Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation. Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells. Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial. Methods HRS cells from archival tumor biopsies were evaluated for 9p24.1 alterations by fluorescence in situ hybridization and for expression of PD ligand 1 (PD-L1) and the antigen presentation pathway components-β2-microglobulin, MHC class I, and MHC class II-by immunohistochemistry. These parameters were correlated with clinical responses and progression-free survival (PFS) after PD-1 blockade. Results Patients with higher-level 9p24.1 copy gain and increased PD-L1 expression on HRS cells had superior PFS. HRS cell expression of β2-microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy. In contrast, HRS cell expression of MHC class II was predictive for complete remission. In patients with a > 12-month interval between myeloablative autologous stem-cell transplantation and nivolumab therapy, HRS cell expression of MHC class II was associated with prolonged PFS. Conclusion Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade. In cHL, clinical responses to nivolumab were not dependent on HRS cell expression of MHC class I.

Margaretha G M Roemer Robert A Redd Fathima Zumla Cader Christine J Pak Sara Abdelrahman Jing Ouyang Philippe Armand Donna S Neuberg and Margaret A Shipp Dana Farber Cancer Institute; Geraldine S Pinkus Azra H Ligon and Scott J Rodig Brigham and Women's Hospital Boston MA; Margaretha G M Roemer VU University Medical Center; Jan Paul De Boer Antoni van Leeuwenhoek Hospital Lunenburg Phase 1 2 Consortium Amsterdam the Netherlands; Stephanie Sasse University Hospital of Cologne Cologne Germany; Anas Younes Memorial Sloan Kettering Cancer Center New York NY; Michelle Fanale University of Texas MD Anderson Cancer Center Houston TX; Armando Santoro Humanitas University Rozzano Milan; Pier Luigi Zinzani University of Bologna Bologna Italy; John Timmerman University of California Los Angeles Medical Center Los Angeles CA; Graham P Collins Churchill Hospital Oxford United Kingdom; Radhakrishnan Ramchandren Barbara Ann Karmanos Cancer Institute Detroit MI; Jonathon B Cohen Emory University Atlanta GA; John Kuruvilla Princess Margaret Cancer Centre Toronto Ontario Canada; Kerry J Savage British Columbia Cancer Agency Center for Lymphoid Cancer Vancouver British Columbia Canada; Marek Trneny Charles University Prague General University Hospital Prague Prague Czech Republic; Stephen Ansell Mayo Clinic Rochester MN; and Kazunobu Kato Benedetto Farsaci and Anne Sumbul Bristol Myers Squibb Princeton NJ

J Clin Oncol. 2018 Sep 1;36(25):2657. doi: 10.1200/JCO.2018.78.9826. PubMed

J Clin Oncol. 2018 Sep 1;36(25):2656. doi: 10.1200/JCO.2018.78.4116. PubMed

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Prognostic Significance of Immune-checkpoint Molecule PD-L1 in Classical Hodgkin Lymphoma: A Clinicopathologic Study of 120 Cases

Nivolumab for Newly Diagnosed Advanced-Stage Classic Hodgkin Lymphoma: Safety and Efficacy in the Phase II CheckMate 205 Study

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