In patients with diffuse large B-cell lymphoma (DLBCL), a high pretreatment level of circulating DNA (ctDNA) was found to be prognostic for survival. Patients with high levels had significantly inferior rates of event-free survival (EFS) in both frontline (P = .007) and salvage settings (P = .01) at 24 months compared with those who had low levels of ctDNA. And, in the salvage setting, a high level of ctDNA forecasted significantly worse overall survival (P = .024).
In a study published in the Journal of Clinical Oncology, investigators sought to discover new tools of prognosis that could be more reliable than current risk-stratification methods.1 They looked at 217 evaluable patients across 6 different institutions from December 1999 to September 2016, with follow-up concluding in February 2018 (for a median follow-up time of 31.2 months). They sequenced 212 of the patient samples via cancer personalized profiling by deep sequencing (CAPP-Seq) before and during therapy to gauge if the level of ctDNA helped predict EFS at 24 months and overall survival (OS).
Absolute ctDNA concentration in patients was similar across sites of enrollment and pretreatment ctDNA was also associated with International Prognostic Index (IPI) and total metabolic tumor volume (TMTV). “This suggests ctDNA could serve as both a prognostic factor and a quantitative proxy for disease burden, another known prognostic factor for lymphoma,” the investigators wrote.1
And, the researchers also found that the change in ctDNA following treatment initiation was predictive of response to drug therapy, regardless of type of therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone plus rituximab [EPOCH-R]) and line (frontline vs salvage). Changes in these levels could accurately predict a complete response, the authors wrote, and “by the midpoint of the first cycle (6 to 16 days), patients could be perfectly discriminated as responders and nonresponders.”1 In the discovery cohort, for example, a complete response could be predicted with a 100-fold (or 2-log) drop in ctDNA levels by the start of treatment cycle 3.
Across all cohorts, a 2.5-log drop by treatment cycle 3 was defined as a major molecular response (MMR). Both MMR and early molecular response (EMR) were prognostic for EFS and OS in frontline settings (EMR, P = .0015 and P < .011, respectively; MMR, P < .001 and P = .0047, respectively). Lastly, the combination of molecular response and interim positron emission tomography/computed tomography (PET/CT) response allowed researchers to stratify patients by risk.
“Additional studies exploring approaches for integrating ctDNA with traditional risk-assessment tools will be useful,” the authors concluded.
- Kurtz DM, Scherer F, Jin MC, et al. Circulating tumor DNA measurements as early outcome predictors in diffuse large B-cell lymphoma [published online August 20, 2018]. J Clin Oncol. doi: 10.1200/JCO.2018.78.5246