Despite Advances, Rheumatic Effects of Checkpoint Therapy Poorly Defined
SCOTTSDALE, Arizona — The rheumatic effects of checkpoint therapy remain, despite their increased spotlight in recent years, among the most poorly defined of the immune-related adverse events associated with the emerging cancer treatment, according to Cassandra Calabrese, DO, of the Cleveland Clinic.
“While we have learned a lot more about them in the past couple years, rheumatic [immune-related adverse events] irAEs are still one of the most poorly defined irAEs,” Calabrese told attendees at the Basic and Clinical Immunology for the Busy Clinician annual symposium. “Their prevalence is not entirely known, for many reasons, and there is quite a spectrum of irAEs that have been described, including arthritis, sicca symptoms, polymyalgia rheumatica, giant cell arteritis, myositis, vasculitis, but that list is not exhaustive.”
In addition, new research has suggested that rheumatic adverse effects from checkpoint therapy are unique among all other such events in that they appear to be persistent, with conditions becoming chronic in a third to one-half of patients, according to Calabrese.
“This is even after checkpoint treatment has stopped,” she added.
Despite these concerns and dangers, many fundamental questions remain, including the issue of prevalence.
According to Calabrese, the current best prevalence estimates of 5% are likely low, as they are not captured well in oncology clinical trial data. In addition, there is no standardization for coding rheumatic symptoms, she said.
“In these clinical trials, they use the Common Terminology Criteria for Adverse Events, or CTCAE, which is a rating system that grades on a scale of 1 to 5, with 1 being mild and 5 being death,” Calabrese said. “Clinical trials often only capture events of grade 3 or higher, which means those who have been hospitalized, and as we all know, someone can have very severe and debilitating inflammatory arthritis and still not be required to be in the hospital. That rating system is poorly applicable to our diseases.”
In addition, Calabrese said there is a decreased understanding of musculoskeletal complaints, and conditions like arthritis, myalgia and knee pain are often coded in a variety of different ways.
All of this, she said, have led to an incomplete understanding of rheumatic events related to checkpoint therapy. However, that is not the extent of the current uncertainty.
Although systematic reviews and studies have provided answers on managing these symptoms and conditions — including guidelines from the Society for Immunotherapy of Cancer that call for rigorous diagnostic evaluations based on early recognition and ruling out other causes, and often high-dose glucocorticoids and sometimes DMARDs — many just as often introduce new questions. These include:
- Does the occurrence of an immune-related adverse event serve as a biomarker of anti-tumor response?
- What is the safety of ICI therapy in patients with pre-existing autoimmune diseases?
- Do biomarkers exist to help predict these events?
- Will immunosuppressive medications used to treat irAE blunt the antitumor response?
Regarding the last question, Calabrese said research has provided mixed results, with suggestions that high dose glucocorticoids and more than 10 mg of prednisone at baseline have negative effects.
To combat these events as well as to mitigate these uncertainties, Calabrese stressed the importance of an interdisciplinary approach, using the Cleveland Clinic’s own “tumor board” on irAEs caused by checkpoint therapy as an example.
“Major centers need to develop interprofessional groups with interested and invested consultants in all specialties,” she said. “We started our tumor board 2 years ago, where numerous subspecialists talk about cases in real time, review the data and make decisions.”
“In addition, triage systems are essential for optimal care — these patients need to be seen yesterday, not in May or whenever your next available appointment is,” she added. “Education is also critically needed at many levels, including community oncologist, specialists, general practitioners and advanced practitioners.” – by Jason Laday
Calabrese C. Immune related adverse events from cancer immunotherapy. Presented at Basic and Clinical Immunology for the Busy Clinician; Feb. 28-29, 2020; Scottsdale, Arizona.
Disclosure: Calabrese reports no relevant financial disclosures.