ctDNA predicts early outcomes in DLBCL

Measurement of circulating tumor DNA (ctDNA) could be a new and useful tool for predicting survival outcomes and response to therapy in patients with diffuse large B-cell lymphoma (DLBCL), according to authors of a recent prospective study.

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Pretreatment ctDNA levels predicted 24-month event-free survival – an important disease milestone in DLBCL – as well as overall survival in the study, which included more than 200 patients at six institutions in North America and Europe.

Changes in ctDNA during treatment were prognostic for outcomes as early as 21 days into therapy, according to corresponding author Ash A. Alizadeh, MD, PhD, of Stanford (Calif.) University and his coinvestigators.

“Our data suggest that both pretreatment and dynamic assessments of ctDNA are feasible and can add to established risk factors,” Dr. Alizadeh and his coauthors reported in the Journal of Clinical Oncology.

ctDNA was detected in 98% of the 217 patients evaluated, which demonstrated the “potentially universal applicability” of this approach, they wrote in the report.

In an evaluation of pretreatment ctDNA levels, investigators found a 2.5 log haploid genome equivalents per milliliter (hGE/mL) threshold stratified patient outcomes. Event-free survival was significantly inferior at 24 months in patients with ctDNA above that threshold, with hazard ratios of 2.6 (P = .007) for frontline treatment and 2.9 (P = 0.01) for salvage.

On-treatment ctDNA levels were favorably prognostic for outcomes in patients receiving frontline therapy, according to investigators. An early molecular response (EMR), defined as a 2-log decrease in ctDNA levels after one cycle of treatment, was associated with a 24-month event-free survival of 83% versus 50% for no EMR (P = .0015).

Major molecular response (MMR), defined as a 2.5-log drop in ctDNA after two cycles of treatment, was associated with a 24-month event-free survival of 82% versus 46% for no MMR in patients on frontline therapy (P less than .001).

In one cohort of patients receiving salvage therapy, EMR also predicted superior 24-month event-free survival, according to investigators.

The EMR measure was also favorably prognostic for overall survival in both the frontline and salvage settings.

The prognostic value of measuring ctDNA was independent of International Prognostic Index (IPI) and interim PET/CT studies, results of multivariable analysis showed.

Patients had “excellent outcomes” if they had both molecular response and favorable interim PET results, and conversely, patients were at “extremely high risk” for treatment failure if they had no molecular response and a positive PET scan.

“The identification of patients at exceptionally high risk (i.e., interim PET/CT positive and not achieving EMR/MMR) could provide an opportunity for early intervention with alternative treatments, including autologous bone marrow transplantation or chimeric antigen receptor T cells,” the researchers wrote.

Patients in the study were all treated with combination immunochemotherapy according to local standards.

Dr. Alizadeh reported disclosures related to CiberMed, Forty Seven, Janssen Oncology, Celgene, Roche/Genentech, and Gilead, as well as patent filings on ctDNA detection assigned to Stanford University.

SOURCE: Kurtz DM et al. J Clin Oncol. 2018 Aug 20. doi: 10.1200/JCO.2018.78.5246.