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Optimization of immune checkpoint inhibitor treatment planning for relapsed or refractory extranodal NK/T cell lymphoma

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Abstract

Pembrolizumab (anti-programmed cell death-ligand 1 inhibitor) is a promising salvage therapeutic option for relapsed/refractory extranodal NK/T-cell lymphoma (R/R ENKTL). However, the appropriate duration of pembrolizumab use in R/R ENKTL patients and the optimal timing for administering pembrolizumab remain undetermined. We collected and analyzed clinical information on R/R ENKTL 58 patients who received pembrolizumab to evaluate the optimal treatment durations and clinical information for considering treatment interruption. Treatment outcomes were assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and Epstein Barr virus DNA (EBV DNA) every 3 months. Nineteen (32.8%) patients had been treated with more than three chemotherapies before pembrolizumab administration. The best response rate towards the first try of pembrolizumab was 38.9% (31.5% complete response rate (CR), 7.4% partial response (PR)). During the 41.8-month median follow-up duration, the median progression-free survival (PFS) was 3.1 months, and the median overall survival (OS) was 7.1 months. The failure group, which was characterized by Deaville score (DS) 3–4 and circulating EBV detection, or DS 5 with/without EBV detection, had the worst PFS (p < 0.001) and OS (p < 0.001), followed by the high (DS 1–2 and EBV detection, or DS 3–4 and EBV not detected) and low-risk groups (DS 1–2 and EBV not detected). Among the 21 patients who achieved the best response at the first pembolizumab try, the patients who received planned 24 cycles presented better PFS than those who received incomplete cycles (57.6 months vs 20.9 months, P-value = 0.012). Among 13 patients who received avelumab or pembrolizumab in advance, a few who responded to the second trial of pembrolizumab administration had over one year of chemotherapy vacation. Determining the discontinuation or continuation of pembrolizumab would be considered in selected cases assessed by PET-CT and EBV monitoring. Disruption of pembrolizumab treatment may be advisable for the low-risk group(DS 1–2 and EBV not detected), whereas continuation could be warranted for the high-risk group (DS 1–2 and EBV detection, or DS 3–4 and EBV not detected). Moreover, it might be critical to maintain over 24 cycles to improve the survival outcome of R/R ENKTL.

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References

  1. Kommalapati A, Tella SH, Ganti AK, Armitage JO (2018) Natural killer/t-cell neoplasms: analysis of incidence, patient characteristics, and survival outcomes in the United States. Clin Lymphoma Myeloma Leuk 18:475–479. https://doi.org/10.1016/j.clml.2018.04.009

    Article  PubMed  Google Scholar 

  2. Tse E, Kwong YL (2017) The diagnosis and management of NK/T-cell lymphomas. J Hematol Oncol 10:85. https://doi.org/10.1186/s13045-017-0452-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang L, Li LR, Zhang L, Wang JW (2020) The landscape of new drugs in extranodal NK/T-cell lymphoma. Cancer Treat Rev 89:102065. https://doi.org/10.1016/j.ctrv.2020.102065

    Article  CAS  PubMed  Google Scholar 

  4. Fox CP et al (2020) Survival outcomes of patients with extranodal natural-killer T-cell lymphoma: a prospective cohort study from the international T-cell Project. Lancet Haematol 7:e284–e294. https://doi.org/10.1016/S2352-3026(19)30283-2

    Article  PubMed  Google Scholar 

  5. Kim SJ et al (2013) Extranodal natural killer/T-cell lymphoma involving the gastrointestinal tract: analysis of clinical features and outcomes from the Asia Lymphoma Study Group. J Hematol Oncol 6:86. https://doi.org/10.1186/1756-8722-6-86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lim SH 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 28:2199–2205. https://doi.org/10.1093/annonc/mdx316

    Article  CAS  PubMed  Google Scholar 

  7. Youk HJ, Hwang SH, Oh HB, Ko DH (2022) Evaluation and management of platelet transfusion refractoriness. Blood Res 57:6–10. https://doi.org/10.5045/br.2022.2021229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nairismägi M et al (2018) Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma. Leukemia 32:1147–1156. https://doi.org/10.1038/s41375-017-0004-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Song TL et al (2018) Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma. Blood 132:1146–1158. https://doi.org/10.1182/blood-2018-01-829424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li X et al (2018) Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma. J Hematol Oncol 11:15. https://doi.org/10.1186/s13045-018-0559-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tse E et al (2022) Extranodal natural killer/T-cell lymphoma: An overview on pathology and clinical management. Semin Hematol 59:198–209. https://doi.org/10.1053/j.seminhematol.2022.10.002

    Article  PubMed  Google Scholar 

  12. Kwong YL et al (2017) PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood 129:2437–2442. https://doi.org/10.1182/blood-2016-12-756841

    Article  CAS  PubMed  Google Scholar 

  13. Chan TSY et al (2018) PD1 blockade with low-dose nivolumab in NK/T cell lymphoma failing L-asparaginase: efficacy and safety. Ann Hematol 97:193–196. https://doi.org/10.1007/s00277-017-3127-2

    Article  CAS  PubMed  Google Scholar 

  14. Kim SJ et al (2020) Avelumab for the treatment of relapsed or refractory extranodal NK/T-cell lymphoma: an open-label phase 2 study. Blood 136:2754–2763. https://doi.org/10.1182/blood.2020007247

    Article  CAS  PubMed  Google Scholar 

  15. Danson S et al (2019) Are we over-treating with checkpoint inhibitors? Br J Cancer 121:629–630. https://doi.org/10.1038/s41416-019-0570-y

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kim SJ 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. https://doi.org/10.1016/S2352-3026(15)00002-2

    Article  PubMed  Google Scholar 

  17. Kim SJ 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 

  18. Cho J et al (2020) Immune subtyping of extranodal NK/T-cell lymphoma: a new biomarker and an immune shift during disease progression. Mod Pathol 33:603–615. https://doi.org/10.1038/s41379-019-0392-8

    Article  CAS  PubMed  Google Scholar 

  19. Cheson BD et al (1999) Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17:1244. https://doi.org/10.1200/jco.1999.17.4.1244

    Article  CAS  PubMed  Google Scholar 

  20. Cheson BD 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 

  21. Kim SJ 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. The Lancet Haematology 2:e66–e74

    Article  PubMed  Google Scholar 

  22. Wang L, Wang JW (2020) PD-1 blockade in extranodal NK/T-cell lymphoma: who is in charge? Leukemia 34:3432–3433. https://doi.org/10.1038/s41375-020-01046-8

    Article  CAS  PubMed  Google Scholar 

  23. Jeong SH (2020) Extranodal NK/T cell lymphoma. BR 55:S63–S71. https://doi.org/10.5045/br.2020.S011

    Article  Google Scholar 

  24. Huang HQ et al (2019) Preliminary results from a multicenter, single-arm, Phase 2 Study of CS1001, an anti-programmed death-ligand 1 (PD-L1) human monoclonal antibody (mAb), in patients (pts) with relapsed or refractory extranodal natural killer/t cell lymphoma (rr-ENKTL). Blood 134:2833–2833. https://doi.org/10.1182/blood-2019-121865

    Article  Google Scholar 

  25. Li JY et al (2020) Sintilimab for relapsed/refractory (r/r) extranodal NK/T cell lymphoma (ENKTL): Extended follow-up on the multicenter, single-arm phase II trail (ORIENT-4). J Clin Oncol 38:abstract 8050. https://doi.org/10.1200/JCO.2020.38.15_suppl.8050

    Article  Google Scholar 

  26. Havel JJ, Chowell D, Chan TA (2019) The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 19:133–150. https://doi.org/10.1038/s41568-019-0116-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yi M, Niu M, Xu L, Luo S, Wu K (2021) Regulation of PD-L1 expression in the tumor microenvironment. Journal of Hematology & Oncology 14:10. https://doi.org/10.1186/s13045-020-01027-5

    Article  CAS  Google Scholar 

  28. McGranahan N et al (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351:1463–1469. https://doi.org/10.1126/science.aaf1490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dang TO, Ogunniyi A, Barbee MS, Drilon A (2016) Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. Expert Rev Anticancer Ther 16:13–20. https://doi.org/10.1586/14737140.2016.1123626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. LaFleur MW, Muroyama Y, Drake CG, Sharpe AH (2018) Inhibitors of the PD-1 Pathway in Tumor Therapy. J Immunol 200:375–383. https://doi.org/10.4049/jimmunol.1701044

    Article  CAS  PubMed  Google Scholar 

  31. Boyerinas B et al (2015) Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells. Cancer Immunol Res 3:1148–1157. https://doi.org/10.1158/2326-6066.Cir-15-0059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 28:865–870. https://doi.org/10.1038/leu.2013.212

    Article  CAS  PubMed  Google Scholar 

  33. Wang L et al (2015) 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 6:30317–30326. https://doi.org/10.18632/oncotarget.4505

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lauer EM, Mutter J, Scherer F (2022) Circulating tumor DNA in B-cell lymphoma: technical advances, clinical applications, and perspectives for translational research. Leukemia 36:2151–2164. https://doi.org/10.1038/s41375-022-01618-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ha JY et al (2020) Superiority of Epstein-Barr Virus DNA in the Plasma Over Whole Blood for Prognostication of Extranodal NK/T Cell Lymphoma. Front Oncol 10:594692. https://doi.org/10.3389/fonc.2020.594692

    Article  PubMed  PubMed Central  Google Scholar 

  36. Delivanis DA et al (2017) Pembrolizumab-Induced Thyroiditis: Comprehensive Clinical Review and Insights Into Underlying Involved Mechanisms. J Clin Endocrinol Metab 102:2770–2780. https://doi.org/10.1210/jc.2017-00448

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HR20C0025), a National Research Foundation of Korea grant funded by the Korean government (2022R1F1A1064058), and the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. RS-2023-00222838).

Funding

No commercial funding was received to support this study.

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Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Sang Eun Yoon, Seok Jin Kim & Won Seog Kim

  2. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

    Hyungwoo Cho & Dok Hyun Yoon

  3. Department of Hematology and Oncology, University Hospital Muenster, Muenster, Germany

    Philipp Berning & Norbert Schmit

  4. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Junhun Cho

  5. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Hyun-Young Kim

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Contributions

W.S.K. and S.E.Y. conceived and designed the study. S.E.Y., H.C., P.B., J.C., H.Y.K., D.H.Y., N.S., S.J.K., and W.S.K. gathered patients for the study and collected clinical data. S.E.Y. analyzed the data and wrote the manuscript. All authors edited the manuscript and approved the final version.

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Correspondence to Won Seog Kim.

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Yoon, S.E., Cho, H., Berning, P. et al. Optimization of immune checkpoint inhibitor treatment planning for relapsed or refractory extranodal NK/T cell lymphoma. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05739-3

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