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Original Article

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Blood Res 2021; 56(2):

Published online June 30, 2021

https://doi.org/10.5045/br.2021.2021028

© The Korean Society of Hematology

Clinical impact of cell-free serum Epstein–Barr virus status in patients with newly diagnosed malignant lymphoma

Dong Won Baek1, Jung Min Lee1, Juhyung Kim1, Hee Jeong Cho1, Sang Kyun Sohn1, Ji Yeon Ham2, Soon Hee Chang2, Joon Ho Moon1, Deok-Hwan Yang3

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Departments of 1Hematology/Oncology 2Laboratory Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, 3Department of Hematology/Oncology, Chonnam National University Hwasun Hospital, School of Medicine, Chonnam National University, Hwasun, Korea

Correspondence to : Joon Ho Moon, M.D., Ph.D.
Deok-Hwan Yang, M.D., Ph.D.
Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, 130 Dongdeok-ro, Jung-gu, Daegu 41944, Korea (J.H.M.)
Department of Hematology/Oncology, Chonnam National University Hwasun Hospital, School of Medicine, Chonnam National University, 322 Seoyang-ro, Hwasun-eup, Hwasun 58128, Korea (D.H.Y.)
E-mail: J.H.M., jhmoon@knu.ac.kr D.H.Y., drydh1685@hotmail.com

Received: February 8, 2021; Revised: March 19, 2021; Accepted: March 19, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background
We analyzed cell-free serum Epstein‒Barr virus (EBV) DNA to identify its prognostic role in patients with newly diagnosed lymphoma.
Methods
We retrospectively reviewed patients diagnosed with lymphoma between January 2014 and July 2020. Patients were enrolled according to the following criteria: i) pathologically confirmed lymphomas according to the World Health Organization criteria, ii) age over 18 years, iii) serum EBV DNA measurement using polymerase chain reaction prior to first-line therapy, and iv) receipt of curative standard chemotherapy. In total, 263 patients met these criteria and were included in this study.
Results
Serum EBV DNA was detected in 79 patients (30.0%). Patients with positive serum EBV tended to be older (P =0.090), and the proportion of T-cell lineage lymphomas was higher than that of B-cell lymphomas (P =0.003). EBV positivity was significantly associated with more advanced disease based on the Ann Arbor staging system (P =0.008) and the International Prognostic Index (P =0.009). EBV positivity was also associated with higher disease relapse (P =0.038) and death rates (P =0.005). EBV-positive lymphomas further showed inferior long-term survival outcomes in terms of progression-free survival (PFS) (P=0.053) and overall survival (OS) (P=0.014). In the subgroup analyses, serum EBV positivity was a significant prognostic factor for patients with B-cell lineage lymphomas in terms of PFS (P =0.003) and OS (P=0.033).
Conclusion
We demonstrated that cell-free serum EBV DNA status at the time of diagnosis has potential as a prognostic biomarker for patients with newly diagnosed malignant lymphomas.

Keywords Epstein‒Barr virus, Lymphoma, Prognosis, Biomarker

Article

Original Article

Blood Res 2021; 56(2): 65-71

Published online June 30, 2021 https://doi.org/10.5045/br.2021.2021028

Copyright © The Korean Society of Hematology.

Clinical impact of cell-free serum Epstein–Barr virus status in patients with newly diagnosed malignant lymphoma

Dong Won Baek1, Jung Min Lee1, Juhyung Kim1, Hee Jeong Cho1, Sang Kyun Sohn1, Ji Yeon Ham2, Soon Hee Chang2, Joon Ho Moon1, Deok-Hwan Yang3

Departments of 1Hematology/Oncology 2Laboratory Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, 3Department of Hematology/Oncology, Chonnam National University Hwasun Hospital, School of Medicine, Chonnam National University, Hwasun, Korea

Correspondence to:Joon Ho Moon, M.D., Ph.D.
Deok-Hwan Yang, M.D., Ph.D.
Department of Hematology/Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, 130 Dongdeok-ro, Jung-gu, Daegu 41944, Korea (J.H.M.)
Department of Hematology/Oncology, Chonnam National University Hwasun Hospital, School of Medicine, Chonnam National University, 322 Seoyang-ro, Hwasun-eup, Hwasun 58128, Korea (D.H.Y.)
E-mail: J.H.M., jhmoon@knu.ac.kr D.H.Y., drydh1685@hotmail.com

Received: February 8, 2021; Revised: March 19, 2021; Accepted: March 19, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background
We analyzed cell-free serum Epstein‒Barr virus (EBV) DNA to identify its prognostic role in patients with newly diagnosed lymphoma.
Methods
We retrospectively reviewed patients diagnosed with lymphoma between January 2014 and July 2020. Patients were enrolled according to the following criteria: i) pathologically confirmed lymphomas according to the World Health Organization criteria, ii) age over 18 years, iii) serum EBV DNA measurement using polymerase chain reaction prior to first-line therapy, and iv) receipt of curative standard chemotherapy. In total, 263 patients met these criteria and were included in this study.
Results
Serum EBV DNA was detected in 79 patients (30.0%). Patients with positive serum EBV tended to be older (P =0.090), and the proportion of T-cell lineage lymphomas was higher than that of B-cell lymphomas (P =0.003). EBV positivity was significantly associated with more advanced disease based on the Ann Arbor staging system (P =0.008) and the International Prognostic Index (P =0.009). EBV positivity was also associated with higher disease relapse (P =0.038) and death rates (P =0.005). EBV-positive lymphomas further showed inferior long-term survival outcomes in terms of progression-free survival (PFS) (P=0.053) and overall survival (OS) (P=0.014). In the subgroup analyses, serum EBV positivity was a significant prognostic factor for patients with B-cell lineage lymphomas in terms of PFS (P =0.003) and OS (P=0.033).
Conclusion
We demonstrated that cell-free serum EBV DNA status at the time of diagnosis has potential as a prognostic biomarker for patients with newly diagnosed malignant lymphomas.

Keywords: Epstein‒Barr virus, Lymphoma, Prognosis, Biomarker

Fig 1.

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Figure 1.Kaplan–Meier curves for long-term survival outcomes. Patients with positive serum EBV status showed inferior (A) PFS and (B) OS compared with EBV-negative patients.
Blood Research 2021; 56: 65-71https://doi.org/10.5045/br.2021.2021028

Fig 2.

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Figure 2.Kaplan–Meier curves for long-term survival outcomes. In the B-cell lymphoma group, serum EBV-positive patients showed inferior (A) PFS and (B) OS compared with EBV-negative patients.
Blood Research 2021; 56: 65-71https://doi.org/10.5045/br.2021.2021028

Fig 3.

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Figure 3.Kaplan–Meier curves for long-term survival outcomes. In the T-cell lymphoma group, serum EBV positivity was not a significant factor affecting (A) PFS. However, EBV-positive patients showed inferior (B) OS.
Blood Research 2021; 56: 65-71https://doi.org/10.5045/br.2021.2021028

Table 1 . Patient characteristics..

VariablesN (%)
N263
Age, median years (range)62 (18–87)
Sex
Male141 (53.6)
Female122 (46.4)
Diagnosis
Hodgkin lymphoma11 (4.2)
Diffuse large B-cell lymphoma179 (68.1)
Follicular lymphoma13 (4.9)
Mantle cell lymphoma8 (3.0)
NK/T-cell lymphoma14 (5.3)
Angioimmunoblastic T-cell lymphoma19 (7.2)
Peripheral T-cell lymphoma13 (4.9)
Anaplastic large cell lymphoma6 (2.3)
Ann Arbor staging
I41 (15.6)
II62 (23.6)
III74 (28.1)
IV86 (32.7)
Prognostic risk groupa)
Low risk97 (36.9)
Low-intermediate risk71 (27.0)
High-intermediate risk62 (23.6)
High risk33 (12.5)
Positive serum EBV DNA79 (30.0)
Relapse/refractory67 (25.5)
Death65 (24.7)

a)The International Prognostic Index (IPI) was used for non-Hodgkin lymphoma. The International Prognostic Score (IPS) was adjusted for patients with Hodgkin lymphoma, and IPS 0 and 1 were classified as low risk, 2 as low-intermediate, 3 as high-intermediate, and ≥4 as high-risk group in this analysis..

Abbreviations: EBV, Epstein–Barr virus; NK/T, natural killer T..

Table 2 . Proportion of positive serum EBV according to the lymphoma subtype and clinical outcomes of serum EBV-positive patients..

DiagnosisTotal patients
(N=263)		EBV positive
(N=79)		CR/PR (%)Relapse/refractory (%)Death (%)
Hodgkin lymphoma114 (36.3)2 (50.0)2 (50.0)2 (50.0)
Diffuse large B-cell lymphoma17942 (23.5)40 (95.2)11 (26.2)12 (28.6)
Follicular lymphoma133 (23.1)3 (100)2 (66.7)2 (66.7)
Mantle cell lymphoma85 (62.5)5 (100)4 (80.0)1 (20.0)
NK/T-cell lymphoma148 (57.1)7 (87.5)1 (12.5)2 (25.0)
Angioimmunoblastic T-cell lymphoma199 (47.4)8 (88.9)3 (33.3)4 (44.4)
Peripheral T-cell lymphoma137 (53.8)6 (85.7)3 (42.9)5 (71.4)
Anaplastic large cell lymphoma61 (16.7)01 (100)1 (100)

Abbreviations: CR/PR, complete response/partial response; EBV, Epstein–Barr virus; NK/T, natural killer T-cell..

Table 3 . Clinicopathological characteristics according to serum EBV positivity..

VariablesEBV-negative (%)EBV-positive (%)P
N18479
Age, median years (range)59.6 (19–81)62.5 (18–87)0.090
Sex0.176
Male97 (52.7)44 (55.7)
Female87 (47.3)35 (44.3)
Diagnosis0.003
B cell lineage lymphomas157 (85.3)54 (68.4)
T-cell lineage lymphomas27 (14.7)25 (31.6)
Ann Arbor staging0.008
I32 (17.4)9 (11.4)
II52 (28.3)10 (12.7)
III44 (23.9)30 (38.0)
IV56 (30.4)30 (38.0)
Prognostic risk groupa)0.005
Low risk79 (42.9)18 (22.8)
Low-intermediate risk40 (21.7)31 (39.2)
High-intermediate risk44 (23.9)18 (22.8)
High risk21 (11.4)12 (15.2)
Relapse/refractory39 (21.2)27 (34.2)0.038
Death36 (19.6)29 (36.7)0.005

a)The International Prognostic Index (IPI) was used for non-Hodgkin lymphoma. The International Prognostic Score (IPS) was adjusted for patients with Hodgkin lymphoma, and IPS 0 and 1 were classified as low risk, 2 as low-intermediate, 3 as high-intermediate, and ≥4 as high-risk group in this analysis..

Abbreviation: EBV, Epstein–Barr virus..

Table 4 . Factors affecting long-term clinical outcomes..

UnivariateMultivariate
HR95% CIPHR95% CIP
(A) Factors affecting progression-free survival
Age>70 vs. ≤701.1440.714–1.8350.574
Male vs. female0.9020.589–1.3830.636
B-cell vs. T-cell0.5280.326–0.8530.0090.5030.318–0.7950.003
Ann Arbor staging
III, IV vs. I, II0.9840.525–1.8430.958
Prognostic risk group
High-intermediate, high vs. Low, low-intermediate3.0181.699–5.358<0.0013.0832.022–4.699<0.001
EBV positive vs. negative1.3541.102–1.7230.0451.2111.097–1.5820.048
(B) Factors affecting the OS
Age>70 vs. ≤701.0330.593–1.7990.909
Male vs. Female0.9530.575–1.5780.851
B-cell vs. T-cell0.6180.350–1.0920.0970.6240.358–1.0870.096
Ann Arbor staging
III, IV vs. I, II0.9870.441–2.2090.975
Prognostic risk group
High-intermediate, high vs. Low, low-intermediate4.3892.157–8.929<0.0014.3522.612–7.252<0.001
EBV positive vs. negative1.6470.990–2.7380.0541.6430.108–2.7050.050

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