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Association of Immune-Mediated Cerebellitis With Immune Checkpoint Inhibitor Therapy.

ABSTRACT: Immune-mediated encephalitis related to immune checkpoint inhibitor therapy is a rare but increasingly described condition that can cause significant morbidity. There are several reported cases in the literature but no previously described cases of immune-mediated cerebellitis. We describe a case of acute cerebellitis that developed in a 20-year-old man with primary refractory Hodgkin lymphoma being treated with the immune checkpoint inhibitor nivolumab. After exposure to 3 cycles of nivolumab, the patient had acute onset of headache, ataxia, nausea, and vomiting, with imaging findings of cerebellar edema, early tonsillar herniation, and early hydrocephalus. Immune-mediated cerebellar encephalitis was suspected and high-dose dexamethasone therapy (8 mg every 6 hours) was initiated. Within 4 days of dexamethasone therapy, his symptoms greatly improved with near-complete resolution of symptoms after a 4-week taper. Differential diagnosis of his condition included viral cerebellitis and paraneoplastic cerebellar degeneration. In cerebellar encephalitis suspected to be due to immune checkpoint inhibitor therapy, prompt recognition and early initiation of high-dose corticosteroids is essential for symptom resolution and treatment success, including the prevention of hydrocephalus and tonsillar herniation. Currently, there are no evidence-based guidelines to guide the initial dose, type, or duration of corticosteroids. Further investigation is needed in the pathogenesis and treatment of cerebellar encephalitis related to immune checkpoint inhibitor therapy to effectively treat this rare, disabling condition.

SUBMITTER: Zurko J

PROVIDER: S-EPMC6124334 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Association of Immune-Mediated Cerebellitis With Immune Checkpoint Inhibitor Therapy.

Zurko Joanna J Mehta Amitkumar A

Mayo Clinic proceedings. Innovations, quality & outcomes 20180201 1

Immune-mediated encephalitis related to immune checkpoint inhibitor therapy is a rare but increasingly described condition that can cause significant morbidity. There are several reported cases in the literature but no previously described cases of immune-mediated cerebellitis. We describe a case of acute cerebellitis that developed in a 20-year-old man with primary refractory Hodgkin lymphoma being treated with the immune checkpoint inhibitor nivolumab. After exposure to 3 cycles of nivolumab, ...[more]

PMID: 30225435

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Project description:BackgroundIn the current study, the authors assessed the risks and outcomes of immune checkpoint inhibitor (ICI) rechallenge in patients with resolved grade 3 to 4 ICI hepatitis because current guidelines recommend permanent ICI discontinuation in these patients.MethodsThe authors performed a retrospective cohort study from 2010 through 2019 of patients with melanoma who were treated with ≥1 ICIs and who recovered from grade 3 to 4 ICI hepatitis. The primary outcome was hepatitis recurrence and the secondary outcome was the development of any immune-related adverse event (irAE) requiring the discontinuation of ICI rechallenge. Best overall response and time to all-cause death were compared between the patients who did and those who did not undergo ICI rechallenge. Grading was performed using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0).ResultsOf the 102 patients with melanoma who developed high-grade ICI hepatitis, 31 underwent ICI rechallenge. Although 15 of 31 patients (48%) developed an irAE of any grade, only 6 patients (19%) required ICI discontinuation due to irAE severity (4 of 29 patients [14%] rechallenged with anti-PD-1 or anti-PD-L1 and 2 of 2 patients [100%] rechallenged with ipilimumab). Recurrent hepatitis accounted for 4 of these 6 cases. Rechallenged patients who did not require ICI discontinuation were found to be significantly less likely to receive ipilimumab rather than anti-PD-1 or anti-PD-L1 monotherapy (0% vs 33%; relative risk (RR), 0.1 [95% CI, 0.1-0.3; P = .032]) and significantly less likely to be rechallenged with their original ICI (8% vs 50%; RR, 0.2 [95% CI, 0.1-0.7; P = .038]). There was no difference noted with regard to best overall response or time to death between rechallenged and non-rechallenged patients.ConclusionsICI therapy can be resumed in patients with melanoma who have recovered from grade 3 to 4 ICI hepatitis with a modest risk of serious irAEs. It remains unclear whether ICI retreatment improves clinical outcomes.

Project description:BackgroundThe objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.Subjects, materials, and methodsConsecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).ResultsTwenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor ß (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sjögren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.ConclusionICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sjögren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.Implications for practiceSicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sjögren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.

Dataset Information

Association of Immune-Mediated Cerebellitis With Immune Checkpoint Inhibitor Therapy.

Publications

Association of Immune-Mediated Cerebellitis With Immune Checkpoint Inhibitor Therapy.

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