Annals of Hematology

, Volume 97, Issue 8, pp 1427–1436 | Cite as

Significance of circulating Epstein-Barr virus DNA monitoring after remission in patients with extranodal natural killer T cell lymphoma

  • Jinhyun Cho
  • Seok Jin Kim
  • Silvia Park
  • Kwai Han Yoo
  • Chang-Seok Ki
  • Younghyeh Ko
  • Won Seog Kim
Original Article


Circulating Epstein-Barr virus (EBV)-DNA has been established as a useful parameter for diagnosis and predicting prognosis in patients with extranodal natural killer T cell lymphoma (ENKTL); however, the role of monitoring of circulating EBV-DNA after complete remission (CR) is not well established. From January 2008 to August 2016, 328 ENKTL patents were enrolled in 2 lymphoma cohorts. Of 171 patients achieved a CR, 81 had available monitoring data for circulating EBV-DNA with negative post-treatment EBV-DNA. Measurement of circulating EBV-DNA was performed from unfractionated whole blood and calculated according to WHO international standards. Median duration of follow-up was 40.4 months. In 31 of the 81 patients (38.8%), circulating EBV-DNA was detected at least once during follow-up, and 16 of these patients (51.6%) experienced relapse. In contrast, only 7 out of 50 (14.0%) patients with consistently undetectable circulating EBV-DNA experienced relapse (p < 0.001). In multivariate analysis, positive conversion of circulating EBV-DNA was the only independent prognostic factor for occurrence of relapse (HR = 6.552, p < 0.001), progression-free survival (HR = 4.549, p = 0.01), and overall survival (HR = 8.726, p < 0.001). Patients with a higher level of circulating EBV-DNA than 3310 IU/mL (3.52 log10 IU/mL) showed a strong tendency to relapse (73.3 vs. 31.3%, p = 0.019). In conclusion, positive conversion of circulating EBV-DNA was a valuable indicator of relapse and inferior survival, especially if the level was higher than 3310 IU/mL in ENKTL patients had achieved CR. Close follow-up is necessary for patients developed detectable circulating EBV-DNA after remission.


NK/T cell lymphoma EBV PCR Biomarker Relapse 


Funding information

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI13C2096).

Compliance with ethical standards

The study was reviewed and approved by the institutional review board at Samsung Medical Center. All procedures were performed in accordance with the principles of the Declaration of Helsinki.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

277_2018_3313_MOESM1_ESM.jpg (38 kb)
Supplementary Fig. 1 Determination of cut-off value using receiver operating characteristics (ROC) curve. ROC curve is a useful method to evaluate the performance of a diagnostic test with classification of subjects into two categories of positive and negative. In a ROC curve the sensitivity (true positive rate) is plotted as a function of the false positive rate (1-specificity) for different cut-off points. Each point on the ROC curve represents a sensitivity/specificity pair corresponding to a particular decision threshold. The closer the ROC curve is to the upper left corner, the higher the overall accuracy of the test. (JPEG 37 kb)
277_2018_3313_MOESM2_ESM.jpg (168 kb)
Supplementary Fig. 2 Changes in EBV-DNA viral load in blood from the time of completing treatment to the time of relapse or last follow-up in patients with positive conversion of circulating EBV-DNA (N = 31). (a) Serial changes in circulating EBV-DNA level in patients with relapse (N = 16). Graphs show a trend toward increasing level of circulating EBV-DNA more than 3310 IU/ml (3.52 log10 IU/mL) at the time of relapse or before relapse. (b) Serial changes in circulating EBV-DNA level in patients without relapse (N = 15). Levels of circulating EBV-DNA were relatively low in most patients. (JPEG 167 kb)
277_2018_3313_Fig5_ESM.gif (180 kb)
Supplementary Fig. 3

Percentage change of circulating EBV-DNA level from 3310 IU/mL (3.52 log10 IU/mL) in four non-relapsed patients had higher levels of circulating EBV-DNA than 3310 IU/mL one or more times after remission. (A) Two patients showed fluctuations of circulating EBV-DNA level near 3310 IU/mL. (B) Two patients showed consistently increasing level of circulating EBV-DNA more than 3310 IU/mL (GIF 179 kb)

277_2018_3313_MOESM3_ESM.tif (232 kb)
High resolution image (TIFF 232 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Jinhyun Cho
    • 1
  • Seok Jin Kim
    • 2
  • Silvia Park
    • 2
  • Kwai Han Yoo
    • 3
  • Chang-Seok Ki
    • 4
  • Younghyeh Ko
    • 5
  • Won Seog Kim
    • 2
  1. 1.Division of Hematology-Oncology, Department of Internal Medicine, Inha University HospitalInha University School of MedicineIncheonSouth Korea
  2. 2.Division of Hematology-Oncology, Department of Medicine, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
  3. 3.Division of Hematology and Medical Oncology, Department of Internal MedicineGachon University Gil Medical CenterIncheonSouth Korea
  4. 4.Department of Laboratory Medicine and Genetics, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
  5. 5.Department of Pathology, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea

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