Therapeutic advances in the hematology/oncology world are not uncommon these days given the vast amount of research produced every year.  One class of drugs that has been evaluated extensively in recent years is the checkpoint inhibitors.  These drugs work via an immune mediated mechanism by blocking signaling pathways of effector T-cells (see figure 1 below for mechanism schematic).  These agents have been garnering indications at an amazing rate for a growing number of cancer types.  They are only used in the outpatient setting and generally reserved for treatment after failure of other lines of therapy, however first line indications are also beginning to arise.  Their success rates have been notable and are providing many patients with results that may have not been achievable in the past.  However, these drugs do come with a downside, they have elucidated a new category of adverse effects being referred to as immune related adverse events (IRAE’s).

As expected from the mechanism as shown below, these drugs help attach malignant cells trying to hide by expressing our “self-identifiers”, however, our own “self-cells” get caught in the crossfire and get attacked the same way as the signaling pathways are blocked.  This results in the possibility of inflammation of basically every organ system in the human body (see figure 2).  The incidence of these events can range from 1-10% and have a median onset of 3 months from the initiation of therapy with a range of 2-24 months. 

A complete review of the range of adverse events is beyond the scope of this article however I believe it is important for emergency department providers to recognize that these agents are being used more frequently.  Patients exposed to these agents may present in non-descript ways that mimic other more common disease states (i.e pneumonia, COPD exacerbation, etc.), but the treatments could differ significantly.  Gathering a thorough oncologic history along with a medication history can help identify these patients early enough to screen for these potential adverse effects.

Guidelines have been published by both the European and American oncology societies to help guide the management of these adverse events.  I have referenced them below.  For the most part, treatment of each individual organ system effected is corticosteroids with some discrepancy between the organizations in dosing.  In the ER, 1 mg/kg of methylprednisone would be adequate until further evaluation can be completed.  Other treatment modalities include, infliximab, mycophenolate and other immunosuppressive agents. 

The agents are listed below for reference:

• Anti-CTLA-4 (cytotoxic T-lympochyte antigen)
• Ipilimumab (Yervoy™)
• Anti-PD-L1 (programmed death ligand)
• Atezolizumab (Tecentriq™)
• Durvalumab (Imfinzi™)
• Avelumab (Bavencio™)
• Anti-PD-1 (programmed death)
• Pembrolizumab (Keytruda™)
• Nivolumab (Opdivo™)

 Figure 1. (RadioGraphics 2017; 37:1371–1387)

Figure 2. (Annals of Oncology 27:559-574, 2016)

Benjamin Jagow PharmD

References

1.      ESMO Guidelines – Annals of Oncology 28 (Supplement 4): i119–i142, 2017

2.     ASCO Guidelines – Clinical Oncology 36, no. 17 (June 10 2018) 1714-1768