Pembrolizumab-Induced Overlap Syndrome: Case Report

A case study from Kaiser Permanente's Los Angeles Medical Center examines the potentially fatal complications associated with immune checkpoint inhibitors (ICI). The case, recently published in Cancer Reports, describes the death of an 87-year-old male patient from a rare overlap syndrome triggered by pembrolizumab, used to treat his advanced urothelial carcinoma.¹

An 87-year-old man experienced a rapid decline after receiving pembrolizumab and experiencing an immune-related adverse event manifesting as myasthenia gravis, myositis, and cardiomyopathy.

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"By bringing attention to his clinical course and medical decision-making, we hope to add to the continued discussion regarding effective management of this rare condition," the authors wrote.

The patient, an 87-year-old male with advanced urothelial carcinoma, experienced a rapid decline following the administration of pembrolizumab, an ICI targeting the PD-1 antigen. Despite responding well to the first cycle, the second cycle of pembrolizumab led to severe symptoms, including diffuse pain followed by bilateral ptosis and ophthalmoplegia on day 2.

After presenting with severe symptoms, the patient was hospitalized at Kaiser Permanente's Los Angeles Medical Center. Laboratory tests revealed significantly elevated creatine kinase of 6042 U/L and high sensitivity troponin (hsTrop) levels of 7549 pg/mL. An autoimmune panel was positive for striated muscle antibodies but negative for acetylcholine receptor antibodies. A transthoracic echocardiogram showed mild concentric hypertrophy and hyperdynamic systolic function with an ejection fraction of 70%.

His condition was diagnosed as an immune-related adverse event (irAE) secondary to pembrolizumab, manifesting as myasthenia gravis (MG), myositis, and cardiomyopathy. Therapeutic interventions included pulse-dose methylprednisolone (1 g/day) and pyridostigmine (60 mg, 3 times a day), which initially reduced muscle pain and creatine kinase levels. However, his ptosis and ophthalmoplegia worsened, leading to dysphagia by day 3. Further treatment with 4 days of intravenous immunoglobulin (IVIG) and rituximab also failed to improve his symptoms. He was then treated with a second course of pyridostigmine and later rituximab, which was continued for 4 additional days without any improvement. The patient expired on day 16, experiencing progressive hypotension and increased oxygen requirements.

"Despite recognition of this variant presentation, there are limited available therapeutics for these serious complications with current guideline recommendations for refractory cases beyond corticosteroids and pyridostigmine limited to rituximab and PLEX," the authors wrote.

Less than 1% of patients treated with ICIs experience high-grade neurologic adverse events, including ICI-related myasthenia gravis (ICI-MG), which has a mortality rate significantly higher than its idiopathic counterpart.² It is estimated that multiorgan manifestations, including myositis and cardiomyopathy, occur in 8% to 14% of reported ICI-MG cases and have poorer prognosis.³ Current management strategies for severe ICI-MG are limited, with corticosteroids and pyridostigmine being the first line of treatment. However, refractory cases often require more advanced therapies such as plasma exchange (PLEX), rituximab, and IVIG. In this case, the patient's refusal of PLEX due to personal treatment goals highlighted the challenges in managing severe irAEs with limited therapeutic options.

Although sparse, there are successful cases using abatacept (a checkpoint agonist) to overcome severely refractory cases.^4,5 Abatacept and other checkpoint agonists work in an opposing fashion to promote T cell energy through checkpoint activation, as opposed to inhibition, as in ICIs. "As current guidelines for refractory cases largely include nonspecific anti-inflammatories (high-dose steroids, IVIG) and antibody-reducing agents (PLEX, rituximab), reversal of the strong and highly targeted effects of ICIs with a counteractive checkpoint agonist is an attractive approach in theory," the authors note.

They add, "Taken together, we hope to bring attention and context to this rare and potentially fatal off-target triad of ICI-MG, myositis, and cardiotoxicity resulting from commonly used ICIs such as pembrolizumab, the incidence of which will likely increase in coming years in the setting of expanded approvals for similar agents."

References

1. Newman MT, Bikhchandani M. A fatal case of immune checkpoint inhibitor-mediated myasthenia gravis, myositis, and cardiomyopathy overlap syndrome in urothelial carcinoma. Cancer Rep. 2024;7(7):e2140. doi:10.1002/cnr2.2140
2. Rajendram P, Torbic H, Duggal A, et al. Critically ill patients with severe immune checkpoint inhibitor related neurotoxicity: A multi-center case series. J Crit Care. 2021;65:126-132. doi:10.1016/j.jcrc.2021.05.020
3. Safa H, Johnson DH, Trinh VA, et al. Immune checkpoint inhibitor related myasthenia gravis: single center experience and systematic review of the literature. J Immunother Cancer. 2019;7(1):319. Published November 21, 2019. doi:10.1186/s40425-019-0774-y
4. Salem JE, Allenbach Y, Vozy A, et al. Abatacept for severe immune checkpoint inhibitor-associated myocarditis. N Engl J Med. 2019;380(24):2377-2379.doi:10.1056/NEJMc1901677
5. Wakefield C, Shultz C, Patel B, Malla M. Life-threatening immune checkpoint inhibitor-induced myocarditis and myasthenia gravis overlap syndrome treated with abatacept: a case report. BMJ Case Rep. 2021;14(11):e244334. Published November 2, 2021. doi:10.1136/bcr-2021-244334