Advertisement

The landscape of new drugs in extranodal NK/T-cell lymphoma

  • Author Footnotes
    1 Both authors contributed equally to this work.
    Liang Wang
    Correspondence
    Corresponding author at: Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
    Footnotes
    1 Both authors contributed equally to this work.
    Affiliations
    Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China

    Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University & Capital Medical University, Beijing Tongren Hospital, Beijing 100730, China
    Search for articles by this author
  • Author Footnotes
    1 Both authors contributed equally to this work.
    Lin-Rong Li
    Footnotes
    1 Both authors contributed equally to this work.
    Affiliations
    Department of Breast Surgery, Peking Union Medical College Hospital, Beijing 100032, China
    Search for articles by this author
  • Luo Zhang
    Affiliations
    Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China

    Beijing Key Laboratory of Nasal Disease, Beijing Institute of Otolaryngology, Beijing 100730, China
    Search for articles by this author
  • Jing-Wen Wang
    Affiliations
    Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
    Search for articles by this author
  • Author Footnotes
    1 Both authors contributed equally to this work.

      Highlights

      • There has been no standard treatment for advanced-stage extranodal NK/T-cell lymphoma (ENKTCL).
      • Distinctive molecular subgroups are discovered within the disease entity of ENKTCL.
      • Novel targeted therapy and immunotherapy have emerged to be promising.
      • The treatment paradigm of ENKTCL may change in the near future.

      Abstract

      To date, much progress has been made in early-stage extranodal NK/T-cell lymphoma (ENKTCL), and risk-adapted therapy with radiotherapy (RT) alone for the low-risk group and RT combined with asparaginase-based chemotherapy (CT) for the high-risk group yields favorable outcomes. However, optimal treatment strategies have not been defined yet for advanced-stage ENKTCL. Historically, ENKTCL responded poorly to conventional anthracycline-based chemotherapy probably because of inherent multidrug resistance (MDR). The fact that ENKTCL cells lack asparagine synthetase (ASNS) activity warranted the use of L-asparaginase or pegaspargase as frontline chemotherapies. Even though, due to high mortality of the disease, approximately 50% patients failing the frontline therapy arrived at dismal clinical outcomes with a median progression-free survival (PFS) less than 8 months. As distinctive molecular and biological subgroups are increasingly discovered within the disease entity of ENKTCL, novel targeted therapies and immunotherapy are of the urgent need for those heterogeneous subgroups. In this review, we sought to summarize the preclinical and clinical results of 6 categories of promising targeted therapy and immunotherapy for the treatment of ENKTCL, including monoclonal antibodies, immune checkpoint inhibitors, small-molecular inhibitors, epigenetic therapy, immunomodulatory drugs, and adoptive T-cell therapy, and these might change the landscape of treatment for ENKTCL in the near future.

      Keywords

      To read this article in full you will need to make a payment
      ESMO Member Login
      Login with your ESMO username and password.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Perry A.M.
        • Diebold J.
        • Nathwani B.N.
        • MacLennan K.A.
        • Muller-Hermelink H.K.
        • Bast M.
        • et al.
        Non-Hodgkin lymphoma in the developing world: review of 4539 cases from the International Non-Hodgkin Lymphoma Classification Project.
        Haematologica. 2016 Oct 1; 101: 1244-1250
        • Au W.Y.
        • Weisenburger D.D.
        • Intragumtornchai T.
        • Nakamura S.
        • Kim W.-S.
        • Sng I.
        • et al.
        Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project.
        Blood. 2009 Apr 23; 113: 3931-3937
        • Feng Y.
        • Rao H.
        • Lei Y.
        • Huang Y.
        • Wang F.
        • Zhang Y.
        • et al.
        CD30 expression in extranodal natural killer/T-cell lymphoma, nasal type among 622 cases of mature T-cell and natural killer-cell lymphoma at a single institution in South China.
        Chin J Cancer. 2017; 36
        • Laurini J.A.
        • Perry A.M.
        • Boilesen E.
        • Diebold J.
        • Maclennan K.A.
        • Müller-Hermelink H.K.
        • et al.
        Classification of non-Hodgkin lymphoma in Central and South America: a review of 1028 cases.
        Blood. 2012 Dec 6; 120: 4795-4801
        • Adams S.V.
        • Newcomb P.A.
        • Shustov A.R.
        Racial patterns of peripheral T-Cell Lymphoma Incidence and Survival in the United States.
        J Clin Oncol Off J Am Soc Clin Oncol. 2016 Mar 20; 34: 963-971
        • Peng R.-J.
        • Han B.-W.
        • Cai Q.-Q.
        • Zuo X.-Y.
        • Xia T.
        • Chen J.-R.
        • et al.
        Genomic and transcriptomic landscapes of Epstein-Barr virus in extranodal natural killer T-cell lymphoma.
        Leukemia. 2019; 33: 1451-1462
        • Jaccard A.
        • Hermine O.
        A major turning point in NK/T-cell lymphoma?.
        Blood. 2017; 129: 2342-2343
        • Yang Y.
        • Zhu Y.
        • Cao J.-Z.
        • Zhang Y.-J.
        • Xu L.-M.
        • Yuan Z.-Y.
        • et al.
        Risk-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma: analysis from a multicenter study.
        Blood. 2015 Sep 17; 126: 1424-1432
        • Wang Z.-Y.
        • Li Y.-X.
        • Wang W.-H.
        • Jin J.
        • Wang H.
        • Song Y.-W.
        • et al.
        Primary radiotherapy showed favorable outcome in treating extranodal nasal-type NK/T-cell lymphoma in children and adolescents.
        Blood. 2009 Nov 26; 114: 4771-4776
        • Yamaguchi M.
        • Tobinai K.
        • Oguchi M.
        • Ishizuka N.
        • Kobayashi Y.
        • Isobe Y.
        • et al.
        Concurrent Chemoradiotherapy for Localized Nasal Natural Killer/T-Cell Lymphoma: An Updated Analysis of the Japan Clinical Oncology Group Study JCOG0211.
        J Clin Oncol. 2012 Nov 10; 30: 4044-4046
        • Kwong Y.L.
        • Kim S.J.
        • Tse E.
        • Oh S.Y.
        • Kwak J.Y.
        • Eom H.S.
        • et al.
        Sequential chemotherapy/radiotherapy was comparable with concurrent chemoradiotherapy for stage I/II NK/T-cell lymphoma.
        Ann Oncol. 2018 Jan 1; 29: 256-263
        • Tse E.
        • Kwong Y.-L.
        How I treat NK/T-cell lymphomas.
        Blood. 2013 Jun 20; 121: 4997-5005
        • Wang L.
        • Xia Z.
        • Huang H.
        • Lu Y.
        • Zhang Y.
        Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the treatment of stage IE/IIE extranodal natural killer/T cell lymphoma, nasal type: 13-year follow-up in 135 patients.
        Int J Hematol. 2012 Nov; 96: 617-623
        • Yamaguchi M.
        • Kita K.
        • Miwa H.
        • Nishii K.
        • Oka K.
        • Ohno T.
        • et al.
        Frequent expression of P-glycoprotein/MDR1 by nasal T-cell lymphoma cells.
        Cancer. 1995 Dec 1; 76: 2351-2356
        • Li Y.
        • Zhang X.
        • Hu T.
        • Han L.
        • Li R.
        • Wen J.
        • et al.
        Asparagine synthetase expression and its potential prognostic value in patients with NK/T cell lymphoma.
        Oncol Rep. 2014 Aug; 32: 853-859
        • Ando M.
        • Sugimoto K.
        • Kitoh T.
        • Sasaki M.
        • Mukai K.
        • Ando J.
        • et al.
        Selective apoptosis of natural killer-cell tumours by l-asparaginase.
        Br J Haematol. 2005 Sep; 130: 860-868
        • Yamaguchi M.
        • Suzuki R.
        • Kwong Y.-L.
        • Kim W.S.
        • Hasegawa Y.
        • Izutsu K.
        • et al.
        Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia.
        Cancer Sci. 2008 May; 99: 1016-1020
        • Yamaguchi M.
        • Kwong Y.-L.
        • Kim W.S.
        • Maeda Y.
        • Hashimoto C.
        • Suh C.
        • et al.
        Phase II Study of SMILE Chemotherapy for Newly Diagnosed Stage IV, Relapsed, or Refractory Extranodal Natural Killer (NK)/T-Cell Lymphoma, Nasal Type: The NK-Cell Tumor Study Group Study.
        J Clin Oncol. 2011 Nov 20; 29: 4410-4416
        • Jaccard A.
        • Petit B.
        • Girault S.
        • Suarez F.
        • Gressin R.
        • Zini J.-M.
        • et al.
        L-Asparaginase-based treatment of 15 western patients with extranodal NK/T-cell lymphoma and leukemia and a review of the literature.
        Ann Oncol. 2008 Jul 22; 20: 110-116
        • Ahn H.K.
        • Kim S.J.
        • Hwang D.W.
        • Ko Y.H.
        • Tang T.
        • Lim S.T.
        • et al.
        Gemcitabine alone and/or containing chemotherapy is efficient in refractory or relapsed NK/T-cell lymphoma.
        Invest New Drugs. 2013 Apr 1; 31: 469-472
        • Lim S.H.
        • Hong J.Y.
        • Lim S.T.
        • Hong H.
        • Arnoud J.
        • Zhao W.
        • et al.
        Beyond first-line non-anthracycline-based chemotherapy for extranodal NK/T-cell lymphoma: clinical outcome and current perspectives on salvage therapy for patients after first relapse and progression of disease.
        Ann Oncol. 2017 Sep 1; 28: 2199-2205
        • Xiong J.
        • Cui B.-W.
        • Wang N.
        • Dai Y.-T.
        • Zhang H.
        • Wang C.-F.
        • et al.
        Genomic and Transcriptomic Characterization of Natural Killer T Cell Lymphoma.
        Cancer Cell. 2020 Mar; 37: 403-419.e6
      1. de Mel S, Hue SS-S, Jeyasekharan AD, Chng W-J, Ng S-B. Molecular pathogenic pathways in extranodal NK/T cell lymphoma. J Hematol OncolJ Hematol Oncol [Internet]. 2019 [cited 2019 Aug 23];12(1). Available from: [object Object].

      2. Kim SJ, Yoon SE, Kim WS. Treatment of localized extranodal NK/T cell lymphoma, nasal type: a systematic review. J Hematol OncolJ Hematol Oncol. 2018 20;11(1):140.

        • Lund F.E.
        Signaling properties of CD38 in the mouse immune system: enzyme-dependent and -independent roles in immunity.
        Mol Med Camb Mass. 2006 Dec; 12: 328-333
        • Ng S.-B.
        • Selvarajan V.
        • Huang G.
        • Zhou J.
        • Feldman A.L.
        • Law M.
        • et al.
        Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling.
        J Pathol. 2011 Mar; 223: 496-510
        • Wang L.
        • Wang H.
        • Li P.
        • Lu Y.
        • Xia Z.
        • Huang H.
        • et al.
        CD38 expression predicts poor prognosis and might be a potential therapy target in extranodal NK/T cell lymphoma, nasal type.
        Ann Hematol. 2015 Aug; 94: 1381-1388
        • Hari P.
        • Raj R.V.
        • Olteanu H.
        Targeting CD38 in Refractory Extranodal Natural Killer Cell–T-Cell Lymphoma.
        N Engl J Med. 2016 Oct 13; 375: 1501-1502
      3. Huang H, Kim W-S, Yao M, Kim TM, Yoon D, Cho S-G, et al. Daratumumab Monotherapy for Patients with Relapsed or Refractory (R/R) Natural Killer/T-Cell Lymphoma (NKTCL), Nasal Type: Updated Results from an Open-Label, Single-Arm, Multicenter Phase 2 Study. Blood. 2019 Nov 13;134(Supplement_1):1568–1568.

        • Mustafa N.
        • Nee A.H.F.
        • Chooi J.Y.
        • Toh S.H.M.
        • Hee Y.T.
        • Selvarajan V.
        • et al.
        CD55 and CD59 Can Limit the Anti-Tumor Efficacy of Daratumumab in Natural Killer/T-Cell Lymphoma.
        Blood. 2018; 132: 1663
        • Li P.
        • Jiang L.
        • Zhang X.
        • Liu J.
        • Wang H.
        CD30 expression is a novel prognostic indicator in extranodal natural killer/T-cell lymphoma, nasal type.
        BMC Cancer. 2014 Dec; 14
        • Kim H.K.
        • Moon S.M.
        • Moon J.H.
        • Park J.E.
        • Byeon S.
        • Kim W.S.
        Complete remission in CD30-positive refractory extranodal NK/T-cell lymphoma with brentuximab vedotin.
        Blood Res. 2015; 50: 254
        • Poon L.-M.
        • Kwong Y.-L.
        Complete remission of refractory disseminated NK/T cell lymphoma with brentuximab vedotin and bendamustine.
        Ann Hematol. 2016 Apr; 95: 847-849
        • Kim S.J.
        • Yoon D.H.
        • Kim J.S.
        • Kang H.J.
        • Lee H.W.
        • Eom H.-S.
        • et al.
        Efficacy of Brentuximab Vedotin in Relapsed or Refractory High-CD30-Expressing Non-Hodgkin Lymphomas: Results of a Multicenter, Open-Labeled Phase II Trial.
        Cancer Res Treat. 2020 Apr; 52: 374-387
        • Bien E.
        • Balcerska A.
        Serum soluble interleukin 2 receptor alpha in human cancer of adults and children: A review.
        Biomark Biochem Indic Expo Response Susceptibility Chem. 2008; 13: 1-26
        • Liang W.
        • Ding-zhun L.
        • Jing Z.
        • Zhong-jun X.
        • Xiong-wen P.
        • Yue L.
        Clinical significance of serum soluble interleukin-2 receptor-α in extranodal natural killer/T-cell lymphoma (ENKTL): a predictive biomarker for treatment efficacy and valuable prognostic factor.
        Med Oncol. 2013 Sep 15; 30: 723
        • Wang L.
        • Bi X.
        • Zhu Y.
        • He Y.
        • Lai Q.
        • Xia Z.
        • et al.
        IL-2Rα up-regulation is mediated by latent membrane protein 1 and promotes lymphomagenesis and chemotherapy resistance in natural killer/T-cell lymphoma.
        Cancer Commun. Dec 2018; 38
        • Olin R.L.
        • Nichols K.E.
        • Naghashpour M.
        • Wasik M.
        • Shelly B.
        • Stadtmauer E.A.
        • et al.
        Successful use of the anti-CD25 antibody daclizumab in an adult patient with hemophagocytic lymphohistiocytosis.
        Am J Hematol. 2008 Sep; 83: 747-749
        • Chan J.
        • Tsang W.
        • Ng C.
        Clarification of CD3 immunoreactivity in nasal T/natural killer cell lymphomas: the neoplastic cells are often CD3 epsilon+ [letter; comment].
        Blood. 1996; 87: 839
        • Nagato T.
        • Ohkuri T.
        • Ohara K.
        • Hirata Y.
        • Kishibe K.
        • Komabayashi Y.
        • et al.
        Programmed death-ligand 1 and its soluble form are highly expressed in nasal natural killer/T-cell lymphoma: a potential rationale for immunotherapy.
        Cancer Immunol Immunother. 2017 Jul; 66: 877-890
        • Chanan-Khan A.A.
        • Jagannath S.
        • Munshi N.C.
        • Schlossman R.L.
        • Anderson K.C.
        • Lee K.
        • et al.
        Phase I Study of huN901-DM1 (BB-10901) in Patients with Relapsed and Relapsed/Refractory CD56-Positive Multiple Myeloma.
        Blood. 2007; 110: 1174
        • Ishitsuka K.
        • Jimi S.
        • Goldmacher V.
        • Ab O.
        • Tamura K.
        Targeting CD56 by the maytansinoid immunoconjugate IMGN901 (huN901-DM1): A potential therapeutic modality implication against natural killer/T cell malignancy.
        Br J Haematol. 2008 May 1; 141: 129-131
        • Laurence A.D.J.
        Location, movement and survival: the role of chemokines in haematopoiesis and malignancy: Review.
        Br J Haematol. 2006 Feb; 132: 255-267
        • Kanazawa T.
        • Hiramatsu Y.
        • Iwata S.
        • Siddiquey M.
        • Sato Y.
        • Suzuki M.
        • et al.
        Anti-CCR4 Monoclonal Antibody Mogamulizumab for the Treatment of EBV-Associated T- and NK-Cell Lymphoproliferative Diseases.
        Clin Cancer Res. 2014 Oct 1; 20: 5075-5084
        • Kumai T.
        • Nagato T.
        • Kobayashi H.
        • Komabayashi Y.
        • Ueda S.
        • Kishibe K.
        • et al.
        CCL17 and CCL22/CCR4 signaling is a strong candidate for novel targeted therapy against nasal natural killer/T-cell lymphoma.
        Cancer Immunol Immunother. 2015 Jun; 64: 697-705
        • Fang W.
        • Hong S.
        • Chen N.
        • He X.
        • Zhan J.
        • Qin T.
        • et al.
        PD-L1 is remarkably over-expressed in EBV-associated pulmonary lymphoepithelioma-like carcinoma and related to poor disease-free survival.
        Oncotarget. 2015 Oct 20; 6: 33019-33032
        • Laurent C.
        • Fabiani B.
        • Do C.
        • Tchernonog E.
        • Cartron G.
        • Gravelle P.
        • et al.
        Immune-checkpoint expression in Epstein-Barr virus positive and negative plasmablastic lymphoma: a clinical and pathological study in 82 patients.
        Haematologica. 2016 Aug 1; 101: 976-984
        • Green M.R.
        • Rodig S.
        • Juszczynski P.
        • Ouyang J.
        • Sinha P.
        • O’Donnell E.
        • et al.
        Constitutive AP-1 Activity and EBV Infection Induce PD-L1 in Hodgkin Lymphomas and Posttransplant Lymphoproliferative Disorders: Implications for Targeted Therapy.
        Clin Cancer Res. 2012 Mar 15; 18: 1611-1618
        • Bi X.
        • Wang H.
        • Zhang W.
        • Wang J.
        • Liu W.
        • Xia Z.
        • et al.
        PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma.
        J Hematol Oncol. 2016; 9
        • Xue W.
        • Li W.
        • Zhang T.
        • Li Z.
        • Wang Y.
        • Qiu Y.
        • et al.
        Anti-PD1 up-regulates PD-L1 expression and inhibits T-cell lymphoma progression: possible involvement of an IFN-γ-associated JAK-STAT pathway.
        OncoTargets Ther. 2019 Mar; 12: 2079-2088
        • Kwong Y.-L.
        • Chan T.S.Y.
        • Tan D.
        • Kim S.J.
        • Poon L.-M.
        • Mow B.
        • et al.
        PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase.
        Blood. 2017 Apr 27; 129: 2437-2442
      4. Rong Tao. Sintilimab for relapsed/refractory (r/r) extranodal NK/T cell lymphoma (ENKTL): A multicenter, single-arm, phase 2 trial (ORIENT-4). In Chicago, IL; 2019. p. 102–3.

        • Andrae J.
        • Gallini R.
        • Betsholtz C.
        Role of platelet-derived growth factors in physiology and medicine.
        Genes Dev. 2008 May 15; 22: 1276-1312
      5. Gotlib J, Cools J, M Malone J, L Schrier S, Gary Gilliland D, E Coutré S. The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood. 2004 May 1;103(8):2879–91.

        • Martinho O.
        • Longatto-Filho A.
        • Lambros M.B.K.
        • Martins A.
        • Pinheiro C.
        • Silva A.
        • et al.
        Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomas.
        Br J Cancer. 2009; 101: 973-982
        • Yang J.
        • Du X.
        • Lazar A.J.F.
        • Pollock R.
        • Hunt K.
        • Chen K.
        • et al.
        Genetic aberrations of gastrointestinal stromal tumors.
        Cancer. 2008 Oct 1; 113: 1532-1543
        • Li J.
        • Chen P.
        • Liu W.
        • Xia Z.
        • Shi F.
        • Zhong M.
        Expression and significance of Ku80 and PDGFR-α in nasal NK/T-cell lymphoma.
        Pathol - Res Pract. 2016 Mar; 212: 204-209
        • Huang Y.
        • de Reynies A.
        • de Leval L.
        • Ghazi B.
        • Martin-Garcia N.
        • Travert M.
        • et al.
        Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type.
        Blood. 2010 Feb 11; 115: 1226-1237
        • Lu L.
        • Fu X.
        • Li Z.
        • Qiu Y.
        • Li W.
        • Zhou Z.
        • et al.
        Platelet-derived growth factor receptor alpha (PDGFRα) is overexpressed in NK/T-cell lymphoma and mediates cell survival.
        Biochem Biophys Res Commun. 2018 Oct; 504: 525-531
        • Huang Y.
        • de Leval L.
        • Gaulard P.
        Molecular underpinning of extranodal NK/T-cell lymphoma.
        Best Pract Res Clin Haematol. 2013 Mar; 26: 57-74
        • Yu H.
        • Kortylewski M.
        • Pardoll D.
        Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment: Tumour immunology.
        Nat Rev Immunol. 2007 Jan; 7: 41-51
        • Coppo P.
        • Gouilleux-Gruart V.
        • Huang Y.
        • Bouhlal H.
        • Bouamar H.
        • Bouchet S.
        • et al.
        STAT3 transcription factor is constitutively activated and is oncogenic in nasal-type NK/T-cell lymphoma.
        Leukemia. 2009 Sep; 23: 1667-1678
        • Geng L.
        • Li X.
        • Zhou X.
        • Fang X.
        • Yuan D.
        • Wang X.
        WP1066 exhibits antitumor efficacy in nasal-type natural killer/T-cell lymphoma cells through downregulation of the STAT3 signaling pathway.
        Oncol Rep. 2016 Nov; 36: 2868-2874
        • Koo G.C.
        • Tan S.Y.
        • Tang T.
        • Poon S.L.
        • Allen G.E.
        • Tan L.
        • et al.
        Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma.
        Cancer Discov. 2012 Jul; 2: 591-597
        • Liu J.
        • Liang L.
        • Li D.
        • Nong L.
        • Zheng Y.
        • Huang S.
        • et al.
        JAK3/STAT3 oncogenic pathway and PRDM1 expression stratify clinicopathologic features of extranodal NK/T-cell lymphoma, nasal type.
        Oncol Rep. 2019 Apr; 12: 3219-3232
        • Tao M.
        • Xing H.
        • Bian T.
        • Li X.
        • Yan C.
        • Huang J.
        • et al.
        Expression and significance of PTEN/PI3K/AKT/mTOR signaling pathway in extranodal NK/T cell lymphoma.
        Chongqing Med. 2017; 46: 4514-4519
        • Fu X.
        • Zhang X.
        • Gao J.
        • Li X.
        • Zhang L.
        • Li L.
        • et al.
        Phosphatase and tensin homolog (PTEN) is down-regulated in human NK/T-cell lymphoma and corrects with clinical outcomes.
        Medicine (Baltimore). 2017 Jul; 96e7111
        • Sun L.
        • Zhao Y.
        • Shi H.
        • Ma C.
        • Wei L.
        LMP-1 induces survivin expression to inhibit cell apoptosis through the NF-κB and PI3K/Akt signaling pathways in nasal NK/T-cell lymphoma.
        Oncol Rep. 2015 May; 33: 2253-2260
        • Kawada J.-I.
        • Ito Y.
        • Iwata S.
        • Suzuki M.
        • Kawano Y.
        • Kanazawa T.
        • et al.
        mTOR Inhibitors Induce Cell-Cycle Arrest and Inhibit Tumor Growth in Epstein-Barr Virus-Associated T and Natural Killer Cell Lymphoma Cells.
        Clin Cancer Res. 2014; 20: 5412-5422
        • Huang D.
        • Song T.L.
        • Nairismägi M.
        • Laurensia Y.
        • Pang W.
        • Zhe D.C.M.
        • et al.
        Evaluation of the PIK3 pathway in peripheral T-cell lymphoma and NK/T-cell lymphoma.
        Br J Haematol. 2020; Jan
        • Jumei Liu
        • Li Liang
        • Sixia Huang
        • Ting Li
        PRDM1 expression and its relationship with PI3K/AKT pathway activation in extranodal NK/T cell lymphoma-nasal type.
        Chin J Hematol. 2018; 39: 1010-1016
      6. McDonald DM, Chapman HA, Wei Y, Bhagwandin V, Williamson CW, Christensen JG, et al. Abstract SY41-02: Tumor cell effects of vascular reprogramming: Contributions of c-MET and VEGF. Cancer Res. 2012;72(8 Supplement):SY41-02.

        • Fang H.
        • Hao D.
        • Jun C.
        • Wenhao Z.
        • Rong T.
        Autocrine IGF-1/IGF-1R signaling promotes cell migration and invasion in NK/T-cell lymphoma cells.
        J Clin Hematol. 2015; 27: 334-340
      7. Jorgensen JM, Sorensen FB, Bendix K, Nielsen JL, Funder A, Karkkainen MJ, et al. Correlation between epstein-barr virus (EBV) RNA expression and vascular endothelial growth factor (VEGF) expression in different subtypes of peripheral T-cell lymphomas (PTCL) and prognostic implications. Ann Oncol. 2008;19:113–113.

        • Tang Q.
        • Liu W.
        • Zhang W.
        • Yang F.
        • He M.
        • Xia Q.
        • et al.
        Expression of CYR61 and VEGF in extranodal nasal-type NK/T cell lymphoma and their significances.
        Zhonghua Xue Ye Xue Za Zhi. 2006 Oct; 27: 661-665
        • Kim S.J.
        • Hong M.
        • Do I.-G.
        • Lee S.H.
        • Ryu K.J.
        • Yoo H.Y.
        • et al.
        Serum survivin and vascular endothelial growth factor in extranodal NK/T-cell lymphoma, nasal type: implications for a potential new prognostic indicator.
        Haematologica. 2015 Mar; 100: e106-e109
        • Lam B.Q.
        • Dai L.
        • Qin Z.
        The role of HGF/c-MET signaling pathway in lymphoma.
        J Hematol OncolJ Hematol Oncol. 2016; 9: 135
        • Kumai T.
        • Matsuda Y.
        • Ohkuri T.
        • Oikawa K.
        • Ishibashi K.
        • Aoki N.
        • et al.
        c-Met is a novel tumor associated antigen for T-cell based immunotherapy against NK/T cell lymphoma.
        Oncoimmunology. 2015 Feb; 4e976077
        • Chuang H.-C.
        • Lay J.-D.
        • Hsieh W.-C.
        • Su I.-J.
        Pathogenesis and mechanism of disease progression from hemophagocytic lymphohistiocytosis to Epstein-Barr virus-associated T-cell lymphoma: nuclear factor-kappa B pathway as a potential therapeutic target.
        Cancer Sci. 2007 Sep; 98: 1281-1287
        • Takada H.
        • Imadome K.-I.
        • Shibayama H.
        • Yoshimori M.
        • Wang L.
        • Saitoh Y.
        • et al.
        EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells. Zhang L, editor.
        PLOS ONE. 2017 Mar; 12: e0174136
        • Shen L.
        • Au W.-Y.
        • Guo T.
        • Wong K.-Y.
        • Wong M.L.
        • Tsuchiyama J.
        • et al.
        Proteasome inhibitor bortezomib-induced apoptosis in natural killer (NK)-cell leukemia and lymphoma: an in vitro and in vivo preclinical evaluation.
        Blood. 2007 Jul 1; 110: 469-470
        • Iwata S.
        • Yano S.
        • Ito Y.
        • Ushijima Y.
        • Gotoh K.
        • Kawada J.
        • et al.
        Bortezomib induces apoptosis in T lymphoma cells and natural killer lymphoma cells independent of Epstein-Barr virus infection.
        Int J Cancer. 2011 Nov 1; 129: 2263-2273
        • Tang T.
        • Tay K.
        • Tao M.
        • Quek R.H.H.
        • Farid M.
        • Lim S.T.
        A Phase II Study of Bortezomib-GIFOX (Gemcitabine, Ifosfamide, Oxaliplatin) in Patients with Newly Diagnosed Natural-Killer/T-Cell Lymphoma.
        Blood. 2016; 128: 5353
        • Chen C.
        • He H.
        Treatment of relapsed extranodal natural killer/T-cell lymphoma with bortezomib plus fludarabine.
        Mol Clin Oncol. 2017 Oct; 7: 525-528
        • Granato M.
        • Romeo M.A.
        • Tiano M.S.
        • Santarelli R.
        • Gonnella R.
        • Gilardini Montani M.S.
        • et al.
        Bortezomib promotes KHSV and EBV lytic cycle by activating JNK and autophagy.
        Sci Rep. 2017 Dec; 7: 13052
        • Stoker S.D.
        • Novalić Z.
        • Wildeman M.A.
        • Huitema A.D.R.
        • Verkuijlen S.A.W.M.
        • Juwana H.
        • et al.
        Epstein-Barr virus-targeted therapy in nasopharyngeal carcinoma.
        J Cancer Res Clin Oncol. 2015 Oct; 141: 1845-1857
        • Bird A.
        DNA methylation patterns and epigenetic memory.
        Genes Dev. 2002 Jan 1; 16: 6-21
        • Bose P.
        • Dai Y.
        • Grant S.
        Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights.
        Pharmacol Ther. 2014 Sep; 143: 323-336
        • Yan G.
        • Huang H.
        • Li P.
        • Bing B.
        • Xiaoxiao W.
        • Qixiang R.
        • et al.
        Chidamide, Oral Subtype-Selective Histone Deacetylase Inhibitor (HDACI) Monotherapy Was Effective on the Patients with Relapsed or Refractory Extranodal Natural Killer (NK)/T-Cell Lymphoma.
        Blood. 2017; 130: 2797
        • Tan D.
        • Phipps C.
        • Hwang W.Y.K.
        • Tan S.Y.
        • Yeap C.H.
        • Chan Y.H.
        • et al.
        Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma: an open-label, multicentre phase 2 trial.
        Lancet Haematol. 2015 Aug 1; 2: e326-e333
        • Tan D.
        • Diong C.P.
        • Loh Y.
        • Goh Y.T.
        Histone deacetylase (HDAC) inhibitors when combined with a proteasome inhibitor are safe and effective in patients with extranodal natural killer/T-cell lymphoma (ENKTL).
        Ann Oncol Off J Eur Soc Med Oncol. 2016; 27: 1811-1812
        • McEachron T.A.
        • Kirov I.
        • Wungwattana M.
        • Cortes D.
        • Zabokrtsky K.B.
        • Sassoon A.
        • et al.
        Successful Treatment of Genetically Profiled Pediatric Extranodal NK/T-Cell Lymphoma Targeting Oncogenic STAT3 Mutation.
        Pediatr Blood Cancer. 2016 Apr; 63: 727-730
        • Kim S.J.
        • Kim J.H.
        • Ki C.S.
        • Ko Y.H.
        • Kim J.S.
        • Kim W.S.
        Epstein-Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients: a previously unrecognized serious adverse event in a pilot study with romidepsin.
        Ann Oncol. 2016 Mar; 27: 508-513
        • Malfoy B.
        The revival of DNA methylation.
        J Cell Sci. 2000 Dec 1; 113: 3887-3888
        • Siu L.L.P.
        • Chan J.K.C.
        • Wong K.F.
        • Choy C.
        • Kwong Y.L.
        Aberrant promoter CpG methylation as a molecular marker for disease monitoring in natural killer cell lymphomas.
        Br J Haematol. 2003 Jul; 122: 70-77
        • Kucuk C.
        • Hu X.
        • Jiang B.
        • Klinkebiel D.
        • Geng H.
        • Gong Q.
        • et al.
        Global Promoter Methylation Analysis Reveals Novel Candidate Tumor Suppressor Genes in Natural Killer Cell Lymphoma.
        Clin Cancer Res. 2015 Apr 1; 21: 1699-1711
        • Kucuk C.
        • Iqbal J.
        • Hu X.
        • Gaulard P.
        • De Leval L.
        • Srivastava G.
        • et al.
        PRDM1 is a tumor suppressor gene in natural killer cell malignancies.
        Proc Natl Acad Sci. 2011 Dec 13; 108: 20119-20124
        • Chen Y.-W.
        • Guo T.
        • Shen L.
        • Wong K.-Y.
        • Tao Q.
        • Choi W.W.L.
        • et al.
        Receptor-type tyrosine-protein phosphatase k directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma.
        Blood. 2015; 125: 13
        • Leone G.
        • Teofili L.
        • Voso M.T.
        • Lübbert M.
        DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias.
        Haematologica. 2002 Dec; 87: 1324-1341
        • Go H.
        • Jang J.-Y.
        • Kim C.-W.
        • Huh J.
        • Kim P.-J.
        • Jeon Y.K.
        Identification of microRNAs modulated by DNA hypomethylating drugs in extranodal NK/T-cell lymphoma.
        Leuk Lymphoma. 2019; : 1-9
        • Wang L.
        • Wang Z.-H.
        • Chen X.-Q.
        • Wang K.-F.
        • Huang H.-Q.
        • Xia Z.-J.
        First-line combination of GELOX followed by radiation therapy for patients with stage IE/IIE ENKTL: An updated analysis with long-term follow-up.
        Oncol Lett. 2015 Aug; 10: 1036-1040
        • Wen H.
        • Ma H.
        • Cai Q.
        • Lin S.
        • Lei X.
        • He B.
        • et al.
        Recurrent ECSIT mutation encoding V140A triggers hyperinflammation and promotes hemophagocytic syndrome in extranodal NK/T cell lymphoma.
        Nat Med. 2018 Feb; 24: 154-164
        • Wang L.
        • Wang H.
        • Wang J.
        • Xia Z.
        • Lu Y.
        • Huang H.
        • et al.
        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. 2015 Jul 3; 6: 30317-30326
        • Chiang A.K.
        • Tao Q.
        • Srivastava G.
        • Ho F.C.
        Nasal NK- and T-cell lymphomas share the same type of Epstein-Barr virus latency as nasopharyngeal carcinoma and Hodgkin’s disease.
        Int J Cancer. 1996 Nov 4; 68: 285-290
        • Fox C.P.
        • Haigh T.A.
        • Taylor G.S.
        • Long H.M.
        • Lee S.P.
        • Shannon-Lowe C.
        • et al.
        A novel latent membrane 2 transcript expressed in Epstein-Barr virus-positive NK- and T-cell lymphoproliferative disease encodes a target for cellular immunotherapy.
        Blood. 2010 Nov 11; 116: 3695-3704
        • Sun L.
        • Zhao Y.
        • Shi H.
        • Ma C.
        • Wei L.
        LMP1 promotes nasal NK/T-cell lymphoma cell function by eIF4E via NF-κB pathway.
        Oncol Rep. 2015 Dec; 34: 3264-3271
        • Portis T.
        • Longnecker R.
        Epstein-Barr virus (EBV) LMP2A mediates B-lymphocyte survival through constitutive activation of the Ras/PI3K/Akt pathway.
        Oncogene. 2004 Nov; 23: 8619-8628
        • Cho S.-G.
        • Kim N.
        • Sohn H.-J.
        • Lee S.K.
        • Oh S.T.
        • Lee H.-J.
        • et al.
        Long-term Outcome of Extranodal NK/T Cell Lymphoma Patients Treated With Postremission Therapy Using EBV LMP1 and LMP2a-specific CTLs.
        Mol Ther J Am Soc Gene Ther. 2015 Aug; 23: 1401-1409
        • Kim W.S.
        • Ardeshna K.M.
        • Lin Y.
        • Oki Y.
        • Ruan J.
        • Jacobsen E.D.
        • et al.
        Autologous EBV-Specific T Cells (CMD-003): Early Results from a Multicenter, Multinational Phase 2 Trial for Treatment of EBV-Associated NK/T-Cell Lymphoma.
        Blood. 2017; 130: 4073
        • Bollard C.M.
        • Gottschalk S.
        • Torrano V.
        • Diouf O.
        • Ku S.
        • Hazrat Y.
        • et al.
        Sustained Complete Responses in Patients With Lymphoma Receiving Autologous Cytotoxic T Lymphocytes Targeting Epstein-Barr Virus Latent Membrane Proteins.
        J Clin Oncol. 2014 Mar 10; 32: 798-808