Prognostic Value Of LMP1, CLA, NK-Cell Origin, and Pretreatment Bone Marrow EBER-ISH In Localized NK/T-Cell Lymphoma Prospectively Treated With Concurrent Chemoradiotherapy: An Ancillary Study Of Japan Clinical Oncology Group (JCOG) 0211
Authors: Yamaguchi Motoko , Takata Katsuyoshi , Yoshino Tadashi , Ishizuka Naoki , Oguchi Masahiko , Kobayashi Yukio , Isobe Yasushi , Ishizawa Kenichi , Kubota Nobuko , Itoh Kuniaki , Usui Noriko , Miyazaki Kana , Wasada Izumi , Nakamura Shigeo , Matsuno Yoshihiro , Oshimi Kazuo , Kinoshita Tomohiro , Tsukasaki Kunihiro , Tobinai Kensei 
Published: October 2019

Abstract
Latent membrane protein 1 (LMP1), cutaneous lymphocyte antigen (CLA), NK-cell origin, and pretreatment bone marrow Epstein-Barr virus - encoded RNA by in situ hybridization (EBER-ISH) have been reported as prognostic biomarkers in patients with extranodal NK/T-cell lymphoma (NKTCL), nasal type when treated with conventional therapy (Kanemitsu N, et al. Clin Cancer Res 2012; Yoshino T, et al. Br J Haematol 2002; Kim GE, et al. Head Neck 2004; Lee J, et al. Clin Cancer Res 2007). Recently, concurrent chemoradiotherapy has become a standard management approach for newly diagnosed, localized, nasal NKTCL (Yamaguchi M, et al. J Clin Oncol 2009; Kim SJ, et al. J Clin Oncol 2009). Because it is a new treatment modality for lymphoma, little data are available on the prognostic biomarkers of NKTCL among patients treated with concurrent chemoradiotherapy. To evaluate the prognostic significance of known immunophenotypic biomarkers among patients treated with concurrent chemoradiotherapy, we conducted an ancillary clinicopathologic study of JCOG0211, which was a phase I/II trial of concurrent chemoradiotherapy (RT-DeVIC) for newly diagnosed, localized, nasal NKTCL (Yamaguchi M, et al. J Clin Oncol 2009 & 2012).
The histological diagnoses of all 33 patients who were enrolled in JCOG0211 were confirmed as extranodal NKTCL, nasal type, by the Central Pathology Review. Pathological samples from 32 patients were available for the study. Patients received concurrent chemoradiotherapy comprising RT of 50 Gy and 3 cycles of DeVIC. The expression of LMP1 and CLA in tumor cells was examined using immunohistochemistry with paraffin sections of pretreatment lymphoma samples. Two monoclonal antibodies for TCRβ (βF1) and TCRγ (CγM1) were used to evaluate the cell of origin of lymphoma cells. Preliminary examination revealed that βF1 and CγM1 specifically recognized αβ and γδ T cells, respectively. Cases were considered to be of NK-cell origin if both TCRβ and TCRγ were negative. Cases showing positive staining for one or both of the antibodies (TCRβ and TCRγ) were determined to be of T-cell origin. Pretreatment bone marrow specimens from patients were examined for EBER-ISH.
LMP1 and CLA were positive in 66% (19/29) and 29% (9/31) of the cases, respectively. Among 32 cases examined for cell lineage, 27 (84%) cases were of NK-cell origin. Two (6%) cases were of αβ T-cell origin on the basis of positivity for TCRβ but not TCRγ, and 3 (9%) cases were of γδ T-cell origin on the basis of positivity for TCRγ but not TCRβ. Pretreatment bone marrow EBER-ISH was positive in 2 (7%) out of 29 cases examined.
The median follow-up was 68 months (range, 61-94). The overall survival (OS) was better in the LMP1-positive (LMP1+) group than in the LMP1-negative (LMP1-) group [hazard ratio (HR), 0.240; 95% confidence interval (CI), 0.057-1.013; 80% CI, 0.093-0.615; P=0.035]. The OS at 5 years was 84% (95% CI, 59-95%) in the LMP1+ patients and 50% (95% CI, 18-75%) in the LMP1- patients. The progression-free survival (PFS) at 5 years was 74% (95% CI, 48-88%) in the LMP1+ patients and 50% (95% CI, 18-75%) in the LMP1- patients. The HR of PFS in the LMP1+ patients was 0.421 (95% CI, 0.121-1.463; 80% CI, 0.187-0.950). There were no significant differences in the OS and PFS between the CLA+ and CLA- patients (5-yr OS, 56% vs. 77%; 5-yr PFS, 56% vs. 68%). All 5 patients of T-cell origin achieved complete response by RT-DeVIC and were alive without relapse at the last follow-up. The OS and PFS at 5 years in the 27 patients of NK-cell origin were 67% (95% CI, 46-81%) and 59% (95% CI, 39-75%), respectively. Two patients who were positive for pretreatment bone marrow EBER-ISH survived more than 5 years without disease progression (5-yr OS and PFS, 100%).
Our current study, for the first time, validated a favorable impact on the OS of LMP1 expression in newly diagnosed, localized, nasal NKTCL in a cohort uniformly treated with concurrent chemoradiotherapy. Further evaluation with a larger number of patients is warranted. (Supported in part by The National Cancer Center Research and Development Funds #21-6-3 & #23-A-17)

Disclosures:
Ishizuka: Sanofi: Employment. Oshimi:Eisai: Employment.