Neurological outcomes in immune checkpoint inhibitor-related neurotoxicity

Abstract

While the spectrum of neurological immune checkpoint inhibitor-related adverse events is expanding, patients' outcomes are not well documented. This study aimed to assess outcomes of neurological immune-related adverse events and to identify prognostic factors. All patients experiencing grade ≥2 neurological immune-related adverse events identified at two clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; and OncoNeuroTox, Paris) over five years were included. Modified Rankin scores were assessed at onset, 6, 12, 18 months, and last visit. A multi-state Markov model was used to estimate the transition rates between minor disability (mRS <3), severe disability (mRS 3-5), and death (mRS 6), over the study period. The state-to-state transition rates were estimated using maximum likelihood and variables were introduced into the different transitions to study their effects. A total of 147 patients were included out of 205 patients with a suspicion of neurological immune-related adverse events. The median age was 65 years (range 20-87) and 87/147 patients (59.2%) were male. Neurological immune-related adverse events involved the peripheral nervous system in 87/147 patients (59.2%), the central nervous system in 51/147 (34.7%), and both systems in 9/147 (6.1%). Paraneoplastic-like syndromes were observed in 30/147 patients (20.4%). Cancers included lung cancers (36.1%), melanoma (30.6%), urological cancers (15.6%), and others (17.8%). Patients were treated with programmed cell death protein (ligan) 1 (PD(L)1) inhibitors (70.1%), CTLA4 inhibitors (3.4%) or both (25.9%). Severe disability was reported in 108/144 patients (75.0%) at onset and in 33/146 patients (22.6%) at last visit (median follow-up duration: 12 months, range 0.5-50); 48/147 (32.7%) patients died, from cancer progression (17/48, 35.4%), neurological toxicity (15/48, 31.2%), other causes (10/48, 20.8%) or unknown causes (6/48, 12.5%). The rate of transition from severe to minor disability independently increased with melanoma [compared to lung cancer, hazard ratio = 3.26, 95%CI (1.27; 8.41)] and myositis/neuromuscular junction disorders [hazard ratio = 8.26, 95%CI (2.90; 23.58)], and decreased with older age [hazard ratio = 0.68, 95%CI (0.47; 0.99)] and paraneoplastic-like syndromes [hazard ratio = 0.29, 95%CI (0.09; 0.98)]. In patients with neurological immune-related adverse events, myositis/neuromuscular junction disorders and melanoma increase the transition rate from severe to minor disability, while older age and paraneoplastic-like syndromes result in poorer neurological outcomes; future studies are needed to optimize the management of such patients.

Keywords: cancer immunotherapy complications; immune checkpoint inhibitors; neurological immune-related adverse events; neurotoxicity; paraneoplastic neurological syndromes.

Graphical Abstract

Figure 1

Flow chart of patients indicating the observed clinical phenotypes. ^aγ-aminobutyric acid type B receptor- and Sox1-associated limbic encephalitis (n = 1), multifocal motor neuropathy (n = 1), critical illness neuropathy (n = 1), and seronegative rapidly progressive cerebellar ataxia (n = 1); ^bDiplopia (n = 1), muscle weakness (n = 1), myalgias (n = 1) and paresthaesia (n = 1); ^cAlcohol-related dementia (n = 2), Alzheimer disease (n = 2), arthralgias (n = 1), diabetes-related carpal tunnel syndrome (n = 1), clivus chondroma (n = 1), neurological functional disorder (n = 3), multifactorial gait disorder (n = 1), Parkinson disease (n = 1), primary headache (n = 1), sepsis-associated encephalopathy (n = 3) and steroid myopathy (n = 2). Abbreviations: CIP, chronic intestinal pseudo-obstruction; LEMS, Lambert–Eaton myasthenic syndrome; MG, myasthenia gravis; NMJ, neuromuscular junction; NMT, neuromyotonia.

Figure 2

Clinical presentations according to the types of ICIs and cancer. Bar chart indicating the number of patients according to the types of cancer and ICI for each clinical phenotype. Anti-CTLA4 immunotherapy was more frequent in patients with polyradiculoneuropathy or meningitis, and less frequent in patients with myositis and/or MG, or limbic encephalitis. Conversely, melanoma was more frequent in meningitis patients, and lung cancer was more frequent in limbic encephalitis patients. Cancers other than melanoma, lung and urological cancer included thymoma (n = 4), Hodgkin lymphoma (n = 3), colorectal adenocarcinoma (n = 3), skin squamous cell carcinoma (n = 3), prostate adenocarcinoma (n = 2), Merkel carcinoma (n = 2), oropharynx squamous cell carcinoma (n = 1), breast adenocarcinoma (n = 1), pleural mesothelioma (n = 1), chordoma (n = 1), ovary carcinoma (n = 1), leiomyosarcoma (n = 1), acute myeloblastic leukaemia (n = 1), liposarcoma (n = 1) and hepatocellular carcinoma (n = 1). Abbreviations: PRN = polyradiculoneuropathy; NMJ = neuromuscular junction.

Figure 3

Outcomes. (A) Disability at onset (M0), 6 months (M6), 12 months (M12) and 18 months (M18). The proportion of patients with minor disability changed from 28/144 (19.4%) patients at onset to 65/116 (56.0%) at 6 months, 56/110 (50.9%) at 12 months, and 35/86 (40.7%) at 18 months, although mortality increased at all time points. (B) Outcome at last visit [median (range) follow-up duration: 12, (0.5–50) months] according to the initial clinical presentation. Less frequent phenotypes (small-fiber neuropathy, n = 2, length-dependent polyneuropathy, n = 1, CIP, n = 1, neuromyotonia, n = 1) are not represented. Abbreviations: mRS = modified Rankin score; NMJ = neuromuscular junction, PRN = polyradiculoneuropathy; SNN = sensory neuronopathy.

Figure 4

Presentation of the multi-state Markov model and multivariate analysis of outcomes. Each patient was categorized into one of three different states of disease at onset, 6 months, 12 months and 18 months: minor disability (mRS ≤2), severe disability (mRS 3-5), and death (mRS = 6); the transition rates from severe disability to a minor disability, severe disability to death and minor disability to death across these time points were estimated using maximum likelihood (A). Exposures were introduced into the different transitions to study their effects; forest plots showing the hazard ratios and confidence intervals according to the multivariate analysis for transition rates from severe disability to minor disability (B), severe disability to death (C) and minor disability to death (D), are represented. Melanoma and myositis/NMJ disorders were independently associated with a transition from severe to minor disability while increasing age and paraneoplastic-like syndromes independently decreased the rate of transition from severe to minor disability. Meanwhile, the transition rate from minor disability to death was decreased in patients with cancers other than lung and melanoma, compared to lung cancer. Abbreviations: CI = confidence interval; HR = hazard ratio; mRS = modified Rankin scale; NMJ = neuromuscular junction.