Clinical impact of Epstein–Barr virus DNA in aggressive NK‐cell leukemia

Background: Aggressive NK-cell leukemia (ANKL) is an uncommon leukemic form of mature NK-cell neoplasm with poor prognosis, which is strongly associated with the Epstein–Barr virus (EBV). The information on EBV-DNA in the blood is limited. Method: We performed a nationwide survey of ANKL patients diagnosed between 2002 and 2021 at 65 institutes in Japan (ANKL22 study). The significance of EBV-DNA in ANKL was retrospectively analyzed. Results: A total of 101 patients with ANKL were enrolled in the ANKL22 study. Patients’ median age was 49 years (range, 17–90) and males accounted for 56%. EBV-DNA in peripheral blood was positive in 70 of 80 patients evaluated (88%). EBV encoded small RNA in situ hybridization (EBER-ISH) of the tissue samples was positive in 59 of 67 patients (88%). The positivity of EBV was consistent with that in the previous reports. Among patients of whom both EBV-DNA and EBER were assessed, the concordance rate was 91%. The median overall survival (OS) was 5.5 months and the 1-year OS of all ANKL patients was 25.2%. OS was not considerably different between EBV-positive (N = 77, either EBV-DNA or EBER-ISH) and EBV-negative patients (N = 10) (P = 0.29). The subjects for the EBV-DNA in peripheral blood measurement varied. EBV-DNA was measured in the whole blood in 54 of 67 patients tested (81%), 8 in plasma (12%) and 5 in serum (7%). Among patients whom EBV-DNA was measured in the whole blood, the EBV-DNA was detected at a median level of 765,000 copies/ml. Among those who received multi-agent chemotherapy, all patients with high EBV-DNA exceeding 106 copies/ml at diagnosis eventually died within 1 year (N = 12). The prognosis of patients with undetectable EBV-DNA after treatment initiation had a significantly better prognosis than those with identifiable EBV-DNA (median OS: 10.2 months vs. 4.0 months; P < 0.001). The median day of initial undetectable EBV-DNA was 92 days after diagnosis. The proportion of EBV-DNA negativity was significantly higher in patients who achieved complete response (CR) after initial chemotherapy than in the others (80% vs. 33%). Sixteen of 24 patients (67%) who achieved CR were treated with SMILE chemotherapy (dexamethasone (steroid), methotrexate, ifosfamide, L-asparaginase, and etoposide). The patients of whom EBV-DNA decreased more than 3 logs from the initial level around 2 months after treatment initiation (17%) had significantly better prognosis than the others (median OS: 10.2 months vs. 5.7 months; P = 0.04). Keywords: Aggressive T-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers, Extranodal non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. A. Fujimoto Honoraria: Chugai Pharmaceutical Co., Ltd., Meiji Seika Pharma, Sanofi T. Maeda Honoraria: Bristol Myers Squibb, Chugai, Janssen, Nippon Shinyaku, Novartis, Ono, Sanofi N. Fukuhara Honoraria: Chugai pharma, Genmab, Abbvie, Takeda, Eli Lilly, astrazeneca, Meiji Seika, Ono Pharmacuetical, Janssen, Bristol-Myers Squibb, Eisai, Kyowa-Hakko Kirin, Symbio and Novartis Research funding: Chugai pharma, Genmab, Abbvie, Takeda, Eli Lilly, Incyte and Chordia Therapeu K. Miyazaki Honoraria: Chugai Pharma, SymBio Pharmaceuticals, Janssen, Eisai, Nippon Shinyaku, AstraZeneca, Bristol-Myers Squibb Japan, Meiji Seika Kaisha, Abbvie, Novartis, Incyte, and Asahi Kasei Research funding: Eisai, Takeda, Nippon Shinyaku, Otsuka, Chugai Pharma, Asahi Kasei, Sumitomo Dainippon Pharma Oncology and Zenyaku Kogyo M. Yamaguchi Honoraria: AbbVie, Bristol Myers Squibb, Chugai Pharma, Janssen, Kyowa Kirin, Meiji Seika Pharma, MSD, Nippon Shinyaku, SymBio pharmaceuticals, Takeda Pharmaceutical Research funding: AstraZeneca, Chugai Pharma, Genmab, Incyte, Kyowa Kirin F. Ishida Honoraria: Janssen, Pfizer, CSL Behring, Astra Zeneca Research funding: Chugai Pharmaceuticals, CSL Behring, Daiichi-Sankyou, Kyowa Kirin R. Suzuki Honoraria: Kyowa-kirin, Chugai, Bristol-Meyer Squib, Eisai, MSD, Shionogi, Janssen, Abbvie, Takeda, Meiji Seika, Ohtsuka, Sumitomo Dainippon, Novartis, AstraZeneca, Nippon Shinyaku Research funding: Kyowa-kirin, Chugai, Taiho, Ohtsuka, Takeda, Shionogi, Eisai, Meiji Seika, Sysmex