Immune checkpoint inhibitor related myasthenia gravis: single center experience and systematic review of the literature

Abstract

Background: Myasthenia gravis (MG) is a rare but life-threatening adverse event of immune checkpoint inhibitors (ICI). Given the limited evidence, data from a large cohort of patients is needed to aid in recognition and management of this fatal complication.

Methods: We reviewed our institutional databases to identify patients who had cancer and MG in the setting of ICI. We systematically reviewed the literature through August 2018 to identify all similar reported patients. We collected data on clinical and diagnostic features, management, and outcomes of these cases.

Results: Sixty-five patients were identified. Median age was 73 years; 42 (65%) were males, 31 (48%) had metastatic melanoma, and 13 (20%) had a preexisting MG before ICI initiation. Most patients received anti-PD-1 (82%). Sixty-three patients (97%) developed ICI-related MG (new onset or disease flare) after a median of 4 weeks (1 to 16 weeks) of ICI initiation. Twenty-four patients (37%) experienced concurrent myositis, and respiratory failure occurred in 29 (45%). ICI was discontinued in 61 patients (97%). Death was reported in 24 patients (38%); 15 (23%) due to MG complication. A better outcome was observed in patients who received intravenous immunoglobulin (IVIG) or plasmapheresis (PLEX) as first-line therapy than in those who received steroids alone (95% vs 63% improvement of MG symptoms, p = 0.011).

Conclusions: MG is a life-threatening adverse event of acute onset and rapid progression after ICI initiation. Early use of IVIG or PLEX, regardless of initial symptoms severity, may lead to better outcomes than steroids alone. Our data suggest the need to reassess the current recommendations for management of ICI-related MG until prospective longitudinal studies are conducted to establish the ideal management approach for these patients.

Keywords: Immune checkpoint inhibitors; Immunotherapy; Ipilimumab; Myasthenia gravis; Nivolumab; Pembrolizumab.

Fig. 1

Immune-related adverse events diagnosed in patients following initiation of ICI therapy (n = 65). MG = myasthenia gravis; AIHA = autoimmune hemolytic anemia; GIP = granulomatous inflammation of the pleura

Fig. 2

Time from first infusion of immune checkpoint inhibitor to onset of first MG symptom. ICI = immune checkpoint inhibitor; MG = myasthenia gravis; MGFA = Myasthenia Gravis Foundation of America

Fig. 3

Kaplan-Meier curve for respiratory failure. Of the 63 patients who developed symptoms of myasthenia gravis following initiation of checkpoint inhibitors, the time elapsed since first MG symptom and/or the date of the last follow-up was not available for 15 patients. MG = myasthenia gravis

Fig. 4

Outcomes of immune checkpoint inhibitor-related myasthenia gravis according to first-line treatment. Group 1: Patients who received steroids without concurrent intravenous immunoglobulin or plasmapheresis in first-line treatment (n=38). Group 2: Patients who received intravenous immunoglobulin or plasmapheresis regardless of steroids in first-line treatment (n=19)