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Early Involvement Critical in Treating Immunotherapy-Induced Overlap Syndrome


A series of case studies reveals the importance of early diagnosis and involvement of special teams of clinicians when dealing with potential cases of overlap syndrome, which encompasses myocarditis, myasthenia gravis, and immune checkpoint inhibitor–related myositis.

Timely recognition and the early involvement of specialty clinicians to manage patients with immunotherapy-induced overlap syndrome is critical to reducing the significant morbidity and mortality associated with the condition, according to a case study of 4 patients with overlap syndrome published in Case Reports in Medicine.

Immune checkpoint inhibitors (ICIs) have become standard care in the treatment of multiple cancer types through a variety of methods, including as dual checkpoint inhibition and in combination with chemotherapy or targeted therapy.

Despite their positive effects on cancers, they can be associated with life-threatening inflammatory and autoimmune-related adverse events (irAEs) that can affect all organs in a patient, the investigators discussed. Such events include overlap syndrome, which is a triad of myocarditis, myasthenia gravis (MG) and ICI-related myositis.

The case series presents 4 patients with ICI-related overlap syndrome, including the first case, to the investigator’s knowledge, that resulted from treatment with avelumab. The investigators sought to provide a discussion on the current management guidelines for this rare condition.

Patient 1 was a 58-year-old man who was referred for oncological care with a new melanoma in his axilla. Following a first cycle of treatment, he was readmitted to the hospital with chest pain, diplopia, and palpitations, upon which he began a once-daily treatment of intravenous methylprednisolone for ICI-related overlap syndrome.

With immunosuppression, the patient’s myocarditis, myositis, and hepatitis improved. Following brief complications, his condition improved with plasmapheresis and rituximab, which resulted in a definitive improvement. The patient was discharged after 3 months in the hospital and 1 month in the Iintensive care unit (ICU).

Patient 2 was a 78-year-old man with grade 3 metastatic bladder cancer. He began chemotherapy with gemcitabine and carboplatin for 6 cycles; once CT scans showed favorable responses with no disease progression, he began maintenance immunotherapy with avelumab, the investigators wrote.

After 2 cycles of avelumab, he was admitted to the emergency department (ED) with extreme fatigue and diplopia. He was later deemed to have ICI-induced myositis, myocarditis, and MG. Upon being transferred to the ICU, he began intravenous immunoglobulin (IVIG), and commenced pyridostigmine after initially avoiding it due to the potential for AEs. He recovered and was discharged after 6 weeks.

Patient 3 was a 77-year-old man with renal cell carcinoma; treatment with an oral tyrosine kinase inhibitor (TKI) achieved a positive response, but a CT of the chest, abdomen, and pelvis 2 years later revealed new metastases. Due to this, the patient began treatment with nivolumab, but developed dysphagia, dysphonia, and ptosis.

Doctors discussing a case | Image Credit: StudioRomantic - stock.adobe.com

Overlap syndrome encompasses myocarditis, myasthenia gravis, and immune checkpoint inhibitor–related myositis | Image Credit: StudioRomantic - stock.adobe.com

His clinicians deemed him to have overlap syndrome after further analysis and the development of chest pain, and he began IVIG. During this time, the patient developed respiratory failure and appeared fatigued; 3 weeks after initially being admitted, he passed away.

Patient 4 was an 86-year-old man who was referred for radiotherapy after a medial maxillectomy with a detailed past medical history. He was deemed not to be a candidate for surgery or stereotactic ablative body radiotherapy and began first-line pembrolizumab.

Two weeks after his first cycle, he was admitted to the ED with tiredness, slurred speech, and diplopia, which was eventually deemed to be ICI-related MG, myocarditis, myositis, and hepatitis. He began methylprednisolone, although after further deterioration of his condition, he began IVIG and intramuscular neostigmine 3 times daily. The patient experienced continued deterioration of his health, and he passed away 2 days after being first admitted.

The investigators noted that the underlying mechanisms of overlap syndrome remains unclear, and that more research is required to establish these mechanisms. Overall, due to the significant mortality and morbidity associated with the condition, the investigators cautioned clinicians to suspect other irAEs when one of them is suspected.

“Further studies are needed to identify which patients might be more at risk, the pathophysiology, potential early biomarkers, and the optimal management approach,” the investigators concluded.


Aggarwal N, Bianchini D, Parkar R, Turner J. Immunotherapy-induced overlap syndrome: myositis, myasthenia gravis, and myocarditis – a case series. Case Reports. 2024;2024:5399073. doi:10.1155/2024/5399073

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