Plasma Epstein-Barr Virus DNA a Potential Marker for Treatment Response in Advanced Hodgkin Lymphoma 

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Plasma Epstein-Barr Virus (EBV) DNA has prognostic significance in Hodgkin lymphoma, both prior to therapy and at 6 months of follow-up, according to results of a study published in Blood. “Plasma EBV-DNA positivity at month 6 is associated with particularly poor outcomes and may serve as an indicator of the need for further therapy,” the researchers concluded.

Using specimens from a Cancer Cooperative Intergroup Hodgkin lymphoma treatment trial, investigators compared pretreatment plasma EBV-DNA quantification with EBV tumor status as detected by in situ hybridization of viral nucleic acid in tumor cells. The clinical trial enrolled 794 eligible patients. Tumor specimens for microarray were available for 315 patients and pretreatment plasma specimens were available for 274 patients.

The researchers chose the plasma cutoff of > 60 viral copies/100 μL for the failure-free survival analysis. This cutoff was used to designate plasma specimens as EBV-negative or EBV-positive. Patients with pretreatment EBV-positive plasma (n = 54) had inferior failure-free survival compared to those with pretreatment EBV-negative plasma (n = 274), log- rank P = .009. No difference in failure-free survival was observed when patients were stratified by in situ hybridization of viral nucleic acid.

Further Analyses

This discrepancy in failure-free survival outcomes led to further analyses and separate evaluations of each component of the International Prognostic Score, but plasma EBV-DNA remained an independent predictor of inferior failure-free survival. In multivariate analysis, pretreatment plasma EBV positivity was associated with inferior failure-free survival, with a hazard ratio of 2.0 (95% confidence interval = 1.2–3.5, P = .01), after adjusting for International Prognostic Score, treatment arm, and histology, the researchers reported.

Using plasma specimen obtained at 6 months after the initiation of therapy, the 3-year failure-free survival estimate for patients who were plasma EBV-positive at 6 months (n = 7) was 48% compared to 79% for patients who were plasma EBV-negative at 6 months (n = 125), log-rank P = .007, the investigators stated. “The median [failure-free survival for patients who were plasma [EBV-positive] at month 6 was 1.3 years and has not yet been reached for patients who were plasma [EBV-negative]. Of note, a few of the patients who were plasma [EBV-positive] at month 6 were pre-treatment plasma [EBV-negative] and/or [negative by in situ hybridization of viral nucleic acid], with failure events not restricted to those known to be [EBV-positive] at baseline.”

Largest Study of Its Kind

This study is “the largest prospective analysis of plasma EBV-DNA” reported in Hodgkin lymphoma patients and “the only such data from a randomized cooperative group trial,” according to the authors. “Plasma EBV-DNA assessment is an attractive potential marker in [Hodgkin lymphoma] given that blood collection is very feasible and the diagnostic technology is already available across clinical and research settings. Furthermore, as an alternative or adjunct, plasma EBV-DNA monitoring may be informative in the posttreatment follow-up of patients with [Hodgkin lymphoma] as a low-risk, high sensitivity screen for relapsed disease,” the researchers wrote.

“We would caution that the results presented here are limited to patients with histologically confirmed classical [Hodgkin lymphoma] with locally extensive or advanced stage disease. They may not be generalizable to early stage, favorable [Hodgkin lymphoma]; HIV-associated [Hodgkin lymphoma], [Hodgkin lymphoma] developing in the post-transplant setting, or other EBV-related lymphomas. Nonetheless, in well-defined populations, pre-treatment plasma EBV-DNA may be useful as a surrogate for [in situ hybridization of viral nucleic acid] and should be considered a potential marker of disease status and treatment response in [Hodgkin lymphoma],” they commented.

“If validated as prognostic, plasma EBV-DNA levels may facilitate conduct of clinical trials through use of the biomarker to stratify or enrich populations based on risk; as part of clinical care, patients might be better informed about treatment choices within a risk-benefit, patient-preference paradigm,” according to an accompanying observation. “Perhaps the most important role of plasma EBV-DNA levels will come with better understandings of the role of EBV in the pathogenesis of Hodgkin lymphoma and whether this varies across patients.” ■

Kanakry JA, et al: Blood 121:3547-3553, 2013.
Meyer RM: Blood 121: 3541-3542, 2013.