RESUMEN
BACKGROUND: The clinical spectrum of melanoma-associated neurological autoimmunity, whether melanoma-associated paraneoplastic neurological syndromes (PNS) or induced by immune checkpoint inhibitors (ICI), is not well characterized. We aim to describe the clinical spectrum of melanoma-associated neurological autoimmunity. METHODS: A systematic review of the literature combined with patients from French databases of paraneoplastic neurological syndromes was conducted. All melanoma patients with a possible immune-mediated neurologic syndrome were included and classified according to whether they had previously been exposed to ICI (ICI-neurotoxicity) or not (ICI-naïve) at first neurological symptoms. RESULTS: Seventy ICI-naïve (literature: n = 61) and 241 ICI-neurotoxicity patients (literature: n = 180) were identified. Neuromuscular manifestations predominated in both groups, but peripheral neuropathies were more frequent in ICI-neurotoxicity patients (39.4% vs 21.4%, p = 0.005) whereas myositis was more frequent in ICI-naïve patients (42.9% vs 18.7%, p < 0.001). ICI-naïve patients had also more frequent central nervous system (CNS) involvement (35.7% vs 23.7%, p = 0.045), classical paraneoplastic syndrome (25.7% vs 5.8%, p < 0.001), and more frequently positive for anti-neuron antibodies (24/32, 75.0% vs 38/90, 42.2%, p = 0.001). Although more ICI-neurotoxicity patients died during the acute phase (22/202, 10.9% vs 1/51, 2.0%, p = 0.047), mostly myositis patients (14/22, 63.6%), mortality during follow-up was higher in ICI-naïve patients (58.5% vs 29.8%, p < 0.001). There was no significant difference in the frequency of life independence (mRS ≤ 2) in the surviving patients in both groups (95.5% vs 91.0%, p = 0.437). CONCLUSIONS: Melanoma-associated PNS appear remarkably rare. The clinical similarities observed in neurological autoimmunity between ICI-treated and ICI-naïve patients, characterized predominantly by demyelinating polyradiculoneuropathy and myositis, suggest a potential prior immunization against melanoma antigens contributing to ICI-related neurotoxicity.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Melanoma , Síndromes Paraneoplásicos del Sistema Nervioso , Humanos , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/inducido químicamente , Autoinmunidad/efectos de los fármacos , Autoinmunidad/inmunología , Masculino , FemeninoRESUMEN
Paraneoplastic neurologic syndromes(PNSs) caused by immune checkpoint inhibitors(ICIs) is rare and requires clinicians to differentiate between disease progression and immune-related adverse effects(irAEs). We hereby report the case of immune-related myelitis accompanied by positive paraneoplastic autoantibodies following durvalumab treatment for extensive-stage small cell lung cancer (ES-SCLC). A 70-year-old Chinese woman with ES-SCLC was administered durvalumab with etoposid-platinum(EP) as first-line treatment. Four cycles after treatment with EP plus ICI, she developed immune-related myelitis with positive paraneoplastic autoantibodies (CV2, SOX1, ZIC4). Spinal MRI showed diffuse abnormal signal shadow in the cervicothoracic spinal cord. She was discontinued for chemotherapy, and treated with high-dose steroids, intravenous immunoglobulin and plasmapheresis, maintenance therapy with steroids resulted in a favorable neurologic outcome. This is the first report of durvalumab-related PNSs. We supposed that the development of paraneoplastic myelitis was causally related to immune activation by durvalumab. Prompt diagnosis and therapeutic intervention are essential for the effective treatment of paraneoplastic myelitis.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Síndromes Paraneoplásicos del Sistema Nervioso/inducido químicamente , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , China , Etopósido/uso terapéutico , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéuticoRESUMEN
We present an illustrative case of a 62-year-old woman with small cell lung cancer who developed progressive worsening of pre-existing anti-Hu antibody associated sensory neuronopathy after treatment with programmed cell death-1 (PD-1) inhibitor, nivolumab. We review the literature and identify 6 reported cases to understand the clinical outcomes of patients with anti-Hu paraneoplastic neurologic syndrome (PNS) treated with anti-PD-1 treatment. The PNS clinical spectrum comprised of encephalitis, a combination of sensory neuronopathy and anti-NMDAR encephalitis, isolated sensory neuronopathy, and encephalomyelitis. Immune checkpoint inhibitor have the potential to worsen pre-existing anti-Hu PNS and may promote the development of anti-Hu PNS.
Asunto(s)
Anticuerpos Antinucleares/sangre , Antineoplásicos Inmunológicos/efectos adversos , Autoantígenos/inmunología , Proteínas ELAV/inmunología , Nivolumab/efectos adversos , Síndromes Paraneoplásicos del Sistema Nervioso/etiología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anticuerpos Antinucleares/inmunología , Anticuerpos Antineoplásicos , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carcinoma de Células Pequeñas/complicaciones , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/inmunología , Carcinoma de Células Pequeñas/secundario , Neoplasias Cerebelosas/complicaciones , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/inmunología , Neoplasias Cerebelosas/secundario , Terapia Combinada , Progresión de la Enfermedad , Etopósido/administración & dosificación , Femenino , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/radioterapia , Persona de Mediana Edad , Nivolumab/uso terapéutico , Síndromes Paraneoplásicos del Sistema Nervioso/inducido químicamente , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Radioterapia Adyuvante , Resultado del TratamientoAsunto(s)
Antígenos de Neoplasias/inmunología , Antineoplásicos Inmunológicos/efectos adversos , Enfermedades Cerebelosas/inducido químicamente , Encefalitis/inducido químicamente , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas del Tejido Nervioso/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/inducido químicamente , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Resultado Fatal , Humanos , MasculinoRESUMEN
OBJECTIVE: To report the induction of anti-Ma2 antibody-associated paraneoplastic neurologic syndrome (Ma2-PNS) in 6 patients after treatment with immune checkpoint inhibitors (ICIs). We also analyzed (1) patient clinical features compared with a cohort of 44 patients who developed Ma2-PNS without receiving ICI treatment and (2) the frequency of neuronal antibody detection before and after ICI implementation. METHODS: Retrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018. RESULTS: Our series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving nivolumab (n = 3), pembrolizumab (n = 2), or a combination of nivolumab and ipilimumab (n = 1) for treatment of neoplasms that included lung (n = 4) and kidney (n = 1) cancers and pleural mesothelioma (n = 1). Clinical syndromes comprised a combination of limbic encephalitis and diencephalitis (n = 3), isolated limbic encephalitis (n = 2), and a syndrome characterized by ophthalmoplegia and head drop (n = 1). No significant clinical difference was observed between our 6 patients and the overall cohort of Ma2-PNS cases. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017-2018 biennium. Eight cases had been detected in the preceding biennium 2015-2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. Despite ICI withdrawal and immunotherapy, 4/6 patients died, and the remaining 2 showed a moderate to severe disability. CONCLUSIONS: We show a clear association between ICI use and increased diagnosis of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS because clinical presentation can be challenging.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Antígenos de Neoplasias/inmunología , Antineoplásicos Inmunológicos/efectos adversos , Encefalitis/inducido químicamente , Encefalitis/inmunología , Factores Inmunológicos/efectos adversos , Ipilimumab/efectos adversos , Neoplasias/tratamiento farmacológico , Proteínas del Tejido Nervioso/inmunología , Nivolumab/efectos adversos , Síndromes Paraneoplásicos del Sistema Nervioso/inducido químicamente , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Anciano , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Immune checkpoint inhibitors (ICIs) are highly efficacious for treating many solid tumor types. Because of their immune-activating mechanism of action, ICIs can trigger various immune-mediated toxicities. We present three cases: i) a woman with anti-Ri brainstem encephalitis; ii) a man with anti-Hu sensory neuronopathy; and iii) a woman with suspected combined anti-Hu and anti-NMDA paraneoplastic syndromes associated with the initiation of the ICIs pembrolizumab and nivolumab. These cases suggest that ICIs can induce both humoral and cell-mediated paraneoplastic neurologic syndromes. Identifying biomarkers that predict risk of developing ICI-associated paraneoplastic syndromes and the development of efficacious treatment strategies for neurologic ICI-toxicities are critical unmet needs.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Nivolumab/efectos adversos , Síndromes Paraneoplásicos del Sistema Nervioso/inducido químicamente , Síndromes Paraneoplásicos del Sistema Nervioso/diagnóstico por imagen , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos Inmunológicos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nivolumab/farmacología , Síndromes Paraneoplásicos del Sistema Nervioso/sangre , Receptor de Muerte Celular Programada 1/sangreRESUMEN
Paraneoplastic neurological syndromes (PNSs) comprise a group of disorders that can affect any part of the nervous system in patients with cancer and frequently result from autoimmune responses triggered by the ectopic expression of neuronal proteins in cancer cells. These disorders are rare, although the introduction of immune-checkpoint inhibitors (ICIs) into cancer treatment algorithms has renewed interest in PNSs. ICIs are associated with a considerably increased incidence of immunological toxicities compared with traditional anticancer therapies, including neurological immune-related adverse effects (nirAEs) that can manifest as PNSs. Theoretically, the use of ICIs might increase the risk of PNSs, in particular, in patients with the types of cancer that are most frequently associated with these disorders (such as small-cell lung cancer), emphasizing the importance of their prompt diagnosis and treatment to prevent irreversible neurological deficits. To facilitate the recognition of these disorders in the context of immune-checkpoint inhibition, we provide an overview of PNSs, including the main syndromes, types of neuronal autoantibodies and associated immunological mechanisms. We also review the scenarios in which nirAEs fulfil the criteria for PNSs and examine their frequency and clinical presentations. Finally, we provide recommendations for the prevention and management of PNSs that can occur during ICI therapy.
Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Factores Inmunológicos/efectos adversos , Inmunoterapia/efectos adversos , Neoplasias/tratamiento farmacológico , Síndromes Paraneoplásicos del Sistema Nervioso/inducido químicamente , Humanos , Inmunoterapia/métodosRESUMEN
Targeting immune cells instead of cancer cells is a new and successful therapeutic approach in patients with a variety of advanced cancers. Blocking antibodies bind to specific immune-checkpoint molecules namely cytotoxic T-lymphocyte-associated antigen 4, programmed cell death protein-1, and programmed cell death-ligand 1. However, their mechanism of action can lead to immune-related adverse events. In particular, neurological immune-related adverse events present, currently, a problem, as they are rare, difficult to diagnose, and are often high grade or even fatal. Here, we describe four cases with metastatic melanoma who developed symptoms of acute progressive weakness 3-9 weeks after therapy onset with immune-checkpoint inhibitors (ICIs) nivolumab and ipilimumab. Neurological examination and diagnostic procedures revealed results partly consistent with neurological disorders such as neuropathy, myositis, and myasthenia. This suggests an overlap of these known diseases indicating a new ICI-induced neuropathy-myositis-myasthenia-like syndrome. Here, we give recommendations for a structured and focused diagnostic assessment in patients presenting with neurological deficits during ICI therapy. This might improve the understanding, management, and ultimately the outcome of ICI-induced neurological adverse events.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Melanoma/tratamiento farmacológico , Miositis/inducido químicamente , Síndromes Paraneoplásicos del Sistema Nervioso/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Neoplasias Cutáneas/tratamiento farmacológico , Enfermedad Aguda , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , SíndromeRESUMEN
The development of new immune treatment in oncology and particularly for lung cancer may induce new complications, particularly activation or reactivation of auto-immune diseases. In this context, a systematic review on the auto-immune paraneoplastic syndromes that can complicate lung cancer appears useful. This article is the third of a series of five and deals mainly with neurological paraneoplastic syndromes involving the central nervous system.
Asunto(s)
Inmunoterapia/efectos adversos , Neoplasias Pulmonares/complicaciones , Enfermedad Autoinmune Experimental del Sistema Nervioso/inducido químicamente , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Carcinoma Pulmonar de Células Pequeñas/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Inglaterra , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Síndromes Paraneoplásicos del Sistema Nervioso/inducido químicamente , Síndromes Paraneoplásicos del Sistema Nervioso/patología , Estudios Prospectivos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológicoRESUMEN
The exact immunopathogenesis and neuroanatomical localization of opsoclonus-myoclonus ataxia syndrome remains unclear. We describe a 1 year 9 month old girl who, shortly after commencement of highly active antiretroviral therapy developed opsoclonus-myoclonus syndrome and subsequently died of disseminated cytomegalovirus infection. We postulate on the etiological factors that may have played a role in the disease pathogenesis of the patient's opsoclonus-myoclonus ataxia. Immune reconstitution inflammatory syndrome was considered the most likely because of the initial CD4 depletion and the onset of symptoms shortly after initiation of antiretroviral therapy. Single photon emission computed tomography (SPECT) proved helpful by localizing the area of dysfunction to the cerebellar vermis.