In a study of patients with diffuse large B-cell lymphoma (DLBCL), levels of pretreatment circulating tumor DNA (ctDNA) and molecular responses were independent predictors of event-free survival (EFS) and overall survival (OS). The results, published in the Journal of Clinical Oncology, suggest that “these risk factors could potentially guide future personalized, risk-directed approaches to treatment,” wrote David M. Kurtz, MD, PhD, from the Stanford University School of Medicine in California, and researchers.
“Using a technique called Cancer Personalized Profiling by Deep Sequencing, or CAPP-Seq, we were able to detect ctDNA in 98 percent of patients prior to treatment,” Dr. Kurtz told ASH Clinical News. “We tracked ctDNA levels over time and found that, much to our surprise, the levels of ctDNA as early as 21 days into therapy were prognostic for clinical outcomes, including survival.”
The investigators analyzed ctDNA from 217 patients with either newly diagnosed or previously treated DLBCL who were undergoing therapy at one of six international institutions between December 1999 and September 2016. Eligible participants had antecedent low-grade lymphoma with histologic transformation, MYC and BCL2/BCL6 rearrangements, pretreatment blood plasma or serum samples available, and a source of germline DNA.
The researchers monitored ctDNA levels during therapy using deep sequencing and also identified the optimal timing and thresholds to predict molecular response through the first two therapy cycles (in patients who received anthracycline- and rituximab-based approaches in the frontline setting) in a “discovery set” of 14 patients.
Based on findings in the discovery set, early molecular response (EMR) was defined as a 2-log decrease in ctDNA levels (assessed via PET/CT imaging) after one cycle of therapy and major molecular response (MMR) was defined as a 2.5-log decrease after two cycles.
The investigators next profiled samples prior to the first, second, and third therapy cycles from the remaining 203 patients. Patients were divided into two cohorts:
- cohort 1, comprising patients receiving care at Stanford Cancer Center, MD Anderson Cancer Center in Houston; and University of Eastern Piedmont in Novara, Italy (n=144)
- cohort 2, comprising patients receiving care at the National Cancer Institute; Centre Hospitalier Universitaire in Dijon, France; and Essen University Hospital in Germany (n=73)
Prior to therapy initiation, 212 patients with DLBCL (98%) had detectable ctDNA. Patients were followed for a median of 31.2 months (range not reported).
In cohort 1, patients with high pretreatment ctDNA levels (≥2.5 log hGE/mL) had significantly lower rates of 24-month EFS in both the frontline and salvage settings, compared with those with low pretreatment ctDNA levels (<2.5 log hGE/mL):
- frontline: hazard ratio (HR) = 2.6 (95% CI 1.3-5.2; p=0.007)
- salvage: HR=2.9 (95% CI 1.3- 6.4; p=0.01)
High levels of ctDNA predicted significantly worse OS in the salvage setting (HR=3.3; 95% CI 1.4-7.5; p=0.0053), but not in the frontline setting (HR=1.6; 95% CI 0.66-3.9; p=0.29).
Pretreatment ctDNA remained a significant predictor of EFS in the frontline setting after adjustment for molecular subtype and other established risk factors, including International Prognostic Index (IPI) and total metabolic tumor volume (TMTV; HR=1.90; 95% CI 1.12-3.23; p=0.018).
These associations were confirmed in the second validation set, when lower pretreatment ctDNA levels during treatment were associated with superior EFS (HR=2.4; 95% CI 1.0-5.7; p=0.045). Again, multivariable analyses showed that changes in ctDNA levels during treatment were significant predictors of EFS and OS (HR=8.58 [3.30- 22.32; p<0.001] for EFS and HR=4.15 [95% CI 1.17-15.57; p=0.029] for OS), independent of other established risk factors like IPI and TMTV.
Limitations of the study include its small sample size and variability in the timing of PET/CT imaging. The researchers suggested that greater insight may be gained from future studies that use “standardized interim PET/CT scans performed at uniform landmarks.”
Ultimately, Dr. Kurtz said, this study showed that by assessing the dynamics of ctDNA over time, physicians can quickly identify patients who are responding to treatment and those who are not. “Our findings open the door to possible studies trying to select therapy for patients based on this assay,” he noted. “The detection of ctDNA was reproducible across all the centers and was prognostic for outcomes. Novel clinical study designs based on ctDNA dynamics are now needed and will pave the way for bringing this type of assay into the clinic for patients.”
The authors report financial relationships with Roche Molecular Diagnostics and Forty Seven.
Kurtz DM, Scherer F, Jin MC, et al. Circulating tumor DNA measurements as early outcome predictors in diffuse large B-cell lymphoma. J Clin Oncol. 2018 August 20. [Epub ahead of print]