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. 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 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, HR = 3.26, 95%CI [1.27; 8.41]) and myositis/neuromuscular junction disorders (HR = 8.26, 95%CI [2.90; 23.58]), and decreased with older age (HR = 0.68, 95%CI [0.47; 0.99]) and paraneoplastic-like syndromes (HR = 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.

Predicting disability and mortality in CV2/CRMP5‐IgG associated paraneoplastic neurologic disorders

“…These two novel cases (not previously reported) suggest that ICI treatment can enhance the immune response and facilitate or augment paraneoplastic neurologic symptoms, as reported in the literature. 7 , 18 Both patients died, consistent with other reports of higher disability and mortality in patients with PND and ICI exposure 19 .…”

Autoimmune Movement Disorders Complicating Treatment with Immune Checkpoint Inhibitors

“…In line with current evidence, we found that only a minority of cases have a paraneoplastic-like syndrome phenotype, which probably differs in terms of pathogenesis, oncological accompaniments, and outcomes from cases with a non-PNS-like syndrome. 37 Other factors, such as cytokines, 38 could play a pathogenetic role in the absence of autoantibodies or in patients not fulfilling PNS criteria.…”

Axicabtagene ciloleucel treatment is more effective in primary mediastinal large B-cell lymphomas than in diffuse large B-cell lymphomas: the Italian CART-SIE study

“…We are currently unable to determine whether the use of CPIs increases axi-cel neurological toxicities, but this is a clinical alert that should be kept into consideration. Notably, the clinical spectrum of neurological events related to CPIs reported in literature is varied, and includes myositis, myasthenic syndromes, peripheral neuropathies, encephalitis, and may be severe and life-threatening [ 24 ].…”