Central nervous system complications associated with immune checkpoint inhibitors.

To describe the spectrum and outcome of central nervous system complications associated with immune checkpoint inhibitors (CNS-ICI). Patients with CNS-ICI were identified and their characteristics compared with ICI-related peripheral neuropathy (PN-ICI). We identified 19 patients with CNS-ICI. The patients were receiving nivolumab (n=8), pembrolizumab (n=6), a combination of ipilimumab-nivolumab (n=3), ipilimumab-durvalumab (n=1), or atezolizumab (n=1). Underlying malignancies included non-small-cell lung cancer (n=8), melanoma (n=3), and other less common tumours (n=8). Neurological phenotypes were limbic encephalitis (n=8), meningoencephalitis (n=4) and cerebellitis (n=4). Two patients developed isolated confusion and one parkinsonism. Associated autoantibodies included onconeural (Ma2, n=7; Hu, n=1), astrocytic (glial fibrillar acidic protein, n=2) and neuronal surface (contactin-associated protein-like 2, n=1) specificities. ICIs were withheld and corticosteroid treatment was given in all cases. Five patients received intravenous immunoglobulin, two rituximab, one plasmapheresis and one infliximab. Overall, six patients died. Readministration of ICI was attempted in three patients, without further relapses. Non-small-cell lung cancer was significantly more frequent in patients with CNS-ICI (p<0.01), while melanoma and ipilimumab treatment were more common in PN-ICI (p<0.01 and p=0.01). Conversely, CNS-ICI cases were more frequently antibody-positive than PN-ICI (p<0.01) and showed a strong trend towards poorer outcome (p=0.053). Three main clinical phenotypes characterise CNS complications of ICIs, each with distinct immunological background, disease course and response to treatment. Other clinical manifestations (including parkinsonism and steroid-responsive confusion) are also possible. Underlying cancers, antibody prevalence and outcome appear different from those of patients with PN-ICI.

Vogrig A ，Muñiz-Castrillo S ，Joubert B ，Picard G ，Rogemond V ，Marchal C ，Chiappa AM ，Chanson E ，Skowron F ，Leblanc A ，Ducray F ，Honnorat J ... -  《-》

Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis.

To provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer. Systematic review and network meta-analysis. Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018. Only head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group. 36 head-to-head phase II and III randomised trials (n=15 370) were included. The general safety of ICI drugs ranked from high to low for all adverse events was as follows: atezolizumab (probability 76%, pooled incidence 66.4%), nivolumab (56%, 71.8%), pembrolizumab (55%, 75.1%), ipilimumab (55%, 86.8%), and tremelimumab (54%, not applicable). The general safety of ICI drugs ranked from high to low for severe or life threatening adverse events was as follows: atezolizumab (49%, 15.1%), nivolumab (46%, 14.1%), pembrolizumab (72%, 19.8%), ipilimumab (51%, 28.6%), and tremelimumab (28%, not applicable). Compared with conventional therapy, treatment-related adverse events for ICI drugs occurred mainly in the skin, endocrine, hepatic, and pulmonary systems. Taking one ICI drug was generally safer than taking two ICI drugs or one ICI drug with conventional therapy. Among the five ICI drugs, atezolizumab had the highest risk of hypothyroidism, nausea, and vomiting. The predominant treatment-related adverse events for pembrolizumab were arthralgia, pneumonitis, and hepatic toxicities. The main treatment-related adverse events for ipilimumab were skin, gastrointestinal, and renal toxicities. Nivolumab had a narrow and mild toxicity spectrum, mainly causing endocrine toxicities. Integrated evidence from the pooled incidences, subgroup, and sensitivity analyses implied that nivolumab is the best option in terms of safety, especially for the treatment of lung cancer. Compared with other ICI drugs used to treat cancer, atezolizumab had the best safety profile in general, and nivolumab had the best safety profile in lung cancer when taking an integrated approach. The safety ranking of treatments based on ICI drugs is modulated by specific treatment-related adverse events. PROSPERO CRD42017082553.

Xu C ，Chen YP ，Du XJ ，Liu JQ ，Huang CL ，Chen L ，Zhou GQ ，Li WF ，Mao YP ，Hsu C ，Liu Q ，Lin AH ，Tang LL ，Sun Y ，Ma J ... -  《BMJ-British Medical Journal》

Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors.

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. Retrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018. 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. 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.

Vogrig A ，Fouret M ，Joubert B ，Picard G ，Rogemond V ，Pinto AL ，Muñiz-Castrillo S ，Roger M ，Raimbourg J ，Dayen C ，Grignou L ，Pallix-Guyot M ，Lannoy J ，Ducray F ，Desestret V ，Psimaras D ，Honnorat J ... -  《Neurology-Neuroimmunology &amp; Neuroinflammation》

Myositis as an adverse event of immune checkpoint blockade for cancer therapy.

Immune checkpoint inhibitors (ICIs) can successfully treat cancer, but their use can be hindered by serious immune-related adverse events. We report six patients receiving ICIs who presented with de novo myositis. We identified patients with myositis who were receiving ICIs between January 2004 and September 2016 at The University of Texas MD Anderson Cancer Center. Six patients developed de novo myositis. The mean age was 64.3 years and five patients were male. Cancer types included melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer. ICI regimens included single-agent ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and ipilimumab (n = 3). The median time to development of de novo myositis from first infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them developed rhabdomyolysis, one with concurrent myocarditis. Five patients were treated with 1-2mg/kg corticosteroids, with variable response rates; one patient received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as a result of cancer progression. We found several occurrences of de novo myositis following ICI therapy. These preliminary data suggest that myositis can occur early after onset of ICI therapy with serious adverse outcomes.

Shah M ，Tayar JH ，Abdel-Wahab N ，Suarez-Almazor ME ... -  《-》

Immune checkpoint inhibitor-associated sarcoidosis: A usually benign disease that does not require immunotherapy discontinuation.

To analyse the clinical patterns of sarcoidosis triggered by immune checkpoint inhibitors (ICIs) in patients with cancer. The ImmunoCancer International Registry is a big data-sharing multidisciplinary network from 18 countries dedicated to evaluating the clinical research of immune-related adverse events related to cancer immunotherapies. We identified 32 patients with biopsy-proven sarcoidosis. Underlying cancer included mainly melanoma (n = 24). Cancer immunotherapy consisted of monotherapy in 19 cases (anti-PD-1 in 18 and ipilimumab in 1) or combined ipilimumab + nivolumab in 13. The time median interval between initiation of ICI and sarcoidosis diagnosis was 3 months (range, 2-29 months). The use of combined ICI was associated with a shorter delay in developing sarcoidosis symptoms. The disease was symptomatic in 19 (59%) cases with mostly cutaneous, respiratory and general symptoms. The organs involved included mainly the mediastinal lymph nodes (n = 32), the lungs (n = 11), the skin (n = 10) and the eyes (n = 5). Pulmonary computed tomography studies showed bilateral hilar lymphadenopathy in all cases. There was no severe manifestation. Specific systemic therapy was required in only 12 patients (37%): oral glucocorticoids in 9, and hydroxychloroquine in 3. ICIs were held in 25 patients (78%) and definitively discontinued in 18 (56%) patients. Seven patients continued ICI treatment with a second flare in one case. In six additional patients, an ICI was reintroduced with no harm, and sarcoidosis relapsed in one of them. Our study shows that ICI-related sarcoidosis seems to have a specific profile, possibly more benign than that of idiopathic sarcoidosis, and does not necessarily imply ICI discontinuation.

Chanson N ，Ramos-Casals M ，Pundole X ，Suijkerbuijk K ，José de Barros E Silva M ，Lidar M ，Benesova K ，Leipe J ，Acar-Denizli N ，Pradère P ，Michot JM ，Voisin AL ，Suárez-Almazor ME ，Radstake TRD ，Fernandes Moça Trevisani V ，Schulze-Koops H ，Melin A ，Robert C ，Mariette X ，Baughman RP ，Lambotte O ，ICIR ，Coordination ，Co-Convenors ，Steering Committee ，Research Fellows ，Data Scientist ... -  《-》