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Circulating tumor DNA may predict outcomes in aggressive lymphoma
Molecular response defined by changes in circulating tumor DNA levels appeared independently prognostic of EFS and OS among patients with aggressive diffuse large B-cell lymphoma, according to published findings.
“These risk factors could potentially guide future personalized risk-directed approaches,” David M. Kurtz, MD, PhD, instructor of medicine and postdoctoral fellow in the divisions of oncology and hematology at Stanford Cancer Center, and colleagues wrote.
Studies have shown clinical and molecular features influence outcomes among patients with DLBCL, which led to the use of several prognostic tools to stratify patients into risk groups.
However, using the International Prognostic Index (IPI) and interim PET to select patients for intensified therapy has failed to improve OS. Thus, alternative prognostic tools are needed.
Circulating tumor DNA is increasingly used as a biomarker across oncology.
A study showed detection of circulating tumor DNA in DLBCL prior to initiation of a third cycle of dose-adjusted chemotherapy predicted time to disease progression. But, the impact of interim circulating tumor DNA on survival outcomes was unknown.
Researchers conducted deep sequencing with CAPP-Seq to characterize circulating tumor DNA of 217 patients treated at six centers in North America and Europe.
To define response-associated thresholds, researchers profiled samples from 14 patients throughout the first two cycles of curative-intent systemic therapy, considered the discovery set. Then, researchers measured these thresholds in profiled samples of the other 203 patients prior to first, second and third cycles of therapy, which became the validation sets.
Prior to therapy, 98% of patients had detectable circulating tumor DNA that appeared prognostic in frontline and salvage settings.
Circulating tumor DNA levels among the discovery set changed rapidly. Researchers used a 2-log decrease — defined as early molecular response — after one cycle, and a 2.5-log decrease, or major molecular response, after two cycles to stratify outcomes.
“Importantly, these thresholds initially found in the discovery set were further confirmed to be the optimum thresholds for determining EFS using bootstrap resampling,” researchers wrote. “Notably, early molecular response and major molecular response were concordant in 92% of patients in whom both were evaluable, demonstrating robust performance of molecular response.”
In one validation set, researchers observed higher rates of 24-month EFS among patients receiving frontline therapy who experienced an early molecular response (83% vs. 50%; P = .0015) or major molecular response (82% vs. 46%; P < .001).
Early molecular response also predicted superior 24-month EFS among patients receiving salvage therapy in the first validation set (100% vs. 13%; P = .011).
The prognostic value of early molecular response and major molecular response persisted in the second validation set.
Researchers then evaluated the prognostic value of circulating tumor DNA with established risk factors, IPI and interim PET/CT scans. They found molecular response remained prognostic for EFS and OS in patients with low or high IPI, as well as in the context of interim PET/CT.
“Patients with favorable results for both molecular response and interim PET had excellent outcomes,” the researchers wrote. “In contrast, the combination of a positive interim PET scan and no molecular response identified a group of patients at extremely high risk for treatment failure.”
Despite increasing use of circulating tumor DNA analyses, “the success of molecularly driven approaches will require standardization, harmonization and broad availability,” the researchers added. “Our data suggest that both pretreatment and dynamic assessments of circulating tumor DNA are feasible and can add to established risk factors.” – by Melinda Stevens
Disclosures: Kurtz reports a consultant/advisory role with Roche Molecular Diagnostics. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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There is great interest in measuring ctDNA in oncology. It could serve as a liquid biopsy, permit detection of early relapse, facilitate discovery of clonal evolution, and serve as a marker of minimal residual disease.
Kurtz and colleagues report on ctDNA measurements as early outcome predictors for DLBCL.
The authors measured ctDNA from 217 patients at six centers using CAPP-Seq methodology and found ctDNA was detectable in 98% of patients. Pretreatment levels were prognostic in both the frontline and the relapsed setting. Researchers defined a two-log drop in ctDNA levels as an early molecular response, whereas a 2.5-log drop after two cycles was defined as a major molecular response. The achievement of early or major molecular response was associated with a substantially higher likelihood of cure, independent of the IPI score in the multivariate analysis.
What are we to make of these findings? One obvious application for ctDNA is as a risk stratification tool. Patients who are “fast responders” based upon early or major molecular response might be candidates for treatment de-escalation. Patients who are “slow responders” could be targeted for therapy intensification or novel strategies.
In the past, similar strategies have been investigated using interim PET imaging, and the results have been largely disappointing. It is possible the PET-based strategies failed because interim PET lacks sufficient discriminatory power. The curve separation — representing the difference in outcomes for fast responders vs. slow responders — is large in the Kurtz study, giving one hope ctDNA can perform better in this role.
Of course, therapy intensification or alteration only works if there is a more effective treatment available. Identifying high-risk patients — without a strategy to help them — is a highly unsatisfying endeavor.
Nevertheless, ctDNA is a first step in early identification of the patients most in need. With the potential of chimeric antigen receptor T-cell therapy, one can envision triaging high-risk patients, likely to be failed by chemotherapy, toward novel immunotherapy approaches on carefully designed prospective trials.