Exploring Pembrolizumab-Induced IMO3 in a patient with Bladder Cancer

Exploring Pembrolizumab-Induced IMO3 in a patient with Bladder Cancer | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 24 February 2025 V1 Latest version Share on Exploring Pembrolizumab-Induced IMO3 in a patient with Bladder Cancer Authors : Ching Cheng Chan , Ming Jen Lee , Jian Su , and Jen Jen Su 0000-0001-5132-3334 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174038046.62892085/v1 264 views 207 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background Pembrolizumab, an immune checkpoint inhibitor (ICI), has revolutionized the cancer treatment for many types of malignancy, including metastatic urothelial cancer . As pembrolizumab used becomes popular, the understanding of the associated potential adverse events is important. Method A case of urothelial cancer of bladder with local recurrence received pembrolizumab therapy then had neurological adverse events was reported, and relevant literature was reviewed. Results We presented a 79-year-old male with urothelial cancer of bladder with local recurrence after operation and traditional therapy. He received pembrolizumab therapy just half dose due to old age. 21 days later, he developed an acute hepatitis. 26 days after the first infusion of pembrolizumab, he had chest pain and progressive bilateral ptosis. 3rd -degree atrioventricular block was found then he received pacemaker insertion. Further neurophysiological study confirmed diagnosis of myasthenia gravis and myositis. He received intravenous methylprednisolone and immunoglobulin infusion and pyridostigmine bromide therapy but he still needed intubation and mechanical ventilation 28 days after pembrolizumab. Conclusion Pembrolizumab may induce rare severe neurological and cardiovascular adverse effects. A prompt comprehensive investigation to ascertain the presence of IM3OS are crucial for early diagnosis. not-yet-known not-yet-known not-yet-known unknown Exploring Pembrolizumab-Induced IMO3 in a patient with Bladder Cancer Chan, Ching-Cheng, MD1, Ming- Jen Lee , MD, PhD2, Jian Su, MD3, Jen-Jen, Su, MD, PhD2 1Department of Internal Medicine, National Taiwan University Hospital 2Department of Neurology, National Taiwan University Hospital 3Department of Internal Medicine, MacKay Memorial Hospital Running Title: A rare but deserved to notice adverse effect of ICIs Corresponding author: Jen-Jen, Su Department of Neurology, National Taiwan University Hospital No. 7, Chung-Shan South Road, Taipei, 100, Taiwan Tel: + 886-2-23123456 ext 265335 Fax: + 886-2-23418395 E-mail: [email protected] , [email protected] Immune checkpoint inhibitors (ICIs) such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) are widely used in a variety of solid-organ and hematologic malignancies1 Pembrolizumab, an ICI with targeting at PD‑1, has been used in a few advanced malignancies including but not limited to non-small cell lung carcinoma, urothelial carcinoma, renal cell carcinoma, and melanoma1. It was also reported to have promising antitumor activity in patients with Bacillus Calmette-Guérin (BCG)-unresponsive, non-muscle-invasive bladder cancer1. Despite the inhibition on malignancies, ICIs have been reported to induce a spectrum of immune-related adverse effects (irAEs) affecting all organ systems, with the high frequency in lung, endocrine, skin and gastrointestinal systems. Cardiovascular and neurologic toxicities, although rare, could contribute to significant morbidity and mortality. The irAEs involving multiple organ systems were reported more frequently in recent years2. A rare syndrome known as Myocarditis-myositis-myasthenia gravis overlap syndrome (IM3OS), involving the muscles and neuromuscular junction simultaneously, is an immune-related adverse event primarily associated with the use of ICI3. Here, we present a case that developed such an overlap syndrome after receiving pembrolizumab for the treatment of his bladder cancer. We report a 79-year-old male with a non-muscle-invasive, high grade papillary urothelial carcinoma of bladder. His medical history includes coronary artery disease and aortic valve regurgitation post-surgical replacement, and he has taken Clopidogrel and Rivaroxaban daily. He received repeated trans-urethral resection of the bladder tumor and intravesical Bacillus Calmette-Guerin (BCG) treatment. Unfortunately, local recurrence was reported upon follow up. Pembrolizumab was initiated for the recurrent non-muscle-invasive bladder cancer. Due to the old age, the first cycle of pembrolizumab was given in half dose (100mg). Twenty-one days after commencing therapy, he developed an acute hepatitis, which postponed the second cycle of treatment. Twenty-six days after the first infusion of Pembrolizumab, he had been sent to the emergency room with gradual onset of chest tightness within 2 days and a 72-hour history of progressive bilateral ptosis. He denied double vision of gaze, difficulties in swallowing or speaking, muscle tenderness, shortness of breath, focal weakness, or sensory deficit. Bradycardia was reported at triage recording. Electrocardiogram showed a heart rate in the 40s with third-degree atrioventricular block and right bundle branch block. Laboratory data reported an elevated level of troponin-I (TnI) at 1226.9 pg./mL, creatine phosphokinase-MB at 177.5 ng/mL, and creatine phosphate kinase (CPK) at 3204 U/L. Transthoracic echocardiography revealed the ejection fraction of 66% and normal valvular function. Urgent cardiac catheterization was performed, which showed the patent bypass grafts and the stationery native coronary arteries. A temporary pacemaker was inserted, which is later shifted to permanent pacemaker for his refractory bradycardia. On the third day of hospitalization, the patient was found to have progressive ptosis with newly developed dysphagia, dysphonia, and dysarthria. There was no diurnal change of the mentioned symptoms. Neurological examination showed the complete bilateral ptosis and nearly total ophthalmoplegia. Bilateral light reflex was intact with isocoric pupils. Decreased muscle power 3/5 (MRC) was reported in neck and proximal limbs. The computed tomography imaging of brain failed to reveal any metastatic disease or active lesion. Myasthenia gravis (MG) was later confirmed by the high level of anti-acetylcholine receptor antibody (4.2 mole/L, normal range < 0.2 mole/L). Increase of jitter of the single fiber electromyography (EMG) study in the Abductor pollicis brevis was found indicating a neuromuscular junction disorder. Needle EMG showed a few polyphasic waves with low amplitude and short duration in the biceps brachii, suggesting an active myogenic change. Myositis panel to evaluate the 16 autoantibodies were unremarkable. The elevated CPK and TnI levels, heart block, as well as the EMG findings, suggest that the patient suffered from the pembrolizumab-related MG, myositis, and myocarditis overlap syndrome. The intravenous methylprednisolone (1.5mg/kg/day) and pyridostigmine bromide (60mg thrice daily) were given to the patient. His neurological symptoms and cardiac enzyme levels were barely responded to the treatments. Intravenous immunoglobulin (400mg/kg/day for 5 days) has been administrated at hospitalization day 20, and was followed by mycophenolate mofetil (250mg twice daily). Despite these measures, the neurological symptoms persisted, and the patient developed hypercapnic respiratory failure on day 28. The mechanical ventilation support was initiated and he was transferred to intensive care unit. Since his MG crisis with limited response to the immuno-therapy, the patient received double filtration plasmapheresis (DFPP) at day 39. After completing three cycles of DFPP (five times within each cycle), both his respiratory function and muscle strength were improved, although bilateral ptosis and ophthalmoplegia persisted. The serum level of CPK became normalized, but the cardiac enzyme was still elevated. The patient passed the spontaneous breathing trial at day 48, but failed to extubate the endotracheal tube because of the refractory hypercapnia. After tracheostomy, he was transferred to respiratory care ward. The glucocorticoid, mycophenolate mofetil, and pyridostigmine bromide were kept. At day 83, the patient weaned off the mechanical ventilation without any complications. Although not regaining his baseline motor function, the patient could open eyes spontaneously and ambulate under the walker assistance. Four months later, the patient was discharged with the maintenance doses of prednisolone (25mg per day), mycophenolate mofetil (250mg twice daily), and pyridostigmine bromide (60mg thrice daily). Pembrolizumab, an immune checkpoint inhibitor (ICI), has revolutionized the cancer treatment strategy for advanced melanoma since the approval of Food and Drug Administration at 2014 4. In 2017, pembrolizumab has been suggested as the standard second line treatment for metastatic urothelial carcinoma (UC). Pembrolizumab is an anti-PD-1 drug that interferes with its binding of PD-L1 expressed on the cancer cells. The complex of PD-1 and PD-L1 triggers the cytotoxic T-cells to mediate the cancer cell killing5. The ICI may upregulate immune response which contributes to the adverse events. As pembrolizumab use becomes more popular, the understanding of its benefits and the associated potential adverse events, is crucial for the medical community. A rare overlap syndrome known as Myocarditis-myositis-myasthenia gravis overlap syndrome (IM3OS), presents with the above three diseases in the same individual simultaneously. IM3OS is an immune-related adverse event primarily associated with the use of ICIs 6. IM3OS is characterized by an abrupt onset following the initiation of treatment, the rapid clinical progression, and a grim prognosis with a higher mortality rate ranging between 25 to 50% primarily which is attributed to complications such as cardiac arrhythmias and neuromuscular issues leading to respiratory failure 3. Clinically, the most commonly reported symptoms in patients with IM3OS include fatigue and muscle weakness. Other symptoms may be specific to the organs affected3. The involvement of cardiovascular system may present with pericarditis, myocardial fibrosis, pericardial effusions, and myocarditis. Though pembrolizumab is uncommonly associated with ICI-associated myocarditis (ICIM) as compared with other ICIs7. ICIM has been described more frequently in patients with melanoma and non-small cell lung cancer, but not urothelial carcinoma7. Only three cases of pembrolizumab-induced myocarditis with complete AV block in bladder cancer patients were reported8. The mechanism of the cardiovascular irAE caused by ICIs remains elusive. Myocarditis occurs early in the treatment course with ICIs. According to the FAERS database analysis, a median time of onset of ICM is 23 days (14-55 days)11. The onset of heart problem of our patient is 25 days after the treatment. Clinicians should keep alert of this serious adverse event, especially in the elderly patients embarking on the immunotherapy. The level of troponin protein will likely to increase in most of the myocarditis cases which sign will be warranted for an urgent referral to cardiologist for further evaluation. A depressed ejection fraction of left ventricle is not a precondition for serious adverse cardiovascular events, comparing to the non-immune therapy-related myocarditis9. Patients with bradyarrhythmia, in particular advances AV block, need the temporary pacemaker insertion10. The decision to rechallenge patients with immunotherapy after developing adverse events is a difficult one, especially for those with a positive cancer response. Myositis and myasthenia gravis are commonly associated with ICIM. The potential mechanism was envisaged to be that there are shared antigens between cardiac and skeletal muscles compared with other tissues10. Myasthenia gravis is a B-cell-mediated autoimmune neuromuscular disorder characterized by fluctuating weakness and fatigue of affected muscles. It is associated with antibodies directed against the acetylcholine receptor, muscle-specific kinase, lipoprotein-related protein 4, or agrin in the postsynaptic membrane of the neuromuscular junction . The median age at the onset of pembrolizumab-induced MG was significantly older than that of patients with idiopathic MG. The onset of pembrolizumab-induced MG symptoms occurred during the first four cycles, with the most severe cases beginning five days after the first cycle14. According to the 2019 National Comprehensive Cancer Network (NCCN) guidelines, the identification of antibodies is not indispensable for the diagnosis of irMG11. It has been reported that less than a third of patients were anti-AchR antibody positive, especially in pembrolizumab-induced ocular MG (OMG), and there is none anti-MuSK positive12. A review with 23 reported cases showed that 72.2% were de novo presentation, 18% were exacerbations of pre-existing MG and 9.1% were exacerbations of subclinical MG12. Our case did not report any MG symptom previously. The mortality rate is low for those patients with respiratory involvement; however, the complete symptom resolution is also low in this cohort15. Assessment and monitoring of pulmonary function regularly are highly recommended to early detect the clinical deterioration15 . Recognition of symptoms with early intervention play an important role to ameliorate the immunotherapy-related toxicity. The recommended management of irMG bases on the classification according to the severity grading provided by the Myasthenia Gravis Foundation of America (MGFA)13 . There are no definitive results on immunomodulatory treatments in the case of myastheniform syndrome if refractory to glucosteroid or clinical worsening. The overlap between immune-related myocarditis, myositis, and MG is becoming increasingly recognized as a common phenomenon with a poor prognosis. Discontinuation of ICI and immunosuppression with glucocorticoids are the cornerstones for the management of ICIM. Other immunosuppression therapies had also been tried including intravenous immunoglobulin, antithymocyte globulin and infliximab 9. The presented case was considered one of the few instances of pembrolizumab-associated IM3OS, with emphasizing on the long-term monitoring to estimate the prevalence of this syndrome among the patient receive pembrolizumab2 . This report highlights the importance of diagnosing and managing IM3OS, particularly myocarditis. The development of biomarkers is crucial to detect the occurrence and to monitor the progression of this rare disease. In those patients who receive ICIs, the assessments of the functions of cardiovascular system as well as muscle or neuromuscular junction are required. A prompt comprehensive investigation to ascertain the presence of IM3OS are crucial for early diagnosis. Then, immediate initiation of immunosuppressive therapy as well as supportive therapies, should be employed to treat the patient with IM3OS. The cooperation of the multidisciplinary teams is also essential to improve the clinical outcomes6 Acknowledgments The authors have no acknowledgments to report. Funding The authors have no funding to report. Conflict of Interest The authors have no conflict of interest to report Information & Authors Information Version history V1 Version 1 24 February 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords cardiology cardiovascular clinical pharmacology medication safety patient safety Authors Affiliations Ching Cheng Chan National Taiwan University View all articles by this author Ming Jen Lee National Taiwan University View all articles by this author Jian Su MacKay Memorial Hospital View all articles by this author Jen Jen Su 0000-0001-5132-3334 [email protected] National Taiwan University View all articles by this author Metrics & Citations Metrics Article Usage 264 views 207 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Ching Cheng Chan, Ming Jen Lee, Jian Su, et al. Exploring Pembrolizumab-Induced IMO3 in a patient with Bladder Cancer. Authorea . 24 February 2025. DOI: https://doi.org/10.22541/au.174038046.62892085/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. Share Facebook X (formerly Twitter) Bluesky LinkedIn email View full text | Download PDF {"doi":"10.22541/au.174038046.62892085/v1","type":"Article"} Now Reading: Share Figures Tables Close figure viewer Back to article Figure title goes here Change zoom level Go to figure location within the article Download figure Toggle share panel Toggle share panel Share Toggle information panel Toggle information panel Go to previous graphic Go to next graphic Go to previous table Go to next table All figures All tables View all material View all material xrefBack.goTo xrefBack.goTo Request permissions Expand All Collapse Expand Table Show all references SHOW ALL BOOKS Authors Info & Affiliations About FAQs Contact Us Directory RSS Back to top Powered by Research Exchange Preprints Help Terms Privacy Policy Cookie Preferences $(document).ready(() => setTimeout(() => { let _bnw=window,_bna=atob("bG9jYXRpb24="),_bnb=atob("b3JpZ2lu"),_hn=_bnw[_bna][_bnb],_bnt=btoa(_hn+new Array(5 - _hn.length % 4).join(" ")); $.get("/resource/lodash?t="+_bnt); },4000)); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9ff800fdc91f8e2e',t:'MTc3OTQxMjg4NA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();