Background/Purpose: Immune checkpoint inhibitors (ICIs) enhance the immune response against tumors but may also trigger immune-related adverse events (IRAEs). Myositis following receipt of ICIs is a rare IRAE. In prior studies, creatine kinase (CK) elevations occurred in just 0.2% of patients treated with avelumab, an anti-programmed death-ligand 1 antibody that has been effective against several solid tumor types. Since effective therapies for thymic epithelial tumors are lacking, we included patients with thymic malignancies in a phase I trial of avelumab administered at 10 or 20 mg/kg (NCT01772004).

Methods: Serum and peripheral blood mononuclear cells (PBMCs) were collected before and after avelumab therapy. Serum creatine kinase (CK) levels were monitored during the trial. Laboratory investigations included the assessment of thymoma- and myositis-associated autoantibodies as well as immunophenotyping of PBMCs by flow cytometry.

Results: Seven recurrent thymoma and 1 thymic carcinoma patients were enrolled. No patient had a history of autoimmunity or weakness and each had normal baseline CK levels. Four thymoma patients developed CK elevations (range 762 to 16,037 IU/L) and proximal weakness 7 to 35 days after avelumab administration consistent with ICI-associated myositis. CK levels normalized in all patients within weeks of starting immunosuppressive therapy. One patient with myositis also had myocarditis and a fifth patient without myositis developed enteritis.

Four patients had preexisting muscle acetylcholine receptor (mAChR) autoantibodies and each developed CK elevations and weakness. No patient without mAChR autoantibodies developed myositis (100% vs. 0%; p=0.029). Electrophysiological studies revealed evidence of myasthenia gravis in just one patient. No patient sera were reactive for any of the 16 myositis autoantigens on EUROLINE Autoimmune Inflammatory Myopathies line blots (EUROIMMUN).

Immunophenotyping of PBMCs collected prior to avelumab therapy showed that patients who developed either myositis or enteritis had lower B cell frequencies (0.19%, 0.12-0.73%; median, interquartile range) than those who did not (12.37%, 5.14-16.5%). The median B cell frequencies of 30 patients with non-thymic malignancies and 15 healthy controls were 8.3% (interquartile range 2.4-11.7%) and 16.3% (interquartile range 11.9-17.65%), respectively.

Conclusion: Myositis is a common IRAE in thymoma patients treated with avelumab. Preexisting mAChR autoantibodies may identify thymoma patients most at risk for developing this complication. Since mAChR autoantibodies are known to cause myasthenia but are not associated with myositis, we conclude that they are a marker of preexisting autoimmunity rather than the direct cause of muscle damage. B cell lymphopenia also appeared to be associated with myositis and enteritis in those treated with avelumab. Additional studies are needed to confirm these findings and to determine whether preexisting autoantibodies or immune cell subset dysregulation predicts which non-thymic tumor patients are at increased risk for IRAEs following treatment with avelumab or other immune checkpoint inhibitors.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/preexisting-anti-acetylcholine-receptor-autoantibodies-and-b-cell-lymphopenia-are-associated-with-the-development-of-myositis-in-thymoma-patients-treated-with-avelumab-an-immune-checkpoint-inhibitor/