Measuring Circulating Tumor DNA for Recurrence in DLBCL

Researchers at the National Cancer Institute are reporting on a new method of determining if patients still have disease following initial therapy; a new method that is more sensitive than anything before it.

Representing as many as half of all non-Hodgkin's lymphoma diagnoses, diffuse large B-cell lymphoma is the most frequently diagnosed subtype. An aggressive disease, it is considered curable with combination chemotherapy.

Testing and treatment for DLBCL

With this disease, patients must then undergo several years of computerized tomography (CT) scanning to check for disease recurrence, which is often indicative of a poor prognosis. However, NCI researchers have found that by measuring the circulating tumor DNA (ctDNA) in a patient's blood, they can detect disease recurrence in DLBCL, often well before the disease could be detected using CT scans (the current standard for disease assessment). Doing so also eliminates the radiation risk associated with frequent scans.

DLBCL is usually curable but when treatment fails, the long-term prognosis is poor. Currently, imaging using CT or interim PET (iPET) scans is used to monitor patients during and after treatment, but is often imprecise. Repeated radiation exposure is a potential health risk and a financial burden. Because relapses of DLBCL most likely occur due to the presence of residual disease at a level below that which can be detected by imaging, a more precise measure of disease recurrence potential was sought.

NCI investigators, led by Wyndham Wilson, M.D., Ph.D., Center for Cancer Research, analyzed serum from 126 patients with DLBCL for the presence of ctDNA. To detect it, the team used a quantitative method that assesses gene segments with advanced sequencing techniques. All patients received therapy involving the drugs etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH), with or without the biologic agent rituximab (R-EPOCH), in clinical trials between May 1993 and December 2013. Serum samples were collected before treatment, during treatment, and for many years after therapy. The patients also had CT scans done at the same time as the blood testing as part of standard surveillance. They were followed for a median of 11 years after the completion of therapy.

A total of 107 patients in the study achieved complete remission; the team found that those who developed detectable ctDNA during surveillance were over 200 times more likely to have their disease progress than those who did not have detectable ctDNA.

The researchers also found that measuring ctDNA enabled the detection of cancer recurrence a median of 3.4 months before clinical evidence of disease – meaning before the patient began to display signs of the disease. The ctDNA test also predicted which patients would not respond to therapy as early as their second cycle of treatment – a strategy known as interim monitoring.

“Interim ctDNA is a promising biomarker to identify patients at high risk of not responding to treatment for their disease,” noted Dr. Wilson. “Even with frequent CT imaging, administered for a median of 11 times per patient in our study, early disease detection was suboptimal. Indeed, a recent study suggested that surveillance CT scans might be no better than an up-to-date patient history and physical exams, supporting the need for more effective monitoring technologies."

The research was reported in the journal Lancet Oncology.