Blood Res.  2020 Jul;55(S1):S63-S71. 10.5045/br.2020.S011.

Extranodal NK/T cell lymphoma

• Jeong SH

• KMID: 2504745
• DOI: http://doi.org/10.5045/br.2020.S011

Abstract

Extranodal natural killer (NK)/T cell lymphoma (ENKTL) is a distinct subtype of Non-Hodgkin’s lymphoma mainly involving the nasal area. Since the entity was first recognized, treatment strategies have been evolving from anthracycline-based chemotherapy and radiotherapy to L-asparaginase containing regimens and recently immune checkpoint inhibitors. With the currently used combined chemotherapy and radiotherapy, more than 70% of patients with localized disease can be cured. L-asparaginase containing regimens have significantly improved treatment outcomes among patients with advanced disease. However, the treatment outcomes of patients with disease refractory to L-asparaginase containing regimens or who experience recurrence remain poor. In this article, we cover the current treatments for ENKTL and emerging treatment approaches.

Keyword

Extranodal natural killer/T cell lymphoma; ENKTL; Non-Hodgkin’s lymphoma; Immunotherapy

Reference

1. Lee J, Park YH, Kim WS, et al. 2005; Extranodal nasal type NK/T-cell lymphoma: elucidating clinical prognostic factors for risk-based stratification of therapy. Eur J Cancer. 41:1402–8. DOI: 10.1016/j.ejca.2005.03.010. PMID: 15963893.

2. Jaffe ES. 1996; Classification of natural killer (NK) cell and NK-like T-cell malignancies. Blood. 87:1207–10. DOI: 10.1182/blood.V87.4.1207.bloodjournal8741207. PMID: 8608206.

3. Nagata H, Konno A, Kimura N, et al. 2001; Characterization of novel natural killer (NK)-cell and gammadelta T-cell lines established from primary lesions of nasal T/NK-cell lymphomas associated with the Epstein-Barr virus. Blood. 97:708–13. DOI: 10.1182/blood.V97.3.708. PMID: 11157488.

4. Harabuchi Y, Takahara M, Kishibe K, Nagato T, Kumai T. 2019; Extranodal natural killer/T-cell lymphoma, nasal type: basic science and clinical progress. Front Pediatr. 7:141. DOI: 10.3389/fped.2019.00141. PMID: 31041299. PMCID: PMC6476925.

5. Swerdlow SH, Campo E, Pileri SA, et al. 2016; The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 127:2375–90. DOI: 10.1182/blood-2016-01-643569. PMID: 26980727. PMCID: PMC4874220.

6. Harabuchi Y, Yamanaka N, Kataura A, et al. 1990; Epstein-Barr virus in nasal T-cell lymphomas in patients with lethal midline granuloma. Lancet. 335:128–30. DOI: 10.1016/0140-6736(90)90002-M. PMID: 1967431.

7. Harabuchi Y, Imai S, Wakashima J, et al. 1996; Nasal T-cell lymphoma causally associated with Epstein-Barr virus: clinicopathologic, phenotypic, and genotypic studies. Cancer. 77:2137–49. DOI: 10.1002/(SICI)1097-0142(19960515)77:10<2137::AID-CNCR27>3.0.CO;2-V. PMID: 8640683.

8. Harabuchi Y, Takahara M, Kishibe K, Moriai S, Nagato T, Ishii H. 2009; Nasal natural killer (NK)/T-cell lymphoma: clinical, histological, virological, and genetic features. Int J Clin Oncol. 14:181–90. DOI: 10.1007/s10147-009-0882-7. PMID: 19593607.

9. Chim CS, Ooi GC, Shek TW, Liang R, Kwong YL. 1999; Lethal midline granuloma revisited: nasal T/Natural-killer cell lymphoma. J Clin Oncol. 17:1322–5. DOI: 10.1200/JCO.1999.17.4.1322. PMID: 10561195.

10. Tse E, Kwong YL. 2016; Diagnosis and management of extranodal NK/T cell lymphoma nasal type. Expert Rev Hematol. 9:861–71. DOI: 10.1080/17474086.2016.1206465. PMID: 27347812.

11. Yoo KH, Lee H, Suh C. CISL. 2018; Lymphoma epidemiology in Korea and the real clinical field including the Consortium for Improving Survival of Lymphoma () trial. Int J Hematol. 107:395–404. DOI: 10.1007/s12185-018-2403-9. PMID: 29357080.

12. Lima M. 2013; Aggressive mature natural killer cell neoplasms: from epidemiology to diagnosis. Orphanet J Rare Dis. 8:95. DOI: 10.1186/1750-1172-8-95. PMID: 23816348. PMCID: PMC3770456.

13. Aozasa K, Takakuwa T, Hongyo T, Yang WI. 2008; Nasal NK/T-cell lymphoma: epidemiology and pathogenesis. Int J Hematol. 87:110–7. DOI: 10.1007/s12185-008-0021-7. PMID: 18256789. PMCID: PMC2276242.

14. Wu X, Li P, Zhao J, et al. 2008; A clinical study of 115 patients with extranodal natural killer/T-cell lymphoma, nasal type. Clin Oncol (R Coll Radiol). 20:619–25. DOI: 10.1016/j.clon.2008.05.011. PMID: 18790372.

15. Au WY, Weisenburger DD, Intragumtornchai T, et al. 2009; 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. 113:3931–7. DOI: 10.1182/blood-2008-10-185256. PMID: 19029440.

16. Kimura H, Kwong YL. 2019; EBV viral loads in diagnosis, monitoring, and response assessment. Front Oncol. 9:62. DOI: 10.3389/fonc.2019.00062. PMID: 30809508. PMCID: PMC6379266.

17. 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. 104:243–9. DOI: 10.1182/blood-2003-12-4197. PMID: 15031209.

18. 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. 28:865–70. DOI: 10.1038/leu.2013.212. PMID: 23842425.

19. Kim SJ, Choi JY, Hyun SH, et al. 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:e66–74. DOI: 10.1016/S2352-3026(15)00002-2.

20. Moon SH, Cho SK, Kim WS, et al. 2013; The role of 18F-FDG PET/CT for initial staging of nasal type natural killer/T-cell lymphoma: a comparison with conventional staging methods. J Nucl Med. 54:1039–44. DOI: 10.2967/jnumed.112.113399. PMID: 23658217.

21. Lee J, Suh C, Park YH, et al. 2006; Extranodal natural killer T-cell lymphoma, nasal-type: a prognostic model from a retrospective multicenter study. J Clin Oncol. 24:612–8. DOI: 10.1200/JCO.2005.04.1384. PMID: 16380410.

22. Ishii H, Ogino T, Berger C, et al. 2007; Clinical usefulness of serum EBV DNA levels of BamHI W and LMP1 for Nasal NK/T-cell lymphoma. J Med Virol. 79:562–72. DOI: 10.1002/jmv.20853. PMID: 17385697.

23. Kim SJ, Yoon DH, Jaccard A, et al. 2016; A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis. Lancet Oncol. 17:389–400. DOI: 10.1016/S1470-2045(15)00533-1. PMID: 26873565.

24. Kim WS, Song SY, Ahn YC, et al. 2001; CHOP followed by involved field radiation: is it optimal for localized nasal natural killer/T-cell lymphoma? Ann Oncol. 12:349–52. DOI: 10.1023/A:1011144911781. PMID: 11332147.

25. Yamaguchi M, Kita K, Miwa H, et al. 1995; Frequent expression of P-glycoprotein/MDR1 by nasal T-cell lymphoma cells. Cancer. 76:2351–6. DOI: 10.1002/1097-0142(19951201)76:11<2351::AID-CNCR2820761125>3.0.CO;2-1. PMID: 8635042.

26. Lee SH, Ahn YC, Kim WS, Ko YH, Kim K, Park K. 2006; The effect of pre-irradiation dose intense CHOP on anthracyline resistance in localized nasal NK/T-cell lymphoma. Haematologica. 91:427–8. PMID: 16503553.

27. Huang WT, Huang CC, Weng SW, Eng HL. 2009; Expression of the multidrug resistance protein MRP and the lung-resistance protein LRP in nasal NK/T cell lymphoma: further exploring the role of P53 and WT1 gene. Pathology. 41:127–32. DOI: 10.1080/00313020802441683. PMID: 18972317.

28. You JY, Chi KH, Yang MH, et al. 2004; Radiation therapy versus chemotherapy as initial treatment for localized nasal natural killer (NK)/T-cell lymphoma: a single institute survey in Taiwan. Ann Oncol. 15:618–25. DOI: 10.1093/annonc/mdh143. PMID: 15033670.

29. Ando M, Sugimoto K, Kitoh T, et al. 2005; Selective apoptosis of natural killer-cell tumours by l-asparaginase. Br J Haematol. 130:860–8. DOI: 10.1111/j.1365-2141.2005.05694.x. PMID: 16156856.

30. Yong W, Zheng W, Zhang Y, et al. 2003; L-asparaginase-based regimen in the treatment of refractory midline nasal/nasal-type T/NK-cell lymphoma. Int J Hematol. 78:163–7. DOI: 10.1007/BF02983387. PMID: 12953813.

31. Wang L, Wang ZH, Chen XQ, et al. 2013; First-line combination of gemcitabine, oxaliplatin, and L-asparaginase (GELOX) followed by involved-field radiation therapy for patients with stage IE/IIE extranodal natural killer/T-cell lymphoma. Cancer. 119:348–55. DOI: 10.1002/cncr.27752. PMID: 22811078.

32. Jiang M, Zhang H, Jiang Y, et al. 2012; Phase 2 trial of "sandwich" L-asparaginase, vincristine, and prednisone chemotherapy with radiotherapy in newly diagnosed, stage IE to IIE, nasal type, extranodal natural killer/T-cell lymphoma. Cancer. 118:3294–301. DOI: 10.1002/cncr.26629. PMID: 22139825.

33. Pokrovsky VS, Vinnikov D. 2017; L-Asparaginase for newly diagnosed extra-nodal NK/T-cell lymphoma: systematic review and meta-analysis. Expert Rev Anticancer Ther. 17:759–68. DOI: 10.1080/14737140.2017.1344100. PMID: 28621166.

34. Yang Y, Cao JZ, Lan SM, et al. 2017; Association of improved locoregional control with prolonged survival in early-stage extranodal nasal-type natural killer/t-cell lymphoma. JAMA Oncol. 3:83–91. DOI: 10.1001/jamaoncol.2016.5094. PMID: 27893001.

35. Vargo JA, Patel A, Glaser SM, et al. 2017; The impact of the omission or inadequate dosing of radiotherapy in extranodal natural killer T-cell lymphoma, nasal type, in the United States. Cancer. 123:3176–85. DOI: 10.1002/cncr.30697. PMID: 28380259.

36. Deng XW, Wu JX, Wu T, et al. 2018; Radiotherapy is essential after complete response to asparaginase-containing chemotherapy in early-stage extranodal nasal-type NK/T-cell lymphoma: a multicenter study from the China Lymphoma Collaborative Group (CLCG). Radiother Oncol. 129:3–9. DOI: 10.1016/j.radonc.2018.04.026. PMID: 29739712.

37. Kim GE, Cho JH, Yang WI, et al. 2000; Angiocentric lymphoma of the head and neck: patterns of systemic failure after radiation treatment. J Clin Oncol. 18:54–63. DOI: 10.1200/JCO.2000.18.1.54. PMID: 10623693.

38. Yamaguchi M, Tobinai K, Oguchi M, et al. 2009; Phase I/II study of concurrent chemoradiotherapy for localized nasal natural killer/T-cell lymphoma: Japan Clinical Oncology Group Study JCOG0211. J Clin Oncol. 27:5594–600. DOI: 10.1200/JCO.2009.23.8295. PMID: 19805668.

39. Yamaguchi M, Tobinai K, Oguchi M, et al. 2012; Concurrent chemoradiotherapy for localized nasal natural killer/T-cell lymphoma: an updated analysis of the Japan Clinical Oncology Group study JCOG0211. J Clin Oncol. 30:4044–6. DOI: 10.1200/JCO.2012.45.6541. PMID: 23045573.

40. Kim SJ, Kim K, Kim BS, et al. 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. 27:6027–32. DOI: 10.1200/JCO.2009.23.8592. PMID: 19884539.

41. Kim SJ, Yang DH, Kim JS, et al. 2014; Concurrent chemoradiotherapy followed by L-asparaginase-containing chemotherapy, VIDL, for localized nasal extranodal NK/T cell lymphoma: CISL08-01 phase II study. Ann Hematol. 93:1895–901. DOI: 10.1007/s00277-014-2137-6. PMID: 24947798.

42. Yoon DH, Kim SJ, Jeong SH, et al. 2016; Phase II trial of concurrent chemoradiotherapy with L-asparaginase and MIDLE chemotherapy for newly diagnosed stage I/II extranodal NK/T-cell lymphoma, nasal type (CISL-1008). Oncotarget. 7:85584–91. DOI: 10.18632/oncotarget.11319. PMID: 27542213. PMCID: PMC5356760.

43. Ke QH, Zhou SQ, Du W, Liang G, Lei Y, Luo F. 2014; Concurrent IMRT and weekly cisplatin followed by GDP chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-cell lymphoma. Blood Cancer J. 4:e267. DOI: 10.1038/bcj.2014.88. PMID: 25501024. PMCID: PMC4315894.

44. Takahara M, Nagato T, Kishibe K, et al. 2017; Novel treatment for early-stage nasal natural killer/T-cell lymphoma: intra-maxillary arterial infusion chemotherapy with concomitant radiotherapy. Hematol Oncol. 35:158–62. DOI: 10.1002/hon.2273. PMID: 26563973.

45. Yamaguchi M, Kwong YL, Kim WS, et al. 2011; 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. 29:4410–6. DOI: 10.1200/JCO.2011.35.6287. PMID: 21990393.

46. Kwong YL, Kim WS, Lim ST, et al. 2012; SMILE for natural killer/T-cell lymphoma: analysis of safety and efficacy from the Asia Lymphoma Study Group. Blood. 120:2973–80. DOI: 10.1182/blood-2012-05-431460. PMID: 22919026.

47. Zhang L, Jiang M, Xie L, et al. 2016; Five-year analysis from phase 2 trial of "sandwich" chemoradiotherapy in newly diagnosed, stage IE to IIE, nasal type, extranodal natural killer/T-cell lymphoma. Cancer Med. 5:33–40. DOI: 10.1002/cam4.569. PMID: 26633585. PMCID: PMC4708906.

48. Wang L, Wang ZH, Chen XQ, Wang KF, Huang HQ, Xia ZJ. 2015; 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. 10:1036–40. DOI: 10.3892/ol.2015.3327. PMID: 26622621. PMCID: PMC4509369.

49. Wei W, Wu P, Li L, Zhang ZH. 2017; Effectiveness of pegaspargase, gemcitabine, and oxaliplatin (P-GEMOX) chemotherapy combined with radiotherapy in newly diagnosed, stage IE to IIE, nasal-type, extranodal natural killer/T-cell lymphoma. Hematology. 22:320–9. DOI: 10.1080/10245332.2016.1264163. PMID: 27917702.

50. Dong LH, Zhang LJ, Wang WJ, et al. 2016; Sequential DICE combined with l-asparaginase chemotherapy followed by involved field radiation in newly diagnosed, stage IE to IIE, nasal and extranodal NK/T-cell lymphoma. Leuk Lymphoma. 57:1600–6. DOI: 10.3109/10428194.2015.1108415. PMID: 26726970.

51. Xu PP, Xiong J, Cheng S, et al. 2017; A phase II study of methotrexate, etoposide, dexamethasone and pegaspargase sandwiched with radiotherapy in the treatment of newly diagnosed, stage IE to IIE extranodal natural-killer/T-Cell lymphoma, nasal-type. EBioMedicine. 25:41–9. DOI: 10.1016/j.ebiom.2017.10.011. PMID: 29056540. PMCID: PMC5704067.

52. Tse E, Kwong YL. 2019; NK/T-cell lymphomas. Best Pract Res Clin Haematol. 32:253–61. DOI: 10.1016/j.beha.2019.06.005. PMID: 31585625.

53. Kwong YL, Kim SJ, Tse E, et al. 2018; Sequential chemotherapy/radiotherapy was comparable with concurrent chemoradiotherapy for stage I/II NK/T-cell lymphoma. Ann Oncol. 29:256–63. DOI: 10.1093/annonc/mdx684. PMID: 29077846.

54. Lee J, Kim CY, Park YJ, Lee NK. 2013; Sequential chemotherapy followed by radiotherapy versus concurrent chemoradiotherapy in patients with stage I/II extranodal natural killer/T-cell lymphoma, nasal type. Blood Res. 48:274–81. DOI: 10.5045/br.2013.48.4.274. PMID: 24466552. PMCID: PMC3894386.

55. Wang JJ, Dong M, He XH, et al. 2016; GDP (gemcitabine, dexamethasone, and cisplatin) is highly effective and well-tolerated for newly diagnosed stage IV and relapsed/refractory extranodal natural killer/T-cell lymphoma, nasal type. Medicine (Baltimore). 95:e2787. DOI: 10.1097/MD.0000000000002787. PMID: 26871836. PMCID: PMC4753932.

56. Jaccard A, Gachard N, Marin B, et al. 2011; Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood. 117:1834–9. DOI: 10.1182/blood-2010-09-307454. PMID: 21123825.

57. Ding H, Chang J, Liu LG, et al. 2015; High-dose methotrexate, etoposide, dexamethasone and pegaspargase (MEDA) combination chemotherapy is effective for advanced and relapsed/refractory extranodal natural killer/T cell lymphoma: a retrospective study. Int J Hematol. 102:181–7. DOI: 10.1007/s12185-015-1809-x. PMID: 25997870.

58. Wang JH, Wang H, Wang YJ, et al. 2016; Analysis of the efficacy and safety of a combined gemcitabine, oxaliplatin and pegaspargase regimen for NK/T-cell lymphoma. Oncotarget. 7:35412–22. DOI: 10.18632/oncotarget.8643. PMID: 27072578. PMCID: PMC5085239.

59. Li X, Cui Y, Sun Z, et al. 2016; DDGP versus SMILE in newly diagnosed advanced natural killer/T-cell lymphoma: a randomized controlled, multicenter, open-label study in China. Clin Cancer Res. 22:5223–8. DOI: 10.1158/1078-0432.CCR-16-0153. PMID: 27060152.

60. Yhim HY, Kim JS, Mun YC, et al. 2015; Clinical outcomes and prognostic factors of up-front autologous stem cell transplantation in patients with extranodal natural killer/T cell lymphoma. Biol Blood Marrow Transplant. 21:1597–604. DOI: 10.1016/j.bbmt.2015.05.003. PMID: 25963920.

61. Fox CP, Boumendil A, Schmitz N, et al. 2015; High-dose therapy and autologous stem cell transplantation for extra-nodal NK/T lymphoma in patients from the Western hemisphere: a study from the European Society for Blood and Marrow Transplantation. Leuk Lymphoma. 56:3295–300. DOI: 10.3109/10428194.2015.1037764. PMID: 25899403.

62. Kharfan-Dabaja MA, Kumar A, Ayala E, et al. 2017; Clinical practice recommendations on indication and timing of hematopoietic cell transplantation in mature T cell and NK/T Cell lymphomas: an international collaborative effort on behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 23:1826–38. DOI: 10.1016/j.bbmt.2017.07.027. PMID: 28797780.

63. Murashige N, Kami M, Kishi Y, et al. 2005; Allogeneic haematopoietic stem cell transplantation as a promising treatment for natural killer-cell neoplasms. Br J Haematol. 130:561–7. DOI: 10.1111/j.1365-2141.2005.05651.x. PMID: 16098071.

64. Tse E, Chan TS, Koh LP, et al. 2014; Allogeneic haematopoietic SCT for natural killer/T-cell lymphoma: a multicentre analysis from the Asia Lymphoma Study Group. Bone Marrow Transplant. 49:902–6. DOI: 10.1038/bmt.2014.65. PMID: 24777195.

65. Kanate AS, DiGilio A, Ahn KW, et al. 2018; Allogeneic haematopoietic cell transplantation for extranodal natural killer/T-cell lymphoma, nasal type: a CIBMTR analysis. Br J Haematol. 182:916–20. DOI: 10.1111/bjh.14879. PMID: 28771676. PMCID: PMC5796874.

66. Jeong SH, Song HN, Park JS, et al. 2018; Allogeneic stem cell transplantation for patients with natural killer/T cell lymphoid malignancy: a multicenter analysis comparing upfront and salvage transplantation. Biol Blood Marrow Transplant. 24:2471–8. DOI: 10.1016/j.bbmt.2018.07.034. PMID: 30064012.

67. Lim SH, Hong JY, Lim ST, et al. 2017; 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. 28:2199–205. DOI: 10.1093/annonc/mdx316. PMID: 28911074.

68. Nagato T, Ohkuri T, Ohara K, et al. 2017; 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. 66:877–90. DOI: 10.1007/s00262-017-1987-x. PMID: 28349165.

69. Kwong YL, Chan TSY, Tan D, et al. 2017; PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood. 129:2437–42. DOI: 10.1182/blood-2016-12-756841. PMID: 28188133.

70. Li X, Cheng Y, Zhang M, et al. 2018; Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma. J Hematol Oncol. 11:15. DOI: 10.1186/s13045-018-0559-7. PMID: 29386072. PMCID: PMC5793390.

71. Chan TSY, Li J, Loong F, Khong PL, Tse E, Kwong YL. 2018; PD1 blockade with low-dose nivolumab in NK/T cell lymphoma failing L-asparaginase: efficacy and safety. Ann Hematol. 97:193–6. DOI: 10.1007/s00277-017-3127-2. PMID: 28879531.

72. Cho J, Kim SJ, Park WY, et al. 2019; Immune subtyping of extranodal NK/T-cell lymphoma: a new biomarker and an immune shift during disease progression. Mod Pathol. [Epub ahead of print]. DOI: 10.1038/s41379-019-0392-8. PMID: 31653980.

73. Wang L, Wang H, Li PF, et al. 2015; CD38 expression predicts poor prognosis and might be a potential therapy target in extranodal NK/T cell lymphoma, nasal type. Ann Hematol. 94:1381–8. DOI: 10.1007/s00277-015-2359-2. PMID: 25865943.

74. Hari P, Raj RV, Olteanu H. 2016; Targeting CD38 in refractory extranodal natural killer cell-T-cell lymphoma. N Engl J Med. 375:1501–2. DOI: 10.1056/NEJMc1605684. PMID: 27732828.

75. Aeppli S, Driessen C, Graf L, Hitz F. 2018; Systemic treatment of a patient with relapsed and refractory extranodal NK/T-cell lymphoma (ENKL) and meningeosis leukemica with daratumumab. Hematol Oncol. 36:713–4. DOI: 10.1002/hon.2533. PMID: 30074631.

76. Feng Y, Rao H, Lei Y, et al. 2017; 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. 36:43. DOI: 10.1186/s40880-017-0212-9. PMID: 28486951. PMCID: PMC5424426.

77. Kim WY, Nam SJ, Kim S, et al. 2015; Prognostic implications of CD30 expression in extranodal natural killer/T-cell lymphoma according to treatment modalities. Leuk Lymphoma. 56:1778–86. DOI: 10.3109/10428194.2014.974048. PMID: 25288491.

78. Kawamoto K, Miyoshi H, Suzuki T, et al. 2018; Frequent expression of CD30 in extranodal NK/T-cell lymphoma: Potential therapeutic target for anti-CD30 antibody-based therapy. Hematol Oncol. 36:166–73. DOI: 10.1002/hon.2482. PMID: 29052238.

79. Kim HK, Moon SM, Moon JH, Park JE, Byeon S, Kim WS. 2015; Complete remission in CD30-positive refractory extranodal NK/T-cell lymphoma with brentuximab vedotin. Blood Res. 50:254–6. DOI: 10.5045/br.2015.50.4.254. PMID: 26770954. PMCID: PMC4705052.

80. Poon LM, Kwong YL. 2016; Complete remission of refractory disseminated NK/T cell lymphoma with brentuximab vedotin and bendamustine. Ann Hematol. 95:847–9. DOI: 10.1007/s00277-016-2627-9. PMID: 26931114.

81. Younes A, Gopal AK, Smith SE, et al. 2012; Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 30:2183–9. DOI: 10.1200/JCO.2011.38.0410. PMID: 22454421. PMCID: PMC3646316.

82. Horwitz SM, Advani RH, Bartlett NL, et al. 2014; Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood. 123:3095–100. DOI: 10.1182/blood-2013-12-542142. PMID: 24652992. PMCID: PMC4425442.

83. Müller P, Martin K, Theurich S, et al. 2014; Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells. Cancer Immunol Res. 2:741–55. DOI: 10.1158/2326-6066.CIR-13-0198. PMID: 24916470.

84. Hu B, Oki Y. 2018; Novel immunotherapy options for extranodal NK/T-cell lymphoma. Front Oncol. 8:139. DOI: 10.3389/fonc.2018.00139. PMID: 29761078. PMCID: PMC5937056.

85. Kumai T, Nagato T, Kobayashi H, et al. 2015; CCL17 and CCL22/CCR4 signaling is a strong candidate for novel targeted therapy against nasal natural killer/T-cell lymphoma. Cancer Immunol Immunother. 64:697–705. DOI: 10.1007/s00262-015-1675-7. PMID: 25754123. PMCID: PMC4648286.

86. Bollard CM, Gottschalk S, Torrano V, et al. 2014; Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol. 32:798–808. DOI: 10.1200/JCO.2013.51.5304. PMID: 24344220. PMCID: PMC3940538.

87. Cho SG, Kim N, Sohn HJ, et al. 2015; Long-term outcome of extranodal NK/T cell lymphoma patients treated with postremission therapy using EBV LMP1 and LMP2a-specific CTLs. Mol Ther. 23:1401–9. DOI: 10.1038/mt.2015.91. PMID: 26017177. PMCID: PMC4817864.

88. de Mel S, Hue SS, Jeyasekharan AD, Chng WJ, Ng SB. 2019; Molecular pathogenic pathways in extranodal NK/T cell lymphoma. J Hematol Oncol. 12:33. DOI: 10.1186/s13045-019-0716-7. PMID: 30935402. PMCID: PMC6444858.

89. McEachron TA, Kirov I, Wungwattana M, et al. 2016; Successful treatment of genetically profiled pediatric extranodal NK/T-cell lymphoma targeting oncogenic STAT3 mutation. Pediatr Blood Cancer. 63:727–30. DOI: 10.1002/pbc.25854. PMID: 26727971.

90. Karube K, Tsuzuki S, Yoshida N, et al. 2013; Comprehensive gene expression profiles of NK cell neoplasms identify vorinostat as an effective drug candidate. Cancer Lett. 333:47–55. DOI: 10.1016/j.canlet.2012.12.022. PMID: 23348693.