Association Between RBC Antigen Allo-Antibodies and Immune-Related Adverse Events During Immune Checkpoint Inhibitor Treatment for Advanced Cancers

Natasha A Jain ¹, Songzhu Zhao ², Lai Wei ², Kerry A Rogers ¹, Gregory A Otterson ¹, Tzu-Fei Wang ³, Dwight H Owen ¹

Affiliations

¹ Division of Medical Oncology, The Ohio State University, Columbus, OH, USA.
² Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
³ Division of Hematology, The Ohio State University, Columbus, OH, USA.

PMID: 33235503
33 References

Abstract

Introduction: Immune checkpoint inhibitors (ICI) have become a primary treatment modality for patients with a variety of malignancies. Given their increasing use, it is essential to be familiar with their immune-related adverse events (irAEs). Here we report a severe case of autoimmune hemolytic anemia (AIHA) associated with cold agglutinin precipitated by pembrolizumab, and a retrospective study of patients treated with ICI utilizing an institutional database where we analyzed the patterns of anti-RBC testing and their ability to predict irAE.

Methods: Patients treated with at least one dose of ICI (PD-1, PD-L1, CTLA-4 inhibitors) for advanced cancer between November 2012 and September 2017 at our institution were included. Electronic Medical Records were reviewed to abstract data. Medians and 95% CIs were estimated using Kaplan-Meier method and differences compared using the Log Rank test. Fisher's exact test and Chi square test were used to analyze clinical associations.

Results: We identified 1065 patients who received at least one dose of ICI: 180/1065 (17%) underwent direct antiglobulin test (DAT) or allo-antibody (alloAb) testing at any time; 127/1065 (12%) had either DAT or alloAb testing pre-ICI; 129 had either DAT or alloAb testing after ICI initiation; and 76 had either DAT or alloAb testing at both time points. There was a significant association between positive alloAb pre-ICI and the development of irAE while on ICI (p = 0.04).

Conclusion: Given the increasing use of ICI, oncologists should be aware of potential irAEs with ICI. We found an association between the presence of an alloAb pre-ICI and the development of irAE, indicating that this previous non-self antigen response may predict immune adverse events. A larger prospective study is needed for systematic evaluation of the association between alloAb testing and irAE, and whether routine testing may inform clinical decision-making for patients.

Keywords: autoimmune hemolytic anemia; direct antiglobulin test; immune checkpoint inhibitors; immune-related adverse events; immunotherapy; red blood cell allo-antibodies.

Other Links

Free PMC article
Full text on Cancer management and research

References

References
Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. Paul A Harris, Robert Taylor, +3 authors, Jose G Conde. less J Biomed Inform, 2008 Oct 22; 42(2). PMID: 18929686 Free PMC article. Highly Cited.
Diagnosis and treatment of autoimmune hemolytic anemia: classic approach and recent advances. Sang Hyuk Park. Blood Res, 2016 Jul 07; 51(2). PMID: 27382547 Free PMC article.
New Insights in the Pathogenesis of Autoimmune Hemolytic Anemia. Wilma Barcellini. Transfus Med Hemother, 2015 Dec 24; 42(5). PMID: 26696796 Free PMC article. Review.
Development of red blood cell autoantibodies following treatment with checkpoint inhibitors: a new class of anti-neoplastic, immunotherapeutic agents associated with immune dysregulation. Laura L Cooling, John Sherbeck, Jonathon C Mowers, Sheri L Hugan. Immunohematology, 2017 Apr 21; 33(1). PMID: 28425751
Development of Hemolytic Anemia in a Nivolumab-Treated Patient with Refractory Metastatic Squamous Cell Skin Cancer and Chronic Lymphatic Leukemia. K S Schwab, A Heine, +2 authors, T Weimann, G Kristiansen, P Brossart. less Case Rep Oncol, 2016 Jul 28; 9(2). PMID: 27462240 Free PMC article.
Autoimmune Hemolytic Anemia as a Complication of Nivolumab Therapy. Amruth R Palla, Devin Kennedy, Hossain Mosharraf, Donald Doll. Case Rep Oncol, 2016 Dec 07; 9(3). PMID: 27920704 Free PMC article.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada. less J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981 Free PMC article. Highly Cited.
Treatment of autoimmune hemolytic anemias. Alberto Zanella, Wilma Barcellini. Haematologica, 2014 Oct 02; 99(10). PMID: 25271314 Free PMC article. Review.
Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Sophia C Weinmann, David S Pisetsky. Rheumatology (Oxford), 2019 Dec 10; 58(Suppl 7). PMID: 31816080 Free PMC article. Review.
Incidence, Risk Factors, and Effect on Survival of Immune-related Adverse Events in Patients With Non-Small-cell Lung Cancer. Dwight H Owen, Lai Wei, +6 authors, Gregory A Otterson. less Clin Lung Cancer, 2018 Sep 11; 19(6). PMID: 30197259 Free PMC article.
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. Robert L Ferris, George Blumenschein, +20 authors, Maura L Gillison. less N Engl J Med, 2016 Oct 11; 375(19). PMID: 27718784 Free PMC article. Highly Cited.
How I manage cold agglutinin disease. Sigbjørn Berentsen. Br J Haematol, 2011 Mar 10; 153(3). PMID: 21385173 Review.
Exacerbation of autoimmune hemolytic anemia induced by the first dose of programmed death-1 inhibitor pembrolizumab: a case report. Kenta Ogawa, Jiro Ito, +5 authors, Nobuyuki Katakami. less Invest New Drugs, 2018 Jan 18; 36(3). PMID: 29340837
Autoimmune hemolytic anemia after nivolumab treatment in Hodgkin lymphoma responsive to immunosuppressive treatment. A case report. Magalie P Tardy, Lauris Gastaud, +3 authors, Antoine Thyss. less Hematol Oncol, 2016 Aug 20; 35(4). PMID: 27539158
Transfusion-related red blood cell alloantibodies: induction and consequences. Christopher A Tormey, Jeanne E Hendrickson. Blood, 2019 Feb 28; 133(17). PMID: 30808636 Free PMC article. Review.
Diagnosis and classification of autoimmune hemolytic anemia. Garrett F Bass, Emily T Tuscano, Joseph M Tuscano. Autoimmun Rev, 2014 Jan 15; 13(4-5). PMID: 24418298 Review.
Cold agglutinin disease. Sigbjørn Berentsen. Hematology Am Soc Hematol Educ Program, 2016 Dec 04; 2016(1). PMID: 27913484 Free PMC article. Review.
Autoimmune hemolytic anemia induced by anti-PD-1 therapy in metastatic melanoma. Benjamin Y Kong, Kenneth P Micklethwaite, +2 authors, Matteo S Carlino. less Melanoma Res, 2016 Jan 23; 26(2). PMID: 26795275
Conditional immune toxicity rate in patients with metastatic renal and urothelial cancer treated with immune checkpoint inhibitors. Pier Vitale Nuzzo, Gregory R Pond, +9 authors, Guru Sonpavde. less J Immunother Cancer, 2020 Apr 03; 8(1). PMID: 32234849 Free PMC article.
Clonal regulatory T cells specific for a red blood cell autoantigen in human autoimmune hemolytic anemia. Frank J Ward, Andrew M Hall, +4 authors, Robert N Barker. less Blood, 2007 Sep 01; 111(2). PMID: 17761830 Free PMC article.
Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting. Ulrich Jäger, Wilma Barcellini, +10 authors, Sigbjørn Berentsen. less Blood Rev, 2019 Dec 17; 41. PMID: 31839434 Review.
PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer. John Dulos, Gregory J Carven, +12 authors, Annemieke M Boots. less J Immunother, 2012 Feb 07; 35(2). PMID: 22306905
Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. Martin Reck, Delvys Rodríguez-Abreu, +16 authors, KEYNOTE-024 Investigators. less N Engl J Med, 2016 Oct 11; 375(19). PMID: 27718847 Highly Cited.
Immunotherapy-Associated Hemolytic Anemia with Pure Red-Cell Aplasia. Ranjit Nair, Shereen Gheith, Suresh G Nair. N Engl J Med, 2016 Mar 18; 374(11). PMID: 26981948
How I treat autoimmune hemolytic anemias in adults. Klaus Lechner, Ulrich Jäger. Blood, 2010 Jun 16; 116(11). PMID: 20548093 Review.
CD4+CD25+ regulatory T cells control induction of autoimmune hemolytic anemia. Amina Mqadmi, Xiaoying Zheng, Karina Yazdanbakhsh. Blood, 2005 Jan 08; 105(9). PMID: 15637139 Free PMC article.
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. Robert J Motzer, Nizar M Tannir, +30 authors, CheckMate 214 Investigators. less N Engl J Med, 2018 Mar 22; 378(14). PMID: 29562145 Free PMC article. Highly Cited.
Regulatory T cells: key controllers of immunologic self-tolerance. S Sakaguchi. Cell, 2000 Jun 13; 101(5). PMID: 10850488 Highly Cited. Review.
Alloimmunization and erythrocyte autoimmunization in transfusion-dependent thalassemia patients of predominantly asian descent. S T Singer, V Wu, +3 authors, R Mignacca, F A Kuypers, P Morel, E P Vichinsky. less Blood, 2000 Nov 09; 96(10). PMID: 11071629
A case of dual-mechanism immune-related anaemia in a patient with metastatic melanoma treated with nivolumab and ipilimumab. Daniel J Olson, Padma Rajagopal, +3 authors, Thomas F Gajewski. less J Immunother Cancer, 2020 Mar 15; 8(1). PMID: 32169870 Free PMC article.
CTLA4 blockade increases Th17 cells in patients with metastatic melanoma. Erika von Euw, Thinle Chodon, +4 authors, Antoni Ribas. less J Transl Med, 2009 May 22; 7. PMID: 19457253 Free PMC article.
Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study. Nicolas Delanoy, Jean-Marie Michot, +34 authors, Olivier Lambotte. less Lancet Haematol, 2018 Dec 12; 6(1). PMID: 30528137
Clinical course of autoimmune hemolytic anemia: an observational study. Maria Christina L A Oliveira, Benigna M Oliveira, +3 authors, Marcos B Viana. less J Pediatr (Rio J), 2006 Mar 15; 82(1). PMID: 16532149

BioKDE: Biomedical Knowledge Discovery Engine

Abstract

Other Links