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Rituximab for nivolumab plus ipilimumab-induced encephalitis in a small-cell lung cancer patient

2017; Elsevier BV; Volume: 28; Issue: 9 Linguagem: Inglês

10.1093/annonc/mdx252

1569-8041

Masaaki Ito, Satoru Fujiwara, Daichi Fujimoto, Ryohei Mori, Hajime Yoshimura, Akito Hata, Nobuo Kohara, Keisuke Tomii,

CAR-T cell therapy research

Immune checkpoint inhibitors (ICIs) have shown antitumor activity against several malignancies. Nivolumab plus ipilimumab has shown promising efficacy in patients with melanoma and small-cell lung cancer (SCLC) [1.Wolchok J.D. Kluger H. Callahan M.K. et al.Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med. 2013; 369: 122-133Crossref PubMed Scopus (3271) Google Scholar, 2.Postow M.A. Chesney J. Pavlick A.C. et al.Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.N Engl J Med. 2015; 372: 2006-2017Crossref PubMed Scopus (2099) Google Scholar, 3.Larkin J. Chiarion-Sileni V. Gonzalez R. et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34Crossref PubMed Scopus (5112) Google Scholar, 4.Antonia S.J. López-Martin J.A. Bendell J. et al.Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.Lancet Oncol. 2016; 17: 883-895Abstract Full Text Full Text PDF PubMed Scopus (903) Google Scholar]. ICI-induced encephalitis is an extremely rare immune-related adverse event and little is known about its clinical course and management [1.Wolchok J.D. Kluger H. Callahan M.K. et al.Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med. 2013; 369: 122-133Crossref PubMed Scopus (3271) Google Scholar, 2.Postow M.A. Chesney J. Pavlick A.C. et al.Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.N Engl J Med. 2015; 372: 2006-2017Crossref PubMed Scopus (2099) Google Scholar, 3.Larkin J. Chiarion-Sileni V. Gonzalez R. et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34Crossref PubMed Scopus (5112) Google Scholar, 4.Antonia S.J. López-Martin J.A. Bendell J. et al.Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.Lancet Oncol. 2016; 17: 883-895Abstract Full Text Full Text PDF PubMed Scopus (903) Google Scholar]. We report a case of encephalitis induced by nivolumab plus ipilimumab in an SCLC patient, who showed remarkable improvement upon treatment with rituximab. A 75-year-old man was diagnosed as having SCLC with brain metastases and underwent brain surgery and whole brain radiotherapy. After four cycles of first-line treatment with carboplatin plus etoposide, nivolumab plus ipilimumab was administered as maintenance therapy (nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for four cycles) in a clinical trial (NCT02538666). After four cycles of the latter, he presented with convulsions that negatively affected his mental status. Computed tomography and magnetic resonance imaging showed no recurrence of brain metastasis, hemorrhage, or infarction. Cerebrospinal fluid (CSF) analysis showed a high protein level and pleocytosis (proteins, 128.4 mg/dl; cell count, 58/3 μl). CSF cytology and culture did not show any definitive evidence of malignancy or infection. Electroencephalography showed no evidence of a seizure. Test results for anti-neural antibodies, including anti-N-methyl-d-aspartate antibody and anti-voltage gated potassium channel antibody, were negative. Therefore, we diagnosed him with encephalitis induced by nivolumab plus ipilimumab. We administered 500 mg (10 mg/kg) of methylprednisolone and 20 g (400 mg/kg) of intravenous immunoglobulin. However, his neurological symptoms did not significantly improve. We thus administered 550 mg (375 mg/m2) of rituximab intravenously. After several days of treatment with rituximab, his cognitive impairment significantly improved and his neurological status was stable for 1 month after treatment. We carried out six lumbar punctures during follow-up and confirmed the improvement (Figure 1). Since his SCLC progressed, ICIs were discontinued. ICI-induced encephalitis is reported to have an incidence of <1% [1.Wolchok J.D. Kluger H. Callahan M.K. et al.Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med. 2013; 369: 122-133Crossref PubMed Scopus (3271) Google Scholar, 2.Postow M.A. Chesney J. Pavlick A.C. et al.Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.N Engl J Med. 2015; 372: 2006-2017Crossref PubMed Scopus (2099) Google Scholar, 3.Larkin J. Chiarion-Sileni V. Gonzalez R. et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34Crossref PubMed Scopus (5112) Google Scholar, 4.Antonia S.J. López-Martin J.A. Bendell J. et al.Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.Lancet Oncol. 2016; 17: 883-895Abstract Full Text Full Text PDF PubMed Scopus (903) Google Scholar]. Williams et al. [5.Williams T.J. Benavides D.R. Patrice K.A. et al.Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer.JAMA Neurol. 2016; 73: 928-933Crossref PubMed Scopus (193) Google Scholar] have reported cases of encephalitis induced by nivolumab plus ipilimumab in a melanoma patient and an SCLC patient. In both cases, the patients showed some neurological symptoms and had similar cognitive dysfunctions such as memory loss. We observed that rituximab improved the patient's neurological symptoms. A previous study also showed the efficacy of rituximab in ICI-induced encephalitis in a melanoma patient [5.Williams T.J. Benavides D.R. Patrice K.A. et al.Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer.JAMA Neurol. 2016; 73: 928-933Crossref PubMed Scopus (193) Google Scholar]. One possible explanation for this efficacy might be due to the suppression of abnormal humoral immunity and T-cell activity through the depletion of B cells. Interestingly, in the present case and two previous cases on ICI-induced encephalitis, each patient had a brain metastasis and underwent brain radiotherapy [5.Williams T.J. Benavides D.R. Patrice K.A. et al.Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer.JAMA Neurol. 2016; 73: 928-933Crossref PubMed Scopus (193) Google Scholar]. A careful evaluation of these cases indicate that disruption of the blood–brain barrier or damage resulting from the brain radiotherapy may have facilitated T-cell and B-cell interactions with neuronal epitopes to induce autoimmune encephalitis [5.Williams T.J. Benavides D.R. Patrice K.A. et al.Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer.JAMA Neurol. 2016; 73: 928-933Crossref PubMed Scopus (193) Google Scholar]. The authors would like to thank Bristol-Myers Squibb for reviewing the manuscript, as well as all the medical staff who were involved in the care of the patient. This work was supported by internal funding from Kobe City Medical Center General Hospital (Hyogo, Japan). No grant numbers applied.