Abstract
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.
Similar content being viewed by others
References
Kwong YL (2005) Natural killer-cell malignancies: diagnosis and treatment. Leukemia 19:2186–2194
Au WY, Pang A, Choy C, Chim CS, Kwong YL (2004) Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients. Blood 104:243–249
Kim SJ, Yoon DH, Jaccard A, Chng WJ, Lim ST, Hong H, Park Y, Chang KM, Maeda Y, Ishida F, Shin DY, Kim JS, Jeong SH, Yang DH, Jo JC, Lee GW, Choi CW, Lee WS, Chen TY, Kim K, Jung SH, Murayama T, Oki Y, Advani R, d'Amore F, Schmitz N, Suh C, Suzuki R, Kwong YL, Lin TY, Kim WS (2016) A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis. Lancet Oncol 17:389–400
Ito Y, Kimura H, Maeda Y, Hashimoto C, Ishida F, Izutsu K, Fukushima N, Isobe Y, Takizawa J, Hasegawa Y, Kobayashi H, Okamura S, Kobayashi H, Yamaguchi M, Suzumiya J, Hyo R, Nakamura S, Kawa K, Oshimi K, Suzuki R (2012) Pretreatment EBV-DNA copy number is predictive of response and toxicities to SMILE chemotherapy for extranodal NK/T-cell lymphoma, nasal type. Clin Cancer Res 18:4183–4190
Kim HS, Kim KH, Kim KH, Chang MH, Ji SH, Lim DH, Kim K, Kim SJ, Ko Y, Ki CS, Jo SJ, Lee JW, Kim WS (2009) Whole blood Epstein-Barr virus DNA load as a diagnostic and prognostic surrogate: extranodal natural killer/T-cell lymphoma. Leuk Lymphoma. 50:757–763
Wang L, Wang H, Wang JH, Xia ZJ, Lu Y, Huang HQ, Jiang WQ, Zhang YJ (2015) Post-treatment plasma EBV-DNA positivity predicts early relapse and poor prognosis for patients with extranodal NK/T cell lymphoma in the era of asparaginase. Oncotarget 6:30317–30326
Kwong YL, Pang AW, Leung AY, Chim CS, Tse E (2014) Quantification of circulating Epstein-Barr virus DNA in NK/T-cell lymphoma treated with the SMILE protocol: diagnostic and prognostic significance. Leukemia 28:865–870
Kim SJ, Choi JY, Hyun SH, Ki CS, Oh D, Ahn YC, Ko YH, Choi S, Jung SH, Khong PL, Tang T, Yan X, Lim ST, Kwong YL, Kim WS, Asia Lymphoma Study Group (2015) Risk stratification on the basis of Deauville score on PET-CT and the presence of Epstein-Barr virus DNA after completion of primary treatment for extranodal natural killer/T-cell lymphoma, nasal type: a multicentre, retrospective analysis. Lancet Haematol 2:e66–e74
Kim SJ, Kim K, Kim BS, Kim CY, Suh C, Huh J, Lee SW, Kim JS, Cho J, Lee GW, Kang KM, Eom HS, Pyo HR, Ahn YC, Ko YH, Kim WS (2009) Phase II trial of concurrent radiation and weekly cisplatin followed by VIPD chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-cell lymphoma: Consortium for Improving Survival of Lymphoma study. J Clin Oncol 27:6027–6032
Yong W, Zheng W, Zhu J, Zhang Y, Wang X, Xie Y, Lin N, Xu B, Lu A, Li J (2009) L-asparaginase in the treatment of refractory and relapsed extranodal NK/T-cell lymphoma, nasal type. Ann Hematol 88:647–652
Huh HJ, Park JE, Kim JY, Yun SA, Lee MK, Lee NY, Kim JW, Ki CS (2017) Performance of the real-Q EBV quantification kit for Epstein-Barr virus DNA quantification in whole blood. Ann Lab Med 37:147–150
Cheson BD (2015) Staging and response assessment in lymphomas: the new Lugano classification. Chin Clin Oncol 4:5
Altman DG, Bland JM (1994) Diagnostic tests 3: receiver operating characteristic plots. BMJ 309:188
Suzuki R, Yamaguchi M, Izutsu K, Yamamoto G, Takada K, Harabuchi Y, Isobe Y, Gomyo H, Koike T, Okamoto M, Hyo R, Suzumiya J, Nakamura S, Kawa K, Oshimi K, the NK-cell Tumor Study Group (2011) Prospective measurement of Epstein-Barr virus-DNA in plasma and peripheral blood mononuclear cells of extranodal NK/T-cell lymphoma, nasal type. Blood 118:6018–6022
Lei KI, Chan LY, Chan WY, Johnson PJ, Lo YM (2002) Diagnostic and prognostic implications of circulating cell-free Epstein-Barr virus DNA in natural killer/T-cell lymphoma. Clin Cancer Res 8:29–34
Preiksaitis JK, Pang XL, Fox JD, Fenton JM, Caliendo AM, Miller GG (2009) Interlaboratory comparison of Epstein-Barr virus viral load assays. Am J Transplant 9:269–279
Hayden RT, Hokanson KM, Pounds SB, Bankowski MJ, Belzer SW, Carr J, Diorio D, Forman MS, Joshi Y, Hillyard D, Hodinka RL, Nikiforova MN, Romain CA, Stevenson J, Valsamakis A, Balfour HH, for the U.S. EBV Working Group (2008) Multicenter comparison of different real-time PCR assays for quantitative detection of Epstein-Barr virus. J Clin Microbiol 46:157–163
Stevens SJ, Vervoort MB, van den Brule AJ, Meenhorst PL, Meijer CJ, Middeldorp JM (1999) Monitoring of epstein-barr virus DNA load in peripheral blood by quantitative competitive PCR. J Clin Microbiol 37:2852–2857
Bai X, Hosler G, Rogers BB, Dawson DB, Scheuermann RH (1997) Quantitative polymerase chain reaction for human herpesvirus diagnosis and measurement of Epstein-Barr virus burden in posttransplant lymphoproliferative disorder. Clin Chem 43:1843–1849
Lucas KG, Burton RL, Zimmerman SE, Wang J, Cornetta KG, Robertson KA, Lee CH, Emanuel DJ (1998) Semiquantitative Epstein-Barr virus (EBV) polymerase chain reaction for the determination of patients at risk for EBV-induced lymphoproliferative disease after stem cell transplantation. Blood 91:3654–3661
Savoie A, Perpete C, Carpentier L, Joncas J, Alfieri C (1994) Direct correlation between the load of Epstein-Barr virus-infected lymphocytes in the peripheral blood of pediatric transplant patients and risk of lymphoproliferative disease. Blood 83:2715–2722
Lo YM, Chan LY, Chan AT, Leung SF, Lo KW, Zhang J, Lee JC, Hjelm NM, Johnson PJ, Huang DP (1999) Quantitative and temporal correlation between circulating cell-free Epstein-Barr virus DNA and tumor recurrence in nasopharyngeal carcinoma. Cancer Res 59:5452–5455
Yamamoto M, Kimura H, Hironaka T, Hirai K, Hasegawa S, Kuzushima K, Shibata M, Morishima T (1995) Detection and quantification of virus DNA in plasma of patients with Epstein-Barr virus-associated diseases. J Clin Microbiol 33:1765–1768
Gallagher A, Armstrong AA, MacKenzie J, Shield L, Khan G, Lake A, Proctor S, Taylor P, Clements GB, Jarrett RF (1999) Detection of Epstein-Barr virus (EBV) genomes in the serum of patients with EBV-associated Hodgkin’s disease. Int J Cancer 84:442–448
Limaye AP, Huang ML, Atienza EE, Ferrenberg JM, Corey L (1999) Detection of Epstein-Barr virus DNA in sera from transplant recipients with lymphoproliferative disorders. J Clin Microbiol 37:1113–1116
Kanakry JA, Hegde AM, Durand CM, Massie AB, Greer AE, Ambinder RF, Valsamakis A (2016) The clinical significance of EBV DNA in the plasma and peripheral blood mononuclear cells of patients with or without EBV diseases. Blood 127:2007–2017
Ouedraogo DE, Bollore K, Viljoen J, Foulongne V, Reynes J, Cartron G, Vendrell JP, Van de Perre P, Tuaillon E (2014) Comparison of EBV DNA viral load in whole blood, plasma, B-cells and B-cell culture supernatant. J Med Virol 86:851–856
Stevens SJ, Pronk I, Middeldorp JM (2001) Toward standardization of Epstein-Barr virus DNA load monitoring: unfractionated whole blood as preferred clinical specimen. J Clin Microbiol 39:1211–1216
Tsai DE, Luskin MR, Kremer BE, Chung AK, Arnoldi S, Paralkar VR, Nasta SD, Stadtmauer EA, Schuster SJ, Xavier M (2015) A pilot trial of quantitative Epstein-Barr virus polymerase chain reaction in patients undergoing treatment for their malignancy: potential use of Epstein-Barr virus polymerase chain reaction in multiple cancer types. Leuk Lymphoma 56:1530–1532
Funding
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).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Electronic supplementary material
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)
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)
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)
Rights and permissions
About this article
Cite this article
Cho, J., Kim, S.J., Park, S. et al. Significance of circulating Epstein-Barr virus DNA monitoring after remission in patients with extranodal natural killer T cell lymphoma. Ann Hematol 97, 1427–1436 (2018). https://doi.org/10.1007/s00277-018-3313-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-018-3313-x