking tool in the frontline treatment of diffuse large B-cell lymphoma (DLBCL), with key novel applications that include identifying genetic subtypes and guiding the escalation or de-escalation of chemotherapy, new research has shown.

“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 Clinic of Hematology, Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland, in presenting the findings at the 18th International Conference on Malignant Lymphoma (ICML) 2025 in Lugano, Switzerland.

“The allocation of patients and treatment based on the combined results of PET and ctDNA is operationally successful,” he said.

The findings are from the preliminary results of the phase 2 SAKK 38/19 trial, which focuses on the goal of identifying patients with key MCD genetic subtypes that are known to respond poorly to the standard of care of R-CHOP (rituximab + cyclophosphamide, doxorubicin hydrochloride [hydroxydaunomycin], vincristine [Oncovin], prednisone) chemotherapy, and who may be more successfully treated with the addition of a Bruton tyrosine kinase inhibitor such as acalabrutinib.

“The most important aspect of this study is the novelty of using ctDNA as a tool to identify a genetic subtype of DLBCL prior to treatment for the purpose of treating that cohort differently precision medicine,” said Mark Roschewski, MD, a senior clinician with the Center for Cancer Research, National Institutes of Health in Bethesda, Maryland, who was a discussant for the study, in comments to Medscape Medical News.

Importantly, there are currently no diagnostic assays available to identify the genetic details of a tumor in DLBCL prior to therapy, which can be so crucial in determining a treatment plan, Roschewski explained.

“We know a lot about the complexity of DLBCL genetics, but the information is not actionable because it is such a challenge to get that information prior to therapy,” he said. “As such, this information is only available after therapy is over and mostly only reported in clinical trials.”

For the study, conducted at 16 sites in Switzerland and 3 in Italy, the authors were able to utilize ctDNA to identify patients with the MCD subtype because of its ability to detect the two mutations known to be present in MCD: MYD88 and CD79B.

Among 230 treatment-naive patients with CD20-positive DLBCL screened for the trial, 194 patients (88.2%) had detectable ctDNA, and 35 (15.9%) had the MYD88 and/or CD79B mutations.

Importantly, the turnaround time for the genetic profiling with ctDNA results among 124 patients in the full analysis set (after screening failures and other exclusions) was only 9 days, and the median time to start treatment was just 15 days.

“These timelines clearly show the operational feasibility of such an approach,” Stathis said.

Overall, in the full analysis set, 72.6% of patients had advanced disease (stages III-IV), and 64.5% had extra-nodal involvement.

With 96 patients excluded due to screening failure, 124 patients were included in the full analysis, and all that were found to have MYD88 and/or CD79B mutations (27; 21.8%) were assigned to receive frontline therapy with acalabrutinib plus six cycles of R-CHOP in a group allocated as cohort A.

Treatment Escalation, De-Escalation

Of the remaining 97 patients who did not have the mutations, all were started on two cycles of R-CHOP and then evaluated with ctDNA and PET to guide treatment escalation or de-escalation on the basis of one of three treatment strategies corresponding to their ctDNA/PET results.

Overall, 6.5% of patients (n = 8) were found to be PET and ctDNA-positive after the two cycles and were therefore allocated to escalation of therapy to four more R-CHOP cycles plus acalabrutinib, followed by 2 months of acalabrutinib (cohort B).

About 30.6% of patients (n = 38) were ctDNA and PET-negative and therefore had their therapy de-escalated, receiving only two more R-CHOP cycles plus two rituximab doses (cohort C).

About 36.5% of patients (n = 44) were either PET or ctDNA-positive after the two cycles and were allocated to receive four more R-CHOP cycles (cohort D).

Preliminary Results

Preliminary results including PET and ctDNA responses show that at the end of therapy, the majority of patients remained ctDNA-negative (79.8% overall), with 7.3% ctDNA-positive and data missing on 12.9% of patients.

Having detectable ctDNA at baseline significantly correlated with factors including the International Prognostic Index (IPI), bulky disease, and PET imaging parameters that indicated a poorer prognosis, including higher metabolic tumor volume (MTV) and total lesion glycolysis (TLG).

While the numbers were small, higher PET scores (indicative of worse prognosis) at the end of treatment (Deauville 4 or 5) correlated with ctDNA positivity, with the ctDNA positivity rate of only 2.6% among 78 patients with lower Deauville scores of 1-3.

Notably, ctDNA negativity at the end of two cycles of R-CHOP showed only a nonsignificant trend in being associated with end-of-treatment negative PET scores.

The only factors found to be predictors of positive PET imaging at the end of treatment included high baseline MTV and TLG (P = .013 and P = .026, respectively), with no association between baseline ctDNA, IPI, or other factors.

Further commenting on the study during his discussion at the meeting, Roschewski agreed that the discrepancies with ctDNA and PET scan results were a limitation.

“We need to have more information on to understand why was there such a discordance in things that we typically think go in the same direction,” he said.

However, “the quantitative level of baseline ctDNA in the study correlated quite nicely with tumor burden as measured by PET scan high-risk features such as IPI.”

“But using it in a more nuanced way, this also was one of the first trials that showed us that you could actually risk stratify the patients based on the mutation profiling from ctDNA, and that was successful in 88% of the patients, and the turnaround time was only 9 days.”

Roschewski noted that key additional studies are also looking at the addition of acalabrutinib to R-CHOP through different trial designs, including the ESCALADE trial, and a study Roschewski and his own team are also conducting looking at molecular profiles of patients who do and do not respond to acalabrutinib.

Ultimately, “the main barrier to precision medicine in large lymphoma remains genetic heterogeneity, and we need to continue to find novel ways to overcome that barrier,” he said.

Stathis disclosed ties with AbbVie, ADC Therapeutics, Amgen, AstraZeneca, Bayer, BMS, Cellista, Debiopharm, Incyte, Loxo Oncology, MSD, Novartis, Pfizer, Philogen, Prelude Therapeutics, and Roche. Roschewski reported having no disclosures.