An overlap syndrome of myasthenia gravis, myocarditis, myositis and hepatitis triggered by immune checkpoint inhibitor use

12025 Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, some immune-related adverse events (irAEs) can be severe, even fatal. ICI-induced myocarditis (ICI-M) carries the highest mortality rate of 30-50%. Notably, ICI myocarditis frequently co-occurs with ICI-induced myositis (ICI-M 2 ) or as a triad of ICI-induced myocarditis, myositis and myasthenia gravis (ICI-M 3 ). Despite this known association, it remains unclear whether these entities represent distinct disease processes or a spectrum of disease severity. Therefore, we sought to compare outcomes among those diagnosed with ICI-M, ICI-M 2 and ICI-M 3 . Methods: We performed a single-institution retrospective cohort study using the electronic health record to identify patients seen in a solid tumor clinic between 1/21/11 – 1/21/25, who had received ICI therapy. There was a concern for myocarditis in 82 patients, of which 33 were deemed to have > grade 2 ICI-induced myocarditis. Of the 33 cases, 36% had ICI-M, 36% had ICI-M 2 and 27% had ICI-M 3 . We then assessed differences in age, sex, cancer type & stage, immunotherapy regimen, number of immune suppressants given, myocarditis grade, and overall survival across these groups. Results: The Table shows patients with ICI-M presented at an earlier cancer stage and more commonly after ICI monotherapy than combination therapy. Despite this, these patients typically had more severe grade ≥ 3 myocarditis (75%) compared with ICI-M 2 (42%) and ICI-M 3 (44%) and had a worse overall survival (33%) as compared to ICI-M 2 and ICI-M 3 (67% and 78% respectively). Notably ICI-M patients typically presented with cardiac-specific symptoms and presented after more cycles of ICI therapy (avg. of 4 cycles). In contrast, ICI-M 2 and ICI-M 3 patients presented after fewer ICI cycles (avg. of 2 cycles) with symptoms of myositis or myasthenia. They typically did not present with cardiac-specific symptoms and were then incidentally found to have mildly elevated troponin levels. Conclusions: Patients with ICI-M presented after more ICI cycles, had more severe myocarditis and worse overall survival as compared to ICI-M 2 and ICI-M 3 patients. Our findings suggest that patients who developed concurrent symptoms of myositis or myasthenia gravis, prompted earlier recognition of mild myocarditis, leading to earlier initiation of immunosuppressive treatment thereby improving clinical outcomes. ICI-M (n = 12) ICI-M 2 (n = 12) ICI-M 3 (n = 9) Total (n = 33) Median Age (yrs) 67 64 77 69 Sex (% male) 50 83 56 64 Cancer type (% melanoma) 42 75 44 55 Cancer stage (% stage IV) 67 92 78 82 ICI treatment (% dual ICI) 33 67 56 55 Avg. # of cycles before toxicity (range) 4.2 (1-13) 2.2 (1-4) 2.1 (1-3) 2.8 (1-13) Severity of myocarditis (% grade ≥ 3) 75 42 44 55 Immunosuppressant agents (% given 2 or more agents) 50 33 78 52 Overall survival (% alive) 33 67 78 58

Use of immune checkpoint inhibitors (ICI) is increasing in patients with oncologic disease. Three classes of checkpoint inhibitors exist: anti-PD1 (nivolumab, pembrolizumab), anti-CTLA4 (ipilimumab), and anti-PDL1 (atezolizumab, avelumab, durvalumab). ICI therapy has been used in multiple malignancies including renal cell cancer, non-small-cell lung cancer, and melanoma. These therapies have led to improved oncologic treatment and outcomes in patients but can lead to immune-related or inflammatory adverse effects. Neuromuscular system side effects, particularly at the neuromuscular junction, have been observed, including myasthenia gravis (MG). This narrative review serves to summarize key available information regarding myasthenia gravis in the setting of immune checkpoint inhibitor use including the molecular targets of checkpoint inhibitors, the clinical manifestations of MG in patients with checkpoint inhibitor therapy, and potential treatment options. Studies have shown that the use of checkpoint inhibitor therapy can trigger MG, and that patients with ICI-related MG can have more severe disease. Recognition and understanding of the range of neurologic complications, including neuromuscular disorders, which can be seen with ICI therapy is a critical step toward developing better treatment algorithms and improved clinical outcomes. Future investigations which include deep mechanistic studies to further our understanding of the immunopathologic triggers and predictive markers of ICI-related MG will be important to address the current knowledge gaps.

e14599 Background: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system to treat malignancy. As a consequence of this activation, ICIs may cause autoimmunity in healthy tissues, termed “immune-related Adverse Events” (irAEs). The literature reports a wide range in irAE incidence (10-80%), with a higher incidence in patients exposed to combination therapy. ICI treatment of patients with pre-existing autoimmune disease presents a dilemma for oncologists because of concern that immune activation will lead to more frequent or severe irAEs. As a result, these patients have been excluded from ICI clinical trials. Prior studies suggested that approximately 40% of patients with pre-existing autoimmune disease experience an autoimmune exacerbation during ICI treatment, but more data are needed on the incidence and severity of irAEs in other tissues. Methods: This retrospective case-control study included adult patients who received an FDA-approved ICI for treatment of a solid malignancy (excluding non-melanoma skin cancer) from 2015-2021 at an academic medical center. Cases were patients with pre-existing autoimmune disease. Controls without pre-existing autoimmunity were matched 2:1 based on age, sex, ICI class, and cancer type. Severe IrAEs were defined as grade three or higher by CTCAE definitions and occurring after ICI exposure. ICD-9 and 10 codes were used to identify patients with subsequent data extraction by manual chart review. Results: Of 3,130 adult cancer patients treated with ICIs, 28 cases were identified with pre-existing autoimmune disease: antiphospholipid syndrome (n=1), inflammatory polyarthritis (n=3), juvenile arthritis (n=1), multiple sclerosis (n=3), psoriatic arthritis (n=3), rheumatoid arthritis (n=14), and type I diabetes (n=3). Six out of 28 cases (21.4%) developed severe irAEs, including three (50%) who received anti-PD1/PDL1 monotherapy and three (50%) who received ICI combination therapy. One case experienced a grade five irAE (death) attributed to ICI-colitis; the remaining five patients (83.3%) successfully recovered with suspension of ICI therapy and treatment with immunosuppressive medications. By comparison, 9/56 (16.1%) controls developed severe irAEs. The odds of developing a severe irAE were not significantly different in patients with pre-existing autoimmunity compared to controls (OR 1.42, 95% CI 0.42-4.68, p=ns). Subgroup analysis of 23 cases and 46 controls treated with anti-PD1/PDL1 monotherapy also found no difference in the odds of severe irAE development (OR 0.84, 0.22-3.70, p=ns). Conclusions: Our data suggest that the majority of solid tumor patients with pre-existing autoimmune disease can safely receive ICI monotherapy and combination therapy. Severe (grade 3 or higher) irAEs were infrequent, often treatable, and did not occur more frequently than in patients without pre-existing autoimmunity.

IMMUNE CHECKPOINT INHIBITOR-INDUCED MYASTHENIA GRAVIS: A RARE NEUROLOGIC COMPLICATION OF IMMUNOTHERAPY FOR UROTHELIAL CELL CANCER

311 Retrospective Analysis of Patients Receiving Immune Checkpoint Inhibitors Presenting to the Emergency Department

Immune checkpoint inhibitors have greatly improved the survival of patients with advanced melanoma and are now becoming standard therapy for treating a wide range of different forms of cancer. Although...

S12-4. Myasthenia gravis induced by immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) have led to improved outcomes for many cancer types. However, their use can also precipitate immune-related adverse events (irAEs) that can affect any organ system. While irAEs are often mild, they rarely affect multiple organ systems concurrently and can be fatal. We report a fatal case of myasthenia gravis, myositis, and cardiotoxicity overlap syndrome precipitated by the ICI pembrolizumab along with a brief review of available literature. Early recognition of high grade irAEs and prompt intervention is essential. Despite the poor prognosis of these overlap syndromes, current recommendations offer little guidance for severe cases and warrant a call for increased awareness and expansion of available therapeutics.

Context: Severe neurological manifestations following use of immune checkpoint inhibitors (ICIs) occur in 0.93% of patients, and together with cardiac toxicity have the higher lethality. Myasthenia gravis (MG) and polymyositis (PM) are rare, and treatment includes discontinuation of the immunotherapy, corticosteroids, and intravenous immunoglobulin (IVIG), with occasional use of plasmapheresis (PLEX). Biomarkers are not consistently reported. We report the case of a patient with MG, PM and myocarditis after ICI, with positive anti-titin antibodies and response to plasmapheresis. Case report: 81-year-old male developed ascending, subacute, progressive tetraparesis, dysphagia, ophthalmoparesis, and respiratory failure 2 weeks after second cycle of nivolumab/ipilimumab for metastatic melanoma. Physical examination showed: globally reduced strength, hypoactive reflexes, bilateral sixth nerve palsy and bilateral semi-ptosis. Prostigmine test was positive and electroneuromyography was compatible with myopathy. Labs revealed CPK 4000 U/L, troponin 9000U/L, autoimmune myositis panel negative, anti-titin antibodies (described in paraneoplastic MG and associated with severity) positive and cardiac MRI without fibrosis. Clinical picture was compatible with MG and PM with cardiac involvement. He received methylprednisolone and six PLEX sessions, with complete recovery. Four months after treatment, he developed cognitive impairment and large B-cell lymphoma (ICI complication). Conclusions: PM and MG may occur after ICI, especially in the first cycles, and anti-titin may be a biomarker of severity in these patients. Although guidelines recommend adding IVIG or PLEX in refractory or severe cases, PLEX may be first choice, especially if multiple ICI are present.

The determinants of very severe immune-related adverse events associated with immune checkpoint inhibitors: A prospective study of the French REISAMIC registry

Patients with advanced malignancies treated with immune checkpoint inhibitors are at increased risk for developing immune-related neurological complications. It is a phenomenon of immunological twist when immunotherapy against co-stimulatory molecules activates previously normal T cells to kill tumor cells but, in so doing, the T cells become unrestrained, triggering other autoimmune diseases for which conventional immunotherapy is needed. The most common autoimmune neurological diseases, usually occurring within 2–12 weeks after immune checkpoint inhibitor initiation, include: inflammatory myopathies, myasthenia gravis, acute and chronic demyelinating polyradiculoneuropathies, vasculitic neuropathies, isolated cranial neuropathies, aseptic meningitis, autoimmune encephalitis, multiple sclerosis and hypophysitis. The neurological events can evolve rapidly, necessitating the need for vigilance at all stages of treatment, even after completion, because early immunotherapeutic interventions are effective. The review addresses these complications and the applied therapies, discusses immune pathomechanisms including triggering preexisting autoimmunity, highlights the distinction between paraneoplastic and autoimmune etiologies, and identifies uncertainties regarding risk factors, use of immune checkpoint inhibitors in patients with known immune diseases or restarting therapy after a neurological event. Although the autoimmune neurological complications are not very common, their incidence will likely increase as the use of immune checkpoint inhibitors in metastatic cancer is growing rapidly.

Introduction: Severe immune-related adverse events (irAEs) occur in up to 60% of melanoma patients treated with immune checkpoint inhibitors (ICIs), causing substantial treatment-related morbidity and in the most severe cases, death. There is no clinical assay to predict who will develop severe ICI-induced irAEs and who will not. Using single-cell profiling assays applied to a retrospective melanoma cohort treated with ICIs, we recently showed that higher baseline levels of circulating CD4 effector memory T (TEM) cells were associated with severe irAE development, independent of the affected organ system (Lozano et al. Nature Medicine, 2022). As part of a prospective validation study of 100 melanoma patients, here we report our initial findings on the first 24 patients accrued to date. Methods: We prospectively collected pre-ICI blood from 24 metastatic melanoma patients from two academic medical centers from February 2021 onward. Peripheral blood was collected pre-treatment on the day of immunotherapy (cycle 1 day 1). We then isolated peripheral blood mononuclear cells (PBMCs) and applied mass cytometry by time of flight (CyTOF) to profile 38 leukocyte markers including markers specific to CD4 TEM cells. Cellular subpopulations were quantified using Cytobank v9. Patients underwent routine medical oncology follow-up during and after ICI treatment including grading of irAEs using the Common Terminology Criteria for Adverse Events v5. Results: Median follow-up time after pre-ICI blood collection was 9.1 months (range 2.6-18.5). Fifteen (63%) patients received combination (anti-PD1/anti-CTLA4) ICIs while the remainder received anti-PD1 monotherapy. Eight patients developed severe (grade 3+) irAEs at a median of 8.5 weeks (range 4-21) after treatment initiation, including 4 who developed life-threatening (grade 4) irAEs. Severe and life-threatening irAE development spanned 9 separate organ systems, most commonly gastrointestinal, dermatological, and hepatic. Using CyTOF, we found that circulating CD4 TEM cells were more abundant in patients who developed severe irAEs compared to those who did not (P = 0.01; AUC = 0.81), irrespective of the involved organ systems. Moreover, median-splitting the patient cohort into two groups based on pretreatment CD4 TEM levels revealed that patients with low CD4 TEMs had significantly longer freedom from severe irAE than those with high CD4 TEMs (not reached vs. 4.6 months; P = 0.013; HR = 6.7). There was no significant difference in pretreatment CD4 TEM levels between patients with and without durable clinical benefit to ICIs (P = 0.75). Conclusion: Circulating CD4 TEM levels measured by CyTOF were associated with severe irAE development, independent of response status, in patients with advanced melanoma. These findings could form the basis for pretreatment ICI risk stratification in the future. Citation Format: Abul Usmani, Noah Earland, Wubing Zhang, Peter K. Harris, Antonietta Bacchiocchi, Aishwarya Nene, David Y. Chen, Mario Sznol, Ruth Halaban, Aaron M. Newman, Aadel A. Chaudhuri. Association between circulating CD4 memory T cell levels and severe immune-related adverse events in melanoma patients treated with immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6670.

PurposeNeuromuscular immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) have been increasingly recognized as a consequence of expanding use of ICIs in advanced cancers. We aimed to evaluate the frequency, phenotypes, rescue treatment, and clinical outcomes of severe neuromuscular irAEs of ICIs at National Cancer Center (NCC), Korea.Materials and methodsConsecutive patients with newly developed severe neuromuscular irAEs (common terminology criteria for adverse events grade 3 or greater) after ICI treatment at NCC in Korea between December 2018 and April 2022 were included by searching neuromuscular diagnostic codes in electronic medical records and/or reviewing neurological consultation documentations.ResultsOf the 1,503 ICI-treated patients, nine (0.6%) experienced severe neuromuscular irAEs; five with pembrolizumab and four with atezolizumab. The patients included five women and four men; their median age at onset was 59 years. The irAEs included Guillain–Barre syndrome (n = 5) and myasthenia gravis (MG) crisis with myositis (n = 4), and developed after a median of one (range 1–5) ICI cycle. The median modified Rankin score (mRS) was 4 (range 3–5) at the nadir. ICIs were discontinued in all patients, and rescue immunotherapy included corticosteroids (n = 9), intravenous immunoglobulin (n = 7), and plasmapheresis (n = 2). Eight patients showed improvements, with a median mRS of 3 (range 1–4); however, one patient (who had MG crisis with myocarditis) died.ConclusionsIn this real-world monocentric study, ICI-induced neuromuscular irAEs were rare but potentially devastating; thus, physicians should remain vigilant to enable prompt recognition and management of irAEs.

Meta-analysis of immune-related adverse events in phase 3 clinical trials assessing immune checkpoint inhibitors for lung cancer.

Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by fatigable muscle weakness. While commonly linked to acetylcholine receptor (AChR) antibodies, other reported antibodies include muscle-specific kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), agrin, striated muscle, myosin, ryanodine receptor, and titin. Notably, titin antibodies are being highlighted for their role in MG pathogenesis, as they have been associated with increased disease severity. Immune checkpoint inhibitors (ICIs), while highly effective for solid tumors, can rarely induce immune-related myasthenia gravis (irMG), a neurological adverse effect with higher mortality than classic MG. We present a case of MG with atypical serology, highlighting the challenges of classifying and treating classic MG, paraneoplastic syndromes, and irMG. A 68-year-old man with a history of stage IV left renal cell carcinoma (RCC) with lung metastases after undergoing left nephrectomy and right segmental lung lobectomy presented with one month of palpebral ptosis, shortness of breath, dysphagia, and generalized muscle weakness. He had recently received two doses of 200 mg pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor. Physical examination revealed bilateral palpebral ptosis, symmetric, primarily proximal weakness, including bulbar and facial muscles with fatigability, and normal reflexes. Serum studies were positive for anti-striated muscle (>1:2560) and anti-titin (>2.71) antibodies, suggesting irMG or a paraneoplastic syndrome, with negative anti-AChR and anti-MuSK antibodies. Computed tomography (CT) of the chestshowed no thymic disease. The patient improved with high-dose steroids followed by plasma exchange and intravenous immunoglobulin (IVIG). Repeated striated muscle antibodies were decreased, but anti-titin antibodies were persistently elevated. He is neurologically stable on pyridostigmine 60 mg, 3 liters of nasal cannula oxygen, and nighttime bilevel positive airway pressure (BiPAP) but experiences residual muscle weakness that requires wheelchair use. In summary, we present a case of MG with the presence of titin and striated muscle antibodies in a patient with metastatic RCC undergoing checkpoint immunomodulating therapy. Management remains challenging in patients with underlying malignancy treated with ICIs.