BACKGROUND/AIM: Classic Hodgkin lymphoma (cHL) is a common B-cell malignancy. Despite the good prognosis, in some patients the standard chemotherapy and radiotherapy-based approach does not lead to long-term remission, and these patients eventually relapse. Moreover, the primary refractory disease is of major concern regarding prognosis. PATIENTS AND METHODS: We performed a retrospective analysis to evaluate PD-L1 expression in 120 patients with classic Hodgkin lymphoma (cHL). RESULTS: The median follow-up of the entire group of patients was 90 months. After initial therapy, complete remission was achieved in 113 (94.2%) patients. During the follow-up, cHL relapse/refractory disease was reported in 23 (19.2%) cases. A total of five patients died during the follow-up period, all from cHL progression. When determining PD-L1 expression on Hodgkin-Reed-Sternberg (HRS) cells, 37 cases (30.8%) were evaluated as negative, and 83 cases (69.2%) as positive. In the negative PD-L1 group of patients, no cHL relapse/refractory disease was observed during the follow-up period. However, out of 83 patients with positive PD-L1 expression on HRS cells, 23 (28%) showed relapse/refractory cHL. CONCLUSION: A significantly higher relapse rate was observed in PD-L1-positive patients diagnosed with cHL.

Department of Children's Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic;

Department of Pathology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Institute of Biostatistics and Analyses Faculty of Medicine Masaryk University Brno Czech Republic

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Glaser S, Jarrett R. 1 The epidemiology of Hodgkin’s disease. Baillière’s Clinical Haematology. 2020;9(3):401–416. doi: 10.1016/S0950-3536(96)80018-7. PubMed DOI

Rozalli F, Chua S, Green D. Elucidation of acute renal failure due to recurrent non-Hodgkin lymphoma by F-18 FDG PET/CT. Clinical Nuclear Medicine. 2021;33(3):201–203. doi: 10.1097/RLU.0b013e318162ddc7. PubMed DOI

Ansell S. Hodgkin lymphoma: 2018 update on diagnosis, risk-stratification, and management. American Journal of Hematology. 2021;93(5):704–715. doi: 10.1002/ajh.25071. PubMed DOI

Longo D, Duffey P, Young R, Hubbard S, Ihde D, Glatstein E, Phares J, Jaffe E, Urba W, Devita V. Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin’s disease after combination chemotherapy: the low probability for cure. Journal of Clinical Oncology. 2022;10(2):210–218. doi: 10.1200/JCO.1992.10.2.210. PubMed DOI

Master S, Koshy N, Wilkinson B, Rosen K, Mills G, Mansour R, Shi R. Effect of radiation therapy on survival in Hodgkin’s lymphoma: A SEER data analysis. Anticancer Res. 2017;37:3035–3043. doi: 10.21873/anticanres.11658. PubMed DOI

Küppers R, Engert A, Hansmann M-L. Hodgkin lymphoma. J Clin Invest. 2012;122:3439–3447. doi: 10.1172/JCI61245. PubMed DOI PMC

Yamamoto R, Nishikori M, Kitawaki T, Sakai T, Hishizawa M, Tashima M, Kondo T, Ohmori K, Kurata M, Hayashi T, Uchiyama T. PD-1–PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 2008;111:3220–3224. doi: 10.1182/blood-2007-05-085159. PubMed DOI

Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704. doi: 10.1146/annurev.immunol.26.021607.090331. PubMed DOI PMC

Ishida M, Iwai Y, Tanaka Y, Okazaki T, Freeman G, Minato N, Honjo T. Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunology Letters. 2023;84(1):57–62. doi: 10.1016/S0165-2478(02)00142-6. PubMed DOI

Francisco L, Salinas V, Brown K, Vanguri V, Freeman G, Kuchroo V, Sharpe A. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. Journal of Experimental Medicine. 2020;206(13):3015–3029. doi: 10.1084/jem.20090847. PubMed DOI PMC

Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2021;116(7):1757–1766. doi: 10.1002/cncr.24899. PubMed DOI

Geng L, Huang D, Liu J, Qian Y, Deng J, Li D, Hu Z, Zhang J, Jiang G, Zheng S. B7-H1 up-regulated expression in human pancreatic carcinoma tissue associates with tumor progression. Journal of Cancer Research and Clinical Oncology. 2019;134(9):1021–1027. doi: 10.1007/s00432-008-0364-8. PubMed DOI

Gao Q, Wang X, Qiu S, Yamato I, Sho M, Nakajima Y, Zhou J, Li B, Shi Y, Xiao Y, Xu Y, Fan J. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clinical Cancer Research. 2022;15(3):971–979. doi: 10.1158/1078-0432.CCR-08-1608. PubMed DOI

Loos M, Giese N, Kleeff J, Giese T, Gaida M, Bergmann F, Laschinger M, Büchler M, Friess H. Clinical significance and regulation of the costimulatory molecule B7-H1 in pancreatic cancer. Cancer Letters. 2019;268(1):98–109. doi: 10.1016/j.canlet.2008.03.056. PubMed DOI

Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M, Nakajima Y. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clinical Cancer Research. 2023;13(7):2151–2157. doi: 10.1158/1078-0432.CCR-06-2746. PubMed DOI

Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proceedings of the National Academy of Sciences. 2022;104(9):3360–3365. doi: 10.1073/pnas.0611533104. PubMed DOI PMC

He J, Hu Y, Hu M, Li B. Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Scientific Reports. 2023;5(1):13110. doi: 10.1038/srep13110. PubMed DOI PMC

Barrett MT, Anderson KS, Lenkiewicz E, Andreozzi M, Cunliffe HE, Klassen CL, Dueck AC, McCullough AE, Reddy SK, Ramanathan RK, Northfelt DW, Pockaj BA. Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer. Oncotarget. 2015;6:26483–26493. PubMed PMC

Sunshine J, Taube J. PD-1/PD-L1 inhibitors. Current Opinion in Pharmacology. 2020;23:32–38. doi: 10.1016/j.coph.2015.05.011. PubMed DOI PMC

Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, Timmerman JM, Collins GP, Ramchandren R, Cohen JB, De Boer JP, Kuruvilla J, Savage KJ, Trneny M, Shipp MA, Kato K, Sumbul A, Farsaci B, Ansell SM. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 trial. J Clin Oncol. 2018;36(14):1428–1439. doi: 10.1200/JCO.2017.76.0793. PubMed DOI PMC

Engert A, Franklin J, Eich HT, Brillant C, Sehlen S, Cartoni C, Herrmann R, Pfreundschuh M, Sieber M, Tesch H, Franke A, Koch P, de Wit M, Paulus U, Hasenclever D, Loeffler M, Müller RP, Müller-Hermelink HK, Dühmke E, Diehl V. Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin’s lymphoma: final results of the GHSG HD7 trial. J Clin Oncol. 2007;25(23):3495–3502. doi: 10.1200/JCO.2006.07.0482. PubMed DOI

Salmaninejad A, Khoramshahi V, Azani A, Soltaninejad E, Aslani S, Zamani M, Zal M, Nesaei A, Hosseini S. PD-1 and cancer: molecular mechanisms and polymorphisms. Immunogenetics. 2022;70(2):73–86. doi: 10.1007/s00251-017-1015-5. PubMed DOI

Engert A, Plütschow A, Eich H, Lohri A, Dörken B, Borchmann P, Berger B, Greil R, Willborn K, Wilhelm M, Debus J, Eble M, Sökler M, Ho A, Rank A, Ganser A, Trümper L, Bokemeyer C, Kirchner H, Schubert J, Král Z, Fuchs M, Müller-Hermelink H, Müller R, Diehl V. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. New England Journal of Medicine. 2020;363(7):640–652. doi: 10.1056/NEJMoa1000067. PubMed DOI

Von Tresckow B, Plütschow A, Fuchs M, Klimm B, Markova J, Lohri A, Kral Z, Greil R, Topp M, Meissner J, Zijlstra J, Soekler M, Stein H, Eich H, Mueller R, Diehl V, Borchmann P, Engert A. Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin study group HD14 trial. Journal of Clinical Oncology. 2022;30(9):907–913. doi: 10.1200/JCO.2011.38.5807. PubMed DOI

Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A, Zijlstra J, Král Z, Fuchs M, Hallek M, Kanz L, Döhner H, Dörken B, Engel N, Topp M, Klutmann S, Amthauer H, Bockisch A, Kluge R, Kratochwil C, Schober O, Greil R, Andreesen R, Kneba M, Pfreundschuh M, Stein H, Eich H, Müller R, Dietlein M, Borchmann P, Diehl V. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. The Lancet. 2018;379(9828):1791–1799. doi: 10.1016/S0140-6736(11)61940-5. PubMed DOI

Gordon LI, Hong F, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, Wagner H, Stiff PJ, Cheson BD, Gospodarowicz M, Advani R, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496) J Clin Oncol. 2013;31(6):684–691. doi: 10.1200/JCO.2012.43.4803. PubMed DOI PMC

Von Tresckow B, Engert A. The role of autologous transplantation in Hodgkin lymphoma. Current Hematologic Malignancy Reports. 2020;6(3):172–179. doi: 10.1007/s11899-011-0091-0. PubMed DOI

Morschhauser F, Brice P, Fermé C, Diviné M, Salles G, Bouabdallah R, Sebban C, Voillat L, Casasnovas O, Stamatoullas A, Bouabdallah K, André M, Jais J, Cazals-Hatem D, Gisselbrecht C. Risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation for first relapse/refractory Hodgkin’s lymphoma: results of the prospective multicenter H96 trial by the GELA/SFGM study group. Journal of Clinical Oncology. 2022;26(36):5980–5987. doi: 10.1200/JCO.2007.15.5887. PubMed DOI

Moskowitz C, Nadamanee A, Masszi T, Agura E, Holowiecki J, Abidi M, Chen A, Stiff P, Gianni A, Carella A, Osmanov D, Bachanova V, Sweetenham J, Sureda A, Huebner D, Larsen E, Hunder N, Walewski J. The Aethera trial: Results of a randomized, double-blind, placebo-controlled phase 3 study of brentuximab vedotin in the treatment of patients at risk of progression following autologous stem cell transplant for Hodgkin lymphoma. Blood. 2019;124(21):673–673. doi: 10.1182/blood.V124.21.673.673. DOI

Tanaka Y, Maeshima A, Nomoto J, Makita S, Fukuhara S, Munakata W, Maruyama D, Tobinai K, Kobayashi Y. Expression pattern of PD-L1 and PD-L2 in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and gray zone lymphoma. European Journal of Haematology. 2021;100(5):511–517. doi: 10.1111/ejh.13033. PubMed DOI

Vranic S, Ghosh N, Kimbrough J, Bilalovic N, Bender R, Arguello D, Veloso Y, Dizdarevic A, Gatalica Z. PD-L1 status in refractory lymphomas. PLoS One. 2016;11:e0166266–e0166266. PubMed PMC

Dilly-Feldis M, Aladjidi N, Refait JK, Parrens M, Ducassou S, Rullier A. Expression of PD-1/PD-L1 in children’s classical Hodgkin lymphomas. Pediatr Blood Cancer. 2019;66:e27571. doi: 10.1002/pbc.27571. PubMed DOI

Koh Y, Jeon Y, Yoon D, Suh C, Huh J. Programmed death 1 expression in the peritumoral microenvironment is associated with a poorer prognosis in classical Hodgkin lymphoma. Tumor Biology. 2019;37(6):7507–7514. doi: 10.1007/s13277-015-4622-5. PubMed DOI

Paydas S, Bağır E, Seydaoglu G, Ercolak V, Ergin M. Programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and EBV-encoded RNA (EBER) expression in Hodgkin lymphoma. Annals of Hematology. 2020;94(9):1545–1552. doi: 10.1007/s00277-015-2403-2. PubMed DOI

Roemer M, Advani R, Ligon A, Natkunam Y, Redd R, Homer H, Connelly C, Sun H, Daadi S, Freeman G, Armand P, Chapuy B, De Jong D, Hoppe R, Neuberg D, Rodig S, Shipp M. PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. Journal of Clinical Oncology. 2022;34(23):2690–2697. doi: 10.1200/JCO.2016.66.4482. PubMed DOI PMC

Hollander P, Amini R, Ginman B, Molin D, Enblad G, Glimelius I. Expression of PD-1 and PD-L1 increase in consecutive biopsies in patients with classical Hodgkin lymphoma. PLOS ONE. 2018;13(9):e0204870. doi: 10.1371/journal.pone.0204870. PubMed DOI PMC

Roemer M, Redd R, Cader F, Pak C, Abdelrahman S, Ouyang J, Sasse S, Younes A, Fanale M, Santoro A, Zinzani P, Timmerman J, Collins G, Ramchandren R, Cohen J, De Boer J, Kuruvilla J, Savage K, Trneny M, Ansell S, Kato K, Farsaci B, Sumbul A, Armand P, Neuberg D, Pinkus G, Ligon A, Rodig S, Shipp M. Major histocompatibility complex class II and programmed death ligand 1 expression predict outcome after programmed death 1 blockade in classic Hodgkin lymphoma. Journal of Clinical Oncology. 2022;36(10):942–950. doi: 10.1200/JCO.2017.77.3994. PubMed DOI PMC

Armand P, Shipp M, Ribrag V, Michot J, Zinzani P, Kuruvilla J, Snyder E, Ricart A, Balakumaran A, Rose S, Moskowitz C. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. Journal of Clinical Oncology. 2022;34(31):3733–3739. doi: 10.1200/JCO.2016.67.3467. PubMed DOI PMC