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J Clin Oncol. 2018 Apr 1;36(10):942-950. doi: 10.1200/JCO.2017.77.3994. Epub 2018 Feb 2.

Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma.

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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 I/II 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 in Prague, General University Hospital in Prague, Prague, Czech Republic; Stephen Ansell, Mayo Clinic, Rochester, MN; and Kazunobu Kato, Benedetto Farsaci, and Anne Sumbul, Bristol-Myers Squibb, Princeton, NJ.


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.


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