Fellow summary authored by James Smithy, MD, MHS

Systemic Toxicity Associated With Immune Checkpoint Inhibitors

Dr. Kerry Reynolds, the clinical director of inpatient oncology at Massachusetts General Hospital (MGH), presented an overview of systemic toxicity related to immune checkpoint inhibitors (ICIs) as well as efforts at her institution to organize research efforts around these phenomena. Dr. Reynolds first presented a broad overview about how ICIs targeting CTLA-4, PD-1/PD-L1, and LAG-3 have been approved in over 80 oncology indications, and how many upcoming approvals will involve new combinations and new disease settings such as adjuvant treatment. Of the patients treated with ICIs, around 69,000 patients are estimated to experience severe immune-related adverse events (irAEs) this year in the United States alone. While irAEs can affect many organ systems, myocarditis and neurological toxicity are associated with the highest mortality. These particular toxicities are treated with the highest steroid doses. Current management guidelines for irAEs, published separately by the Society for Oncology of Cancer (SITC), National Comprehensive Cancer Network (NCCN), and the American Society of Clinical Oncology (ASCO) are based on expert opinion and there is scant prospective evidence to guide management decisions. To address this, Dr. Reynolds and her colleagues created an interdisciplinary Immunotherapy Toxicity Service, bringing together oncologists and other subspecialists who have expertise in managing these toxicities. Dr. Reynolds’s group is focused on developing best practices, identifying predictors of severe toxicity, and identifying the pathophysiology behind severe irAEs. By admitting patients with irAEs to a dedicated inpatient team, they are able to develop concentrated expertise and build streamlined research processes such as consent to research protocols and collection of biospecimens. Initial analysis of this service’s implementation showed that while admission to this service was not associated with a decreased hospital length of stay, it was significantly associated with a decreased risk of readmission for the same irAE (p = 0.3036; Zubiri et al, JITC 2021). Dr. Reynolds then focused on cardiac toxicity as a case study to demonstrate the research advantages of this model. Different investigators at MGH had used ECG changes, global longitudinal strain on echocardiography, and late gadolinium enhancement on MRI to risk-stratify patients for the incidence of major adverse cardiac events (MACE). They found that QRS prolongation (Zlotoff et al, JITC 2021) and lower global longitudinal strain (Awadalla et al, JACC 2020) were associated with increased risk of MACE, while late gadolinium enhancement (LGE) was not (Zhang et al, EHJ 2020). To gather prospective data on how to best manage patients with ICI myocarditis, MGH is leading the multicenter phase 3 ATRIUM study, which will randomize 390 patients admitted with ICI myocarditis to abatacept or placebo. This trial will have a strong translational component as well, with exploratory endpoints including circulating tumor DNA as well as miRNA levels associated with cardiac injury. Going forward, the infrastructure created in MGH’s immunotherapy toxicity service will enable the conduct of more prospective trials and translational initiatives that will further inform our understanding of the clinical management and underlying mechanisms of irAEs.