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Comparison analysis of first-line asparaginase- versus non-asparaginase-based regimens for early-stage extranodal NK/T-cell lymphoma

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Abstract

The present study investigated the efficacy and toxicity profile of first-line asparaginase (ASP)-based versus non-ASP-based regimens in treating early-stage extranodal NK/T-cell lymphoma (ENKTCL) in non-anthracycline therapy era. This multi-center, real-world retrospective study consisted 305 newly diagnosed localized ENKTCL patients who were treated with sequential chemoradiation between 2010 and 2020 in China: 190 cases received ASP-based regimens and 115 cases received non-ASP-based regimens. Propensity score matching and multivariable analyses were used to compare survivals and toxicities between the two treatment groups. Non-ASP-based regimens achieved comparable survivals compared with ASP-based regimens in the entire cohort. The 5-year overall survival (OS), progression-free survival (PFS) rates were 84.7% and 73.5% for non-ASP-based regimens, and 87.7% (P=0.464) and 74.6% (P=0.702) for ASP-based regimens. The non-inferior survivals of non-ASP-based regimens were consistent after adjustment using PSM and multivariable analyses. However, survival benefits of ASP varied in different treatment modalities. Among patients receiving sequential chemotherapy and radiation (CT+RT±CT), ASP-based regimens achieved higher complete remission rate (54.3 vs. 34.5%, P=0.047) and more favorable survivals compared with non-ASP-based regimens (5-year OS, 87.0 vs. 69.0%, P=0.028). However, for patients receiving sequential radiation and chemotherapy (RT+CT), non-ASP-based regimens achieved comparable favorable survivals as ASP-based regimens. Besides, liver injury, malnutrition, and coagulative dysfunction were significantly more commonly documented in ASP-based regimens. These findings suggested that ASP was an effective agent in treating ENKTCL, especially among those receiving induction CT and RT. For patients who received upfront RT, non-ASP-based regimens might be a comparably effective and more tolerable treatment option.

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References

  1. Liu Z, Bi X, Zhang X, Lei D, Liu P, Yang H, Gao Y, Jiang Y, Jiang W, Xia Y (2019) Characteristics, prognostic factors, and survival of patients with NK/T-cell lymphoma of non-upper aerodigestive tract: a 17-year single-center experience. Cancer Res Treat 51:1557–1567. https://doi.org/10.4143/crt.2018.681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tamaru JI (2017) 2016 revision of the WHO classification of lymphoid neoplasms. Rinsho Ketsueki. 58:2188-2193. https://doi.org/10.11406/rinketsu.58.2188.

  3. Haverkos BM, Pan Z, Gru AA, Freud AG, Rabinovitch R, Xu-Welliver M, Otto B, Barrionuevo C, Baiocchi RA, Rochford R et al. Extranodal NK/T cell lymphoma, nasal type (ENKTL-NT): an update on epidemiology, clinical presentation, and natural history in North American and European cases. Curr Hematol Malig Rep 11:514-527. https://doi.org/10.1007/s11899-016-0355-9

  4. Yang Y, Zhu Y, Cao JZ, Zhang YJ, Xu LM, Yuan ZY, Wu JX, Wang W, Wu T, Lu B et al (2015) Risk-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma: analysis from a multicenter study. Blood. 126:1424–1432, 1517. https://doi.org/10.1182/blood-2015-04-639336

    Article  CAS  PubMed  Google Scholar 

  5. Vargo JA, Patel A, Glaser SM, Balasubramani GK, Farah RJ, Marks SM, Beriwal S (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 123:3176–3185. https://doi.org/10.1002/cncr.30697

    Article  CAS  PubMed  Google Scholar 

  6. Jiang L, Li SJ, Jiang YM, Long JX, Wang RS, Su J, Zhang Y (2014) The significance of combining radiotherapy with chemotherapy for early stage extranodal natural killer/T-cell lymphoma, nasal type: a systematic review and meta-analysis. Leuk Lymphoma 55:1038–1048. https://doi.org/10.3109/10428194.2013.827789

    Article  CAS  PubMed  Google Scholar 

  7. Mundy-Bosse B, Weinstock DM (2020) Breaking down the barriers to define and treat NK/T cell lymphoma. Cancer Cell 37:263–265. https://doi.org/10.1016/j.ccell.2020.02.009

    Article  CAS  PubMed  Google Scholar 

  8. Wang L, Xia ZJ, Huang HQ, Lu Y, Zhang YJ (2012) 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 96:617–623. https://doi.org/10.1007/s12185-012-1174-y

    Article  CAS  PubMed  Google Scholar 

  9. Yamaguchi M, Suzuki R, Oguchi M (2018) Advances in the treatment of extranodal NK/T-cell lymphoma, nasal type. Blood 131:2528–2540. https://doi.org/10.1182/blood-2017-12-791418

    Article  CAS  PubMed  Google Scholar 

  10. Jaccard A, Gachard N, Marin B, Rogez S, Audrain M, Suarez F, Tilly H, Morschhauser F, Thieblemont C, Ysebaert L 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. 117:1834–1839. https://doi.org/10.1182/blood-2010-09-307454

    Article  CAS  PubMed  Google Scholar 

  11. 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 17:759–768. https://doi.org/10.1080/14737140.2017.1344100

    Article  CAS  PubMed  Google Scholar 

  12. Yong W, Zheng W, Zhu J, Zhang Y, Wang X, Xie Y, Lin N, Xu B, Lu A, Li J (2009) L-asparaginase in the treatment of refractory and relapsed extranodal NK/T-cell lymphoma, nasal type. Ann Hematol 88:647–652. https://doi.org/10.1007/s00277-008-0669-3

    Article  CAS  PubMed  Google Scholar 

  13. Kwong YL, Kim WS, Lim ST, Kim SJ, Tang T, Tse E, Leung AY, Chim CS (2012) SMILE for natural killer/T-cell lymphoma: analysis of safety and efficacy from the Asia Lymphoma Study Group. Blood 120:2973–2980. https://doi.org/10.1182/blood-2012-05-431460

    Article  CAS  PubMed  Google Scholar 

  14. Yoon DH, Kim SJ, Jeong SH, Shin DY, Bae SH, Hong J, Park SK, Yhim HY, Yang DH, Lee H 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 7:85584-85591. https://doi.org/10.18632/oncotarget.11319

  15. Xu P, Xiong J, Cheng S, Zhao X, Wang C, Cai G, Zhong H, Huang H, Chen J, Zhao W (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 25:41–49. https://doi.org/10.1016/j.ebiom.2017.10.011

    Article  PubMed  PubMed Central  Google Scholar 

  16. Bi XW, Xia Y, Zhang WW, Sun P, Liu PP, Wang Y, Huang JJ, Jiang WQ, Li ZM (2015) Radiotherapy and PGEMOX/GELOX regimen improved prognosis in elderly patients with early-stage extranodal NK/T-cell lymphoma. Ann Hematol 94:1525–1533. https://doi.org/10.1007/s00277-015-2395-y

    Article  CAS  PubMed  Google Scholar 

  17. Zhu F, Liu T, Pan H, Xiao Y, Li Q, Liu X, Chen W, Wu G, Zhang L (2020) Long-term outcomes of upfront concurrent chemoradiotherapy followed by P-GDP regimen in newly diagnosed early stage extranodal nasal-type NK/T cell lymphoma. Medicine 99:e21705. https://doi.org/10.1097/MD.0000000000021705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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 10:1036–1040. https://doi.org/10.3892/ol.2015.3327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jiang M, Zhang H, Jiang Y, Yang Q, Xie L, Liu W, Zhang W, Ji X, Li P, Chen N 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 118:3294–3301. https://doi.org/10.1002/cncr.26629

    Article  CAS  PubMed  Google Scholar 

  20. Qi SN, Yang Y, Song YQ, Wang Y, He X, Hu C, Zhang LL, Wu G, Qu BL, Qian LT et al (2020) First-line non-anthracycline-based chemotherapy for extranodal nasal-type NK/T-cell lymphoma: a retrospective analysis from the CLCG. Blood Adv. 4:3141–3153. https://doi.org/10.1182/bloodadvances.2020001852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Qi F, Wang WH, He XH, Chen B, Gui L, Fang H, Liu P, Wang SL, Yang JL, Song YW et al (2018) Phase 2 study of first-line intensity modulated radiation therapy followed by gemcitabine, dexamethasone, and cisplatin for high-risk, early stage extranodal nasal-type NK/T-cell lymphoma: the GREEN Study. Int J Radiat Oncol Biol Phys. 102:61–70. https://doi.org/10.1016/j.ijrobp.2018.05.046

    Article  CAS  PubMed  Google Scholar 

  22. Yamaguchi M, Tobinai K, Oguchi M, Ishizuka N, Kobayashi Y, Isobe Y, Ishizawa K, Maseki N, Itoh K, Usui N 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. 27:5594–5600. https://doi.org/10.1200/JCO.2009.23.8295

    Article  CAS  PubMed  Google Scholar 

  23. Kim SJ, Kim K, Kim BS, Kim CY, Suh C, Huh J, Lee SW, Kim JS, Cho J, Lee GW 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. 27:6027–6032. https://doi.org/10.1200/JCO.2009.23.8592

    Article  CAS  PubMed  Google Scholar 

  24. Tsai H, Lin S, Chen C, Chen T, Su W, Hwang W, Lin J, Chiou T, Kao W, Chiu C et al (2015) Long-term results of a phase II trial with frontline concurrent chemoradiotherapy followed by consolidation chemotherapy for localized nasal natural killer/T-cell lymphoma. European Journal of Haematology. 94:130–137. https://doi.org/10.1111/ejh.12405

    Article  CAS  PubMed  Google Scholar 

  25. Yang Y, Cao JZ, Lan SM, Wu JX, Wu T, Zhu SY, Qian LT, Hou XR, Zhang FQ, Zhang YJ 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. https://doi.org/10.1001/jamaoncol.2016.5094

    Article  PubMed  Google Scholar 

  26. Kim TM, Heo DS (2009) Extranodal NK / T-cell lymphoma, nasal type: new staging system and treatment strategies. Cancer Sci 100:2242–2248. https://doi.org/10.1111/j.1349-7006.2009.01319.x

    Article  CAS  PubMed  Google Scholar 

  27. Qi SN, Xu LM, Yuan ZY, Wu T, Zhu SY, Shi M, Su H, Wang Y, He X, Zhang LL et al (2019) Effect of primary tumor invasion on treatment and survival in extranodal nasal-type NK/T-cell lymphoma in the modern chemotherapy era: a multicenter study from the China Lymphoma Collaborative Group (CLCG). Leuk Lymphoma. 60:2669–2678. https://doi.org/10.1080/10428194.2019.1602265

    Article  PubMed  Google Scholar 

  28. Project INLP (1993) A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 329:987–994. https://doi.org/10.1056/NEJM199309303291402

    Article  Google Scholar 

  29. Chen SY, Yang Y, Qi SN, Wang Y, Hu C, He X, Zhang LL, Wu G, Qu BL, Qian LT et al (2021) Validation of nomogram-revised risk index and comparison with other models for extranodal nasal-type NK/T-cell lymphoma in the modern chemotherapy era: indication for prognostication and clinical decision-making. Leukemia. 35:130–142. https://doi.org/10.1038/s41375-020-0791-3

    Article  CAS  PubMed  Google Scholar 

  30. Yang Y, Zhang YJ, Zhu Y, Cao JZ, Yuan ZY, Xu LM, Wu JX, Wang W, Wu T, Lu B et al (2015) Prognostic nomogram for overall survival in previously untreated patients with extranodal NK/T-cell lymphoma, nasal-type: a multicenter study. Leukemia. 29:1571–1577. https://doi.org/10.1038/leu.2015.44

    Article  CAS  PubMed  Google Scholar 

  31. Kim SJ, Yoon DH, Jaccard A, Chng WJ, Lim ST, Hong H, Park Y, Chang KM, Maeda Y, Ishida F 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. https://doi.org/10.1016/S1470-2045(15)00533-1

    Article  CAS  PubMed  Google Scholar 

  32. Pokrovsky VS, Vinnikov D (2019) Defining the toxicity of current regimens for extranodal NK/T cell lymphoma: a systematic review and metaproportion. Expert Rev Anticancer Ther 19:93–104. https://doi.org/10.1080/14737140.2019.1549992

    Article  CAS  PubMed  Google Scholar 

  33. Yahalom J, Illidge T, Specht L, Hoppe RT, Li YX, Tsang R, Wirth A (2015) Modern radiation therapy for extranodal lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 92:11–31. https://doi.org/10.1016/j.ijrobp.2015.01.009

    Article  PubMed  Google Scholar 

  34. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E et al (2007) Revised response criteria for malignant lymphoma. J Clin Oncol. 25:579–586. https://doi.org/10.1200/JCO.2006.09.2403

    Article  PubMed  Google Scholar 

  35. Li YX, Liu QF, Wang WH, Jin J, Song YW, Wang SL, Liu YP, Liu XF, Zhou LQ, Yu ZH (2011) Failure patterns and clinical implications in early stage nasal natural killer/T-cell lymphoma treated with primary radiotherapy. Cancer 117:5203–5211. https://doi.org/10.1002/cncr.26167

    Article  PubMed  Google Scholar 

  36. Kim SJ, Yoon SE, Kim WS (2018) Treatment of localized extranodal NK/T cell lymphoma, nasal type: a systematic review. J Hematol Oncol 11:140. https://doi.org/10.1186/s13045-018-0687-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang Y, Cao J, Lan S, Wu J, Wu T, Zhu S, Qian L, Hou X, Zhang F, Zhang Y 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. https://doi.org/10.1001/jamaoncol.2016.5094

    Article  PubMed  Google Scholar 

  38. Huang M, Jiang Y, Liu W, Li Z, Li M, Zhou L, Xu Y, Yu C, Li Q, Peng F et al (2008) Early or up-front radiotherapy improved survival of localized extranodal NK/T-cell lymphoma, nasal-type in the upper aerodigestive tract. Int J Radiat Oncol Biol Phys 70:166–174. https://doi.org/10.1016/j.ijrobp.2007.05.073

    Article  PubMed  Google Scholar 

  39. Zang J, Li C, Luo SQ, Wang JH, Xu M, Zhao LN, Li WW, Yang H, Xiao F, Hitchcock YJ et al (2015) Early radiotherapy has an essential role for improving survival in patients with stage I-II nasal-type of NK/T cell lymphoma treated with L-asparaginase-containing chemotherapy–a single institution experience. Ann Hematol. 94:583–591. https://doi.org/10.1007/s00277-014-2244-4

    Article  CAS  PubMed  Google Scholar 

  40. Qi F, Chen B, Wang J, Lin X, Qi S, Yang J, Zhou S, Wang S, Gui L, Fang H et al. (2019) Upfront radiation is essential for high-risk early-stage extranodal NK/T-cell lymphoma, nasal type: comparison of two sequential treatment modalities combining radiotherapy and GDP (gemcitabine, dexamethasone, and cisplatin) in the modern era. Leukemia Lymphoma 1-10. https://doi.org/10.1080/10428194.2019.1599111

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Acknowledgements

The authors would like to thank all the doctors and nurses who participated in this study as well as all the enrolled patients at Peking University Hospital, and Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College.

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  1. Mei Dong and Jun Zhu contributed equally to this work and share corresponding authorship.

Authors and Affiliations

  1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, 100142, China

    Fei Qi, Yan Xie, Dedao Wang, Weiping Liu, Ning Ding, Lan Mi, Yuqin Song & Jun Zhu

  2. Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Yue Chai, Yuce Wei, Lin Gui & Mei Dong

  3. Department of Radiation Oncology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Bo Chen, Shunan Qi, Hui Fang, Yong Yang & Yexiong Li

  4. Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China

    Yan Sun & Dan Zhao

  5. Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Xiaoli Feng

  6. Department of Biomedical Engineering, Peking University, Beijing, China

    Shaokun Shu

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  1. Fei Qi
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Contributions

JZ and MD designed the study. FQ, BC, DZ, DW, YY, DZ, YS, SQ, XF, FH, LG, SS, YS, YL, and ZC contributed to the acquisition of data. FQ and LM analyzed and interpreted the data. FQ and YW contributed to the writing of the manuscript. All authors revised the manuscript and gave final approval.

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Correspondence to Mei Dong.

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Fig. S1

The comparison of PFS and OS between different responses from induction therapies in the entire cohort. (PNG 61 kb)

High Resolution (TIF 272 kb)

Fig. S2

Tree plot of patient characteristic and survival benefits of ASP- and non-ASP-based regimens. (PNG 845 kb)

High Resolution (TIF 1460 kb)

Supplementary Table 1

(DOCX 30 kb)

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Qi, F., Xie, Y., Wang, D. et al. Comparison analysis of first-line asparaginase- versus non-asparaginase-based regimens for early-stage extranodal NK/T-cell lymphoma. Ann Hematol 101, 2021–2034 (2022). https://doi.org/10.1007/s00277-022-04892-x

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