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

Natasha A Jain,1,2 Songzhu Zhao,3 Lai Wei,3 Kerry A Rogers,1,2 Gregory A Otterson,1 Tzu-Fei Wang,2 Dwight H Owen1 1Division of Medical Oncology, The Ohio State University, Columbus, OH, USA; 2Division of Hematology, The Ohio State University, Columbus, OH, USA; 3Center for Biostatistics, The Ohio State University, Columbus, OH, USACorrespondence: Dwight H OwenDivision of Medical Oncology, The Ohio State University, Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43212, USATel +1 614 – 685 – 2039Email Dwight.owen@osumc.eduIntroduction: 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, immune-related adverse events, direct antiglobulin test, immunotherapy, immune checkpoint inhibitors, red blood cell allo-antibodies