Lymphopenia As an Early Predictor of Immune Related Adverse Events
Authors: Kamran Amir , Otaibi Zach , Shah Rupin Arun , Finley Gene 
Published: October 2019

Abstract
Introduction
Immune checkpoint inhibitors (ICI) are a novel class of medications which offer a potential curative option for many cancer patients who previously had a more dismal prognosis. Programmed cell death protein 1 (PD-1) is a molecule that modulates cellular immunity to limit autoimmunity, but can also be co-opted by cancers and infections to create immune tolerance. Nivolumab and pembrolizumab are fully human IgG4 PD-1 checkpoint-inhibitors. Ipilimumab on the other hand is an inhibitor of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). ICI can result in immune activation in non-target tissues, resulting in immune-related adverse events (irAEs) in a subset of patients and these toxicities have varying times to onset and affect different organs. Some studies suggest that patients with irAEs have higher response rates than patients without such events, but these findings have not been universally verified. There are few studies which also showed relationship between lymphopenia and survival in patient on chemotherapy. In this single center retrospective study we analyzed the relationship between CBC parameters and rates of irAEs.
Methods
We conducted a retrospective study at a single health care network aimed at understanding if CBC parameters could be used for early prediction of irAEs. Between July 2015 and September 2017 we found 106 patients who developed irAEs across three cancer types, renal cell carcinoma, melanoma, and lung cancer. Patients who did not receive immunotherapy as a first-line therapy were excluded from this study. All patients had stage IV disease at the start of ICI. A total of 34 patients met inclusion criteria, but, 5 patients were excluded on the basis of only receiving one dose of ICI so there were no other CBC to compare. We then analyzed the CBC and differential of this population prior to the commencement of immunotherapy and immediately prior to reported irAEs and before the start of systemic steroids. The primary objective of the study was to find a hematological parameter which can predict the onset of irAEs.
Results
The average age of the study population was 59.9 years and was predominantly male (62.1%). The most frequent CBC parameter which changed prior to the onset of irAE was a reduction in the lymphocyte count (14%). We found that nearly 70% (20/29) of patient had reduction in their lymphocyte count immediately prior to the onset of the reported irAE. The vast majority of patients had grade 3 toxicities and there was a trend towards higher toxicities being associated with a greater degree of lymphopenia. In addition, lymphopenia was more frequently found in patients treated with Nivolumab than other ICIs. We found that the average number of ICIs cycles were 9.1 and 9.0 in the groups which developed and did not develop lymphopenia, respectively. In terms of the other CBC parameters, we found no significant differences in hemoglobin/hematocrit, platelet count, neutrophil count, basophil count, or eosinophil count before IO and prior to the development of irAEs.
Conclusion
Lymphopenia may be an early indicator of irAEs and should be investigated further in prospective trials.

Disclosures
No relevant conflicts of interest to declare.