FUJIMOTO Wataru

TANAKA Ryo

砂田 芳秀

TANAKA, Ryo

SUNADA, Yoshihide

FUJIMOTO, Wataru

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Successful reinstitution of nivolumab in combination with corticosteroids for metastatic malignant melanoma with myasthenia gravis as an immune-related adverse event

Kawasaki Medical School Institutional Repository / 川崎医科大学学術機関リポジトリ

59Kawasaki Medical Journal 43(2)：59－61，2017　doi：10.11482/KMJ-E43(2)59Successful reinstitution of nivolumab in combination  with corticosteroids for metastatic malignant melanoma  with myasthenia gravis as an immune-related adverse eventRyo TANAKA１）,  Yoshihide SUNADA２）,  Wataru FUJIMOTO１）1) Department of Dermatology, Kawasaki Medical School2) Department of Neurology, Kawasaki Medical School doi：10.11482/KMJ-E43(2)59　(Accepted on April 20, 2017)Key words： Melanoma,  Nivolumab,  irAE,  Myasthenia gravis,  PD-1Corresponding authorRyo TanakaDepartment of Dermatology, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192, JapanPhone : 81 86 462 1111Fax : 81 86 462 1199E-mail: ryot@med.kawasaki-m.ac.jp〈Letter to the Editor〉   Nivolumab is an immune checkpoint inhibitor directly targeting a negative immunoregulatory molecule of T cells, programmed cell death protein 1 (PD-1), with anti-tumor immune activity.The clinical benefits from anti-PD-1 antibodies against melanoma is quite remarkable. However, various immune-related adverse events (irAEs), such as interstitial pneumonia, have been reported１）. Grade3-4 irAEs were observed in 11.7%１）, and 9.9%２） of nivolumab-treated melanoma patients１）. Myasthenia gravis (MG) is an autoimmune disease mediated by B-cells, which affects neuromuscular junctions. Anti-acetylcholine receptor antibodies (AChR-Ab) are highly specific for diagnosis３）. Several cases of the onset of MG by anti PD-1 antibody have been reported４－８）. Here, we report a case that a patient with melanoma developed MG after the second administration of nivolumab. The metastatic melanoma was successfully controlled by reinstituting nivolumab in combination with a low dose of corticosteroids.   A woman in her 70s presented with malignant melanoma in the middle of the lumbar region. Primary resection and sentinel lymph node (SLN) biopsy were performed. Pathologically, right inguinal SLN metastasis was positive. Then, right inguinal lymph node dissection (LND) was performed. Postoperatively, interferon beta treatment was initiated as an adjuvant therapy. Approximately 5 months after surgery, several subcutaneous, in-transit and lymph node metastasis were observed. After possible resection of these metastatic lesions, nivolumab therapy was started with a dose of 2 mg/kg every 3 weeks. Focal adjustment disorder appeared around 10 days after the second administration, then ptosis (Fig. 1) and muscle weakness were observed. AChR-Ab was elevated to 4.0 nmol/L (normal range ≤0.2 nmol/L). In addition, single fiber electromyography study was positive because of increased jitter in the frontalis muscle. MG was diagnosed. Nivolumab administration was discontinued and daily oral administration of 10 mg of prednisolone (PSL) and anticholinesterase drug was started, followed by 60 Kawasaki Medical Journalimprovement of the symptoms. Because lymph node metastasis gradually worsened, administration of 2 mg/kg of nivolumab every 3 weeks was reinstituted on the 158th day from the second administration in combination with PSL 10 mg daily. Since recurrence of MG was not observed, PSL was reduced to 5mg after the second restart. Due to that the patient complained discomfort of the eyelids after several weeks, the dose of PSL was increased again to 10 mg. After that, nivolumab treatment was able to be continued every 3 weeks. Lymph node enlargement was controlled, and the patient had a stable disease state for about 18 months. Fig. 2 summarizes the clinical course.    In this case, AChR-Ab was slightly elevated to 1.6 nmol/L using her serum before nivolumab administration in the retrospective examination. Similar cases of MG with AChR-Ab subclinically before nivolumab therapy had been reported７，８）. Sakthivel P et al. showed that an expression of PD-1 on T cells and its ligand PD-L1 on monocytes was elevated in MG patients and suggested that PD-1 and PD-L1 might have a regulatory role behind autoimmune human MG９）. By disrupting interaction between PD-1 and its ligands, it is assumed that nivolumab induced T-cell activation, resulting in elevation of AChR-Ab and consequently induced MG. There is no specific and general method to solve a dilemma related to reinstitution of nivolumab in serious irAE cases. The method Figure１Fig. 1 Bilateral ptosis 24 days after the second treatment of nivolumabFig. 2 The summary of the clinical course61Tanaka R, et al. : nivolumab and myasthenia gravisemployed should be determined according to severity of MG in each case, because different clinically severe, prolonged, and even fatal case has been reported７）. We demonstrated a method which was able to resume nivolumab without regression of MG in combination with PSL 10 mg daily. Although attenuation of the effect of nivolumab by corticosteroids is possible, the development of tumor was suppressed and the effect of nivolumab has been preserved in this case. Even if nivolumab therapy is forced to be discontinued in irAE cases, it is worth considering reinstitution of it with prednisolone in combination.CONFLICT OF INTEREST   NoneREFERENCES１）Robert C, Long GV, Brady B, et al.: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372: 320-330, 2015２）Weber JS, Hodi FS, Wolchok JD, et al.: Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. J Clin Oncol 35: 785-792, 2017３）Gilhus NE: Myasthenia Gravis. N Engl J Med 375: 2570-2581, 2016４）Alnahhas I, Wong J. A Case of new-onset antibody-positive myasthenia gravis in a patient treated with pembrolizumab for melanoma. Muscle Nerve (Epub: 2016.12.9)  doi:10.1002/mus.25496. (Epub ahead of print)５）Lau KH, Kumar A, Yang IH, Nowak RJ: Exacerbation of myasthenia gravis in a patient with melanoma treated with pembrolizumab. Muscle Nerve 54: 157-161, 2016６）Maeda O, Yokota K, Atsuta N, Katsuno M, Akiyama M, Ando Y: Nivolumab for the treatment of malignant melanoma in a patient with pre-existing myasthenia gravis. Nagoya J Med Sci. 78: 119-122, 2016７） Shirai T, Sano T, Kamijo F, Saito N, Miyake T, Kodaira M, Katoh N, Nishie K, Okuyama R, Uhara H: Acetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma. Jpn J Clin Oncol 46: 86-88, 2016８）Kimura T, Fukushima S, Miyashita A, et al.: Myasthenic crisis and polymyositis induced by one dose of nivolumab. Cancer Sci 107: 1055-1058, 2016９）Sakthivel P, Ramanujam R, Wang XB, Pirskanen R, Lefvert AK: Programmed Death-1: from gene to protein in autoimmune human myasthenia gravis. J Neuroimmunol 193: 149-155, 2008

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Successful reinstitution of nivolumab in combination with corticosteroids for metastatic malignant melanoma with myasthenia gravis as an immune-related adverse event

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