Atezolizumab-induced myasthenia gravis in a patient with metastatic urothelial carcinoma

Tocco B, Hijab A, Huddart R, Hafeez S
1 The Royal Marsden NHS Foundation Trust, London, UK 
2 The Institute of Cancer Research, London, UK

Acknowledgements
We acknowledge support from National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Competing interest 
BT and AH have no conflicts to disclose.  RH reports non-financial support from Janssen, grants and personal fees from MSD, personal fees from Bristol Myers Squibb, grants from Cancer Research UK, other from Nektar Therapeutics, personal fees and non-financial support from Roche  outside the submitted work; SH reports non-financial support from Elekta (Elekta AB, Stockholm, Sweden), non-financial support from Merck Sharp & Dohme (MSD), personal fees and non-financial support from Roche outside the submitted work. 

Author for correspondence 
Dr B Tocco
The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT. UK
Boris.Tocco@rmh.nhs.uk 
 
Abstract
Introduction
The increasing use of immune checkpoint blockade in metastatic cancer has resulted in greater prevalence of immune-related adverse events (irAEs). The anti-CTLA-4 and anti-PD-1 action resulting in T-cell mobilisation causes a surge in tumoural immune response but is also well documented to result in autoimmune toxicities [1]. 

The use of atezolizumab in cisplatin-ineligible metastatic bladder cancer was approved in the UK based on the IMvigor trial [2]. The toxicities arising from its use more commonly affect bowel, liver, lung and endocrine tissue[1]. The development of immunotherapy-induced myasthenia gravis has been reported with other checkpoint inhibitors [3] but rarely related to atezolizumab – this report describes a case of atezolizumab-induced myasthenia gravis in the context of metastatic bladder cancer.


Clinical history
A 77 year old gentleman, with a history of hypercholesterolemia, underwent a primary radical cystectomy and bilateral pelvic lymph node dissection for pT3bN2 transitional cell carcinoma of the bladder. He was ineligible for neoadjuvant cisplatin-based chemotherapy due to hearing loss and declined adjuvant treatment. Immunohistochemistry of operative tissue sample revealed a PD-L1 expression of 5-10%. He suffered a nodal relapse 4 months post-operatively.

He was surveyed with interval CT scans which found slowly-progressive disease and, 8 months later, started palliative systemic therapy with 3-weekly intravenous atezolizumab at 1200mg.

After his 2nd cycle of treatment, he presented with double vision and head drop. On examination, he was diplopic throughout all ocular movements with MRC grade 4/5 power of neck extension and proximal muscles groups. Neck flexion and distal muscle group power was preserved. Reflexes were normal and there was no fatigability.

Imaging with MRI head with contrast did not find any abnormality. Blood tests for pituitary, thyroid, and adrenal function were normal. Creatine kinase was elevated at 337 U/L (normal range 55-175 U/L). 

He was started on dexamethasone 4mg once daily for presumed immunotherapy-induced myopathy and reviewed by the local Neurology team who requested an electromyograph which demonstrated myopathic potentials in proximal muscles with sparing of distal muscles suggestive of proximal myopathy or myasthenia gravis.

Serology test was positive for anti-acetylcholine receptor antibodies confirming a diagnosis of immunotherapy-induced myasthenia gravis. Anti-muscle specific tyrosine kinase (MuSK) antibodies were negative.

Commencement of pyridostigmine 60mg three times daily and substitution of dexamethasone with prednisolone 30mg once daily resulted in a complete remission of  symptoms. 

Complete radiological response was maintained on subsequent imaging until the patient died due to a bronchopneumonia 9 months after atezolizumab cessation. He had continued long-term steroids until the time of his death.


Conclusion
Atezolizumab-induced myasthenia gravis has been documented to have poor outcomes whether as an exacerbation of pre-existing disease [4] or de novo presentation [5]. Our case illustrates the need for high suspicion of non-specific neurological symptoms to enable early cessation of checkpoint inhibitors, initiation of immunosuppression and referral to Neurology services.


References:
1.	Baxi S, Yang A, Gennarelli RL, et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ. 2018;360:k793. Published 2018 Mar 14. doi:10.1136/bmj.k793
2.	Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial [published correction appears in Lancet. 2017 Aug 26;390(10097):848]. Lancet. 2017;389(10064):67-76. doi:10.1016/S0140-6736(16)32455-2
3.	Sutaria R, Patel P, Danve A. Autoimmune myositis and myasthenia gravis resulting from a combination therapy with nivolumab and ipilimumab for metastatic melanoma. Eur J Rheumatol. 2019;6(3):153-154. Published 2019 Apr 9. doi:10.5152/eurjrheum.2019.18159
4.	Chae, June; Peikert, Tobias 589: MYASTHENIA GRAVIS CRISIS COMPLICATING ANTI-PD-L1 CANCER IMMUNOTHERAPY, Critical Care Medicine: January 2018 - Volume 46 - Issue 1 - p 280 doi: 10.1097/01.ccm.0000528605.84679.eb 
5.	Thakolwiboon S, Karukote A, Wilms H. De Novo Myasthenia Gravis Induced by Atezolizumab in a Patient with Urothelial Carcinoma. Cureus. 2019;11(6):e5002. Published 2019 Jun 25. doi:10.7759/cureus.5002