Patient Ethnicity Differences in Epstein-Barr Virus and DLBCL Outcomes

Sean Tracy, MD, PhD

As part of OncoTherapy Network’s coverage of the 58th Annual Meeting & Exposition of the American Society of Hematology (ASH), held December 3–6 in San Diego, California, we spoke with Sean Tracy, MD, PhD, at the Mayo Clinic in Rochester, Minnesota.

-Interviewed by Bryant Furlow

OncoTherapy Network: Epstein-Barr virus infection [EBV+] has been found to be associated with poor outcomes among Asian patients with diffuse large B-cell lymphoma [DLBCL]. Your team analyzed possible associations between EBV and immunosuppression with survival endpoints among North American patients with DLBCL. What did you learn?

Dr. Tracy: First we learned that the prevalence of EBV+ DLBCL is relatively low among North American patients, at less than 5% of all DLBCL patients overall, but when present, occurs in adult patients of all ages.

At presentation, patients with EBV+ DLBCL biopsies were more likely also have high expression levels of CD30, as well as to have a nongerminal center B-cell like subtype. These associations have been observed previously, and confirmation of them reinforces that EBV+ DLBCL has unique pathogenic features, that may eventually guide targeted therapeutic interventions. 

Additionally, we learned that the outcomes of patients with DLBCL, as measured by overall survival [OS] and event-free survival [EFS] at 24 months, were not affected by the presence of EBV within the tumor cells themselves, nor by a history of immunosuppression.

Finally, we found little evidence for detectable levels of circulating EBV among our patients. Our results are in general agreement with existing reports focused on Western patients.

However, these findings are in contrast to those of several studies that focused primarily on Asian cohorts of patients. In general, those reports showed that EBV+ DLBCL occurred more frequently (typically accounting for 8% to 14% of all DLBCL patients) as compared to Western cohorts, and was associated with a particularly aggressive course. Among Asian patients, EBV+ DLBCL is also often accompanied by detectable levels of circulating EBV, and predominantly affects elderly patients.

Overall, our findings find no evidence that EBV positivity confers an adverse prognosis among the study cohort, and further reinforces the conclusion that there are biological differences in how EBV+ DLBCL behaves among different ethnic backgrounds. 

OncoTherapy Network:Your team also looked at patients with a history of immunosuppression?

Dr. Tracy: As part of our analysis, we also characterized the presenting clinical features and outcomes of DLBCL patients who had a history of immunosuppression (largely for therapy of autoimmune diseases), and compared them to DLBCL patients who were considered immunocompetent. The intention of this was two-fold; we wished to control for the possibility that immunosuppression could confound comparisons of outcomes between EBV+ and EBV- DLBCL patients, and we additionally wanted to explore whether immunosuppression affected outcomes in general, as existing data regarding this was lacking.

Our work revealed that patients who have a significant history of immunosuppression do not present with unique clinical characteristics, nor experience adverse outcomes as compared to immunocompetent patients. We also found that controlling for a history of immunosuppression did not affect outcomes when comparing EBV+ and EBV- DLBCL patients.

OncoTherapy Network:How do you reconcile your team’s findings in the US with the association between circulating EBV and poor outcomes among Asian patients? Is the difference likely to be due to host-genetic differences? Differences in circulating EBV strains?

Dr. Tracy: The variations in prevalence and biological behavior of EBV+ DLBCL between different ethnicities is reminiscent of other EBV-associated malignancies, including nasopharyngeal carcinoma (NPC) and EBV+ Burkitt lymphoma, which predominantly affect Asian and African patients, respectively.

What’s clear from these other tumor contexts are that separate and complementary mutations, or perturbations in host immune function, are necessary steps for EBV-driven oncogenesis to occur. Among patients with EBV+ DLBCL, it is unknown what these complementary mechanisms may be.

There is evidence of differences in key EBV genes between Asian and Caucasian patients, suggesting differential pathogenic potential of circulating viral strains between these populations. Alternatively, polymorphisms in host genes such as MHC alleles or chemokines have also been proposed as contributory mechanisms.

Our present work does not address what underlying mechanisms may be responsible for the differences in biological behavior of EBV+ DLBCL between different ethnic populations, but does add to the growing body of evidence suggesting such differences are robust and reproducible.

OncoTherapy Network:What are the clinical implications?

Dr. Tracy: The clinical implications of our findings are that patients who have a significant history of immunosuppression and subsequently develop DLBCL are not likely to experience worse outcomes as compared to similar patients without a history of immunosuppression.

A caveat to this is that the majority of the studied patients were immunosuppressed due to receiving methotrexate for a diagnosis of rheumatoid arthritis, while limited numbers of patients received TNF-alpha inhibitors or other iatrogenic immunosuppressive agents. We also excluded HIV+ patients or those who were receiving immunosuppressants to prevent organ rejection after transplantation.

Therefore, direct extrapolation of our findings to such patients should be performed with caution.

Additional implications are that EBV positivity does not appear to affect the outcomes of DLBCL patients. EBV+ DLBCL patients had a higher frequency of CD30 expression, suggesting that CD30-targeting agents, such as brentuximab, may be beneficial in this population, and should be explored in future clinical trials. Our patient cohort was exclusively from North America, and our findings should be extrapolated only to a similar patient population. 

OncoTherapy Network:What’s next?

Dr. Tracy: Discussion of future projects is underway. Possible approaches could include functional studies to characterize the pathogenic potential of observed EBV strain variants and candidate host genes, as well as investigation of promising therapies in this disease context.