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Association of high body mass index (BMI) with longer survival has been reported in patients on immune checkpoint inhibitors (ICIs), but results are inconsistent. This 'obesity paradox' is potentially confounded by the effects of BMI change over time and of skeletal muscle depletion.We conducted a secondary analysis of a prospective cohort, including consecutive patients receiving ICI treatment for melanoma (n = 411) and non-small cell lung cancer (NSCLC) (n = 389) in routine care.In the univariable analysis of the entire population, overweight/obesity (BMI ≥ 25 kg/mThe so-called 'obesity paradox', counterintuitive association between high BMI and longer survival, vanished when controlling for confounders, such as type of cancer, and manifestations of depletion (WL and reduced skeletal muscle mass).

Variation of SIP in the overall ICI cohort and in progressing and non-progressing patients (A). Variation of immunosenescence markers (CD28 absence, CD57 expression, KLRG1 expression) on CD4 and CD8+ T-cells and variation of circulating TEMRA, naïve or TC1 CD8+ T-cells in the overall ICI cohort and in progressing and non-progressing patients (B)

Supplementary Methods

Patients characteristics in ICI discovery and validation cohorts

Purpose:CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non–small cell lung cancer (aNSCLC) is unknown.Experimental Design:The percentage of CD28−, CD57+, KLRG1+ among CD8+ T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cut-off was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8+ T cells were assessed in vitro.Results:In the ICI discovery cohort (N = 37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N = 46), SIP+ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2–19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8+ T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population (N = 83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N = 61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT.Conclusions:Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT.See related commentary by Salas-Benito et al., p. 374

Sarcoid-like granulomatosis (SLG) reaction caused by immunotherapy remains poorly understood. This study aims to investigate the outcome of patients with cancer and SLG associated with immunotherapy.Between April 2016 and June 2020, 434 patients with immunological adverse events were screened from the ImmunoTOX assessment board of Gustave Roussy, an academic cancer centre in France. Among them, 28 patients had SLG associated with immunotherapy (SLG cohort) and 406 patients had other immunological adverse events (control cohort). Clinical characteristics and outcome of patients were compared from SLG and control cohort.The SLG cohort consisted of 28 patients, 14 women and 14 men, with the median (range) age of 56.5 (28.7-75.3) years. Patients in the SLG cohort with sarcoidosis were asymptomatic (only radiographical finding) in 13 (46.4%) cases; otherwise, the most frequent symptoms were dyspnoea in 8 (28.6%) patients and cough in 5 (17.8%) patients. The computerised tomography scan found sarcoidosis localisations in mediastinal or peri-hilar thoracic lymph nodes in 26 (92.9%) patients, and lung parenchymal involvement was found in 14 (50.0%) patients. The radiographic Scadding stages for sarcoidosis classification were distributed in stages 0, I, II, III and IV in 2 patients (7.1%), 13 patients (46.4%), 11 patients (39.3%), 1 patient (3.6%) and 1 patient (3.6%), respectively. Compared with patients with other immunological toxicities (cohort control), patients with sarcoidosis presented most frequently with melanoma (75.0% versus 21.9% of patients; p 0.001) and more often received combined therapies of anti-programmed cell death 1 plus anti-cytotoxic T-lymphocyte antigen 4 protein (46.4% versus 12.6% of patients; p = 0.002). Patients with sarcoidosis had an improved overall survival (OS); the median OS was not reached in the SLG cohort and 40.4 months in the control cohort, hazard ratio = 0.232 (95% confidence interval: 0.086-0.630) (p = 0.002).Sarcoidosis-like reactions in patients receiving immunotherapy were reported as non-severe immunological reactions in most cases and were correlated with improved OS. SLG should not be misdiagnosed as tumour progression in patients receiving immunotherapy treatment for cancer.

Purpose: CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non–small cell lung cancer (aNSCLC) is unknown. Experimental Design: The percentage of CD28−, CD57+, KLRG1+ among CD8+ T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cut-off was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8+ T cells were assessed in vitro. Results: In the ICI discovery cohort (N = 37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N = 46), SIP+ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2–19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8+ T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population (N = 83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N = 61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT. Conclusions: Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT. See related commentary by Salas-Benito et al., p. 374

Numerous retrospective studies and reviews have reported a positive association between immune-related adverse events (irAEs) and survival in non-small cell lung cancer (NSCLC) and melanoma patients treated with immune checkpoint blockers (ICBs). However, some results are controversial and the studies, whose results converge, should be interpreted cautiously because most of them do not deal appropriately with the immortal-time bias. Here, we report an observational real-life study of the association between prospectively collected irAEs and survival of patients treated with ICBs while dealing with the immortal-time bias.Data from patients treated at Gustave Roussy from June 2014 to October 2017 with anti-PD-(L)1 antibodies for a melanoma or NSCLC have been prospectively collected in the REISAMIC database, a pharmacovigilance registry dedicated to irAEs. Adverse events of grade 2 and higher were collected prospectively. To study the association between the occurrence of irAEs and survival, we used both a landmark analysis and a Cox regression model with time-dependent covariate.577 patients were treated with anti-PD-(L)1 antibodies for melanoma (60.3 %) or NSCLC (39.7 %). The occurrence of an irAE was significantly associated with improved overall survival (OS): HR 0.56, 95 % CI [0.41; 0.75], p = 0.0001 and progression-free survival (PFS): HR 0.63, 95 % CI [0.47; 0.83], p = 0.001 using a Cox regression model with time-dependent covariate. In a 12-week landmark analysis, median OS was 21.2 months (95 % CI, 12.2 to 35.7) and 16.4 months (95 % CI, 12.4 to 21.3) p = 0.26 and median PFS was 14.3 months (95 % CI, 9.5 to 24.6) and 13.4 months (95 % CI, 10.2 to 18.3) p = 0.66, for patients with and without irAEs, respectively.In our real-life study of patients with melanoma and NSCLC treated with anti-PD-(L)1 antibodies, we confirm that irAEs are associated with improved survival using a time-varying Cox regression model. Analysis with a landmark method showed no difference in OS or PFS between patients who experienced irAE during the first 12 weeks of treatment and those who did not. Retrospective analysis and reviews including studies that do not deal with the immortal-time bias and studies insufficiently powered for a landmark analysis should be interpreted with caution.

Aging is an important risk factor for cancers and is associated with poor prognosis. Weakness of the immune system, also called immunosenescence may occur with older age. The impact of aging on efficacy and safety of immune checkpoint blockers, such as anti-programmed death (ligand) PD-(L)1, remains undetermined. This study aims to evaluate the incidence of immune-related adverse events (irAEs) in patients aged 70 years or older than their younger counterparts.Patients with advanced solid tumors treated at Gustave Roussy with an anti-PD-(L)1 monotherapy between June 2014 and October 2017 were prospectively included within the dedicated irAEs pharmacovigilance registry REISAMIC (Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie). The incidence of irAEs of grade ≥II was compared between patients aged ≥70 (old patients, OP) versus patients aged 70 years (young patients, YP) using a chi-squared test. Survivals were estimated using the Kaplan-Meier method.Among the 603 patients treated by anti-PD(L)1, 191 were ≥70 y.o (OP) and 424 70 y.o (YP). The median (range) age of OP and YP were respectively 77 (70-93) and 59 years old (17-69). A total of 165 irAEs occurred in these patients (103 grade II and 58 grade III-IV). The overall incidence of grade ≥II irAEs was higher in OP than in YP (33% versus 25%, p = 0.03). In addition, OP were more prone of having multiples irAEs compared with YP (p = 0.037). Skin toxicities were more frequent in OP than in YP (p = 0.007) but endocrine toxicities were less frequent in OP than in YP (p = 0.044). This higher level of irAEs seems to be responsible for a higher rate of treatment discontinuation in OP (p = 0.2). There was no statistical difference in median time to toxicity, exposure to steroids or survival between the two groups.Although anti-PD-(L)1 immunotherapies remain an acceptable treatment option for older patients, prescribers should be aware that irAEs are more frequent in the elderly. Further translational studies are warranted to better understand the relationship between aging and irAEs.

Immune checkpoint inhibitors (ICIs) are changing the treatments of many patients with cancer. These immunotherapies are generally better tolerated than chemotherapy, and their adverse events are immune-related mimicking autoimmune or inflammatory conditions. Although these immune-related adverse events mainly affect the skin, endocrine glands, digestive tract, joints, liver or lungs, all the organs can be theoretically affected, and the haematopoietic system is not spared. This review of the literature will focus on the haematological immune-related adverse events (Haem-irAEs). By reviewing the largest clinical trials of ICIs, we estimate the frequency of Haem-irAEs at 3.6% for all grades and 0.7% for grades III-IV. Frequency of Haem-irAEs of all grades was found to be higher with anti-programmed cell death 1 (4.1%) or anti-programmed cell death ligand 1 (4.7%) than with anti-cytotoxic T-lymphocyte-associated protein 4 (0.5%) (p 0.0001). From the 63 cases with Haem-irAEs reported in the literature, the mean time to the onset was found to be 10 weeks after ICI initiation, and the large range for occurrence (1-84 weeks) and the regular incidence suggest that Haem-irAEs could occur at any time after ICI therapy. Among the 63 reported cases with Haem-irAEs, the distribution was immune thrombocytopenia (n = 18, 29%), pancytopenia or immune aplastic anaemia (n = 12, 19%), neutropenia (n = 11, 17%), haemolytic anaemia (n = 10, 16%), cytokine release syndrome with haemophagocytic syndrome (n = 7, 11%) and other Haem-irAEs including bicytopenia or pure red cell aplasia (n = 5, 8%). Haem-irAEs are generally highly severe adverse reactions with a mortality rate of Haem-irAEs reported to be 14% (9 deaths among the 63 cases reported). The more severe and life-threatening Haem-irAEs were both cytokine release syndrome with haemophagocytic syndrome and pancytopenia or aplastic anaemia. Haem-irAEs induced by ICIs are potentially life-threatening. By discussing their pathophysiological aspects and clinical picture, we propose in this review clinical guidelines for management.

Background Immune-related adverse events (irAEs) remain generally unpredictable, and severe irAEs remain challenging to detect early and manage. Very severe (grade IV–V) irAEs have not been extensively characterised in prospective studies, and their predictive factors remain unknown. Objective The objective of the study was to describe and identify predictive factors of very severe (grade IV–V) irAEs. Design The French Registre des Effets Indesirables Severes des Anticorps Monoclonaux Immunomodulateurs en Cancerologie (REISAMIC) registry has prospectively collected all clinically significant irAEs occurring in patients treated with immune checkpoint inhibitors at Gustave Roussy Institute since 2014. Setting This was a single-centre prospective cohort study at the Gustave Roussy Institute cancer centre (Villejuif, France). Participants The participants were all adult patients with a solid or haematological cancer treated with an anti–programmed cell death 1 (PD-1) or an anti–programmed cell death-ligand 1 (PD-L1) and who presented a clinically significant irAE. Main outcomes and measures The main outcomes included the clinical and laboratory characteristics of patients with very severe irAEs, including tumour type, affected organs, time to irAE occurrence, blood cell count and serum biochemistry parameters. Results Of the 1187 patients prospectively followed in REISAMIC between December 2014 and January 2020, 380 (32.0%) had at least one irAE, and 34 (2.86%) presented with very severe irAEs (grades IV–V). Among the 380 patients with an irAE, the distribution of very severe irAEs (grades IV–V) was 8.95% and death (grade V) was 3.95%. Among the 34 patients with very severe irAEs, 33 were treated with monotherapy of PD-1 or PD-L1 inhibitors, and one patient was treated with a combination of PD-1 and cytotoxic T-lymphocyte–associated protein 4 inhibitors. The median time to occurrence was shorter for very severe irAEs (median [interquartile range]: 41 days [0–634] for grades IV–V; versus 91 days [0–1123] for grades I–III; p = 0.01680). On initiation of immunotherapy, the predictive factors for very severe irAEs were performance status ≥2, elevated neutrophil/lymphocyte ratio and treatment for lung cancer. Conclusions Very severe (grade IV–V) immunological toxicities occurred earlier than mild severe toxicities. On initiation of immunotherapy, patients with poor performance status, elevated neutrophil/lymphocyte ratio and lung cancer are identified at risk of developing these very severe toxicities. These results could help to develop risk scores to identify patients at risk of developing severe toxicities.

Summary Background Anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies are novel immunotherapies for cancer that can induce immune-related adverse events (irAEs). These adverse events can involve all organs, including the haemopoietic system. Thus far, haematological irAEs (haem-irAEs) have not been extensively characterised. This study aims to provide a comprehensive report of the haem-irAEs induced by anti-PD-1 or anti-PD-L1. Methods In this descriptive observational study, we included consecutive patients aged at least 18 years with grade 2 or worse haem-irAEs induced by anti-PD-1 or anti-PD-L1 immunotherapy registered in three French pharmacovigilance databases: the Registre des Effets Indesirables Severes des Anticorps Monoclonaux Immunomodulateurs en Cancerologie (REISAMIC; a prospective registry of patients treated with anti-PD-1 or anti-PD-L1 at a single centre), the ImmunoTOX committee of Gustave Roussy (a national referral database of suspected irAEs in patients treated with immunotherapy), and the registry of the Centre de Reference des Cytopenies Auto-Immunes de l'Adulte (CeReCAI; a national database of autoimmune cytopenias). Cases were reviewed by a central committee; adverse events had to be classed as certainly or probably related to anti-PD-1 or anti-PD-L1 therapy, and their severity was assessed according to the Common Terminology Criteria for Adverse Events (version 4.03). The primary endpoint was clinical description of haem-irAEs, as reported in all databases, and their frequency, as reported in the prospective REISAMIC registry. Findings We screened 948 patients registered in the three databases from June 27, 2014, to June 29, 2018 (745 from REISAMIC, 190 from the ImmunoTOX committee, and 13 from CeReCAI). 35 patients (21 men and 14 women) with haem-irAEs related to anti-PD-1 or anti-PD-L1 were included in the study. Of 745 patients in the REISAMIC registry treated with anti-PD-1 or anti-PD-L1, four had haem-irAEs, giving a frequency of 0·5%. Median age in the 35 patients was 65 years (IQR 51–75), and the most common tumour types were melanoma (15 [43%] patients), non-small-cell lung cancer (12 [34%] patients), and lymphoma (four [11%] patients). 20 (57%) patients received nivolumab, 14 (40%) received pembrolizumab, and one (3%) received atezolizumab. Among the 35 patients, neutropenia, autoimmune haemolytic anaemia, and immune thrombocytopenia were the most common types of haem-irAE (each in nine patients [26%]), followed by pancytopenia or aplastic anaemia (five patients [14%]), bicytopenia (one patients with thrombocytopenia plus anaemia and one patient with neutropenia plus anaemia [6%]), and pure red cell aplasia (one patient [3%]). The maximum grade of severity was grade 2 in three (9%) patients, grade 3 in five (14%) patients, and grade 4 in 25 (71%) patients; two (6%) patients died from febrile neutropenia during haem-irAE related to anti-PD-1. Haem-irAEs resolved in 21 (60%) of the 35 patients. Interpretation Haem-irAEs induced by PD-1 or PD-L1 inhibitors are rare but potentially life-threatening events. The most common clinical presentations are neutropenia, autoimmune haemolytic anaemia, immune thrombocytopenia, and aplastic anaemia. Investigations into earlier detection and better management are warranted. Funding Gustave Roussy and Gustave Roussy Immunotherapy Program.

Neurological immune-related adverse events are complications of programmed-cell death 1 or programmed-cell death 1 ligand immunotherapies that can be life threatening and often lead to anticancer immunotherapy withdrawal. Scant clinical data are available that integrate the clinical presentation, therapeutic management and long-term outcome. All consecutive adult patients treated by programmed-cell death 1 or programmed-cell death 1 ligand immunotherapies, given alone or in combination with other treatment, who experienced a neurological immune-related adverse event with a severity grade ≥2 in Paris Saclay-University hospitals were investigated from June 2014 to February 2019. The frequency of neurological immune-related adverse events was calculated from the prospective Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie cohort. Forty patients presenting with 51 distinct neurological immune-related adverse events were included. The prevalence of grade ≥2 neurological immune-related adverse events was estimated to be 1.22% in the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie cohort. Among 40 patients with neurological immune-related adverse events, 65% received programmed-cell death 1 or programmed-cell death 1 ligand monotherapy and 35% received a combination of programmed-cell death 1 plus anti-CTLA4 (Common Terminology Criteria for Adverse Events). Clinical neurological presentations were peripheral (48%), central (35%), or mixed (18%). The severity of neurological immune-related adverse events was grade 2 for 14 (35%) and ≥grade 3 for 26 patients (65%). The mortality rate related to neurological immune-related adverse events was 8%. Corticosteroid treatment led to neurological recovery in 74%. Long-term follow-up highlighted that 53% of patients experienced long-term neurological sequelae. Five patients were rechallenged by programmed-cell death 1 monotherapy without recurrence of their neurological immune-related adverse event(s). Neurological immune-related adverse events induced by programmed-cell death 1 or programmed-cell death 1 ligand are rare but are severe with a mortality rate of 8% and long-term sequelae for 53% of patients. Corticosteroids should be started when neurological immunological complications are identified to avoid long-term sequelae., Plaçais et al. report a large case-series of 40 patients presenting with 51 neurological adverse events of immune checkpoint inhibitors, wherein corticosteroid therapy was associated with a 74% rate of neurological recovery. Neurological adverse events were severe, as 7.5% of the included patients died and 53% kept long-term neurological sequelae., Graphical Abstract Graphical Abstract

International audience; Objective: Immune checkpoint inhibitor (ICI) antibodies constitute a new generation of cancer treatments, associated with immune-related adverse events (irAEs). A previous retrospective study of patients with metastatic melanoma (treated mostly with anti-CTLA4 antibodies) reported a serious infection rate of 7.3%. The main risk factors were corticoids and infliximab use. We sought to describe infections and risk factors among patients receiving anti-PD-1/PD-L1 ICIs.Patients and methods: We reviewed 200 medical records sampled randomly from a French prospective registry, which collates patients treated with anti-PD-1/PD-L1 ICIs. We recorded demographic data, the occurrence of irAEs, immunosuppressant use, and the outcome.Results: Thirty-six patients (18%) experienced an infection by a median (interquartile range) of 47 (19.2-132) days after initiation of the ICI. Twenty-one patients (58.3%) had a lung infection, seven (19.4%) had a skin infection, seven (19.4%) had a urinary tract infection, and all of them received antibiotics. The infection was generally mild, and the patients were treated as outpatient. There were no infection-related deaths and no opportunistic infection. Sixty percent of the patients were being treated for metastatic melanoma and 35.5% for non-small cell lung cancer, and 106 irAEs (mostly grade II) were reported. Forty-seven patients received steroids for cancer symptoms or irAEs, and five received immunosuppressants during the immunotherapy. We did not observe any association between corticosteroid or immunosuppressant use and the occurrence of an infection.Conclusion: The infection rate in patients treated with an anti-PD-1/PD-L1 ICI was 18%, without any severe or opportunistic infection. The occurrence of an infection was not associated with corticosteroid or immunosuppressant use.

Objective To analyse the clinical patterns of sarcoidosis triggered by immune checkpoint inhibitors (ICIs) in patients with cancer. Patients and methods 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. Results 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. Conclusion 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.

Purpose We investigated the activities of an ImmunoTOX board, an academic, multidisciplinary group of oncologists and organ specialists that adopts a real-life, case-by-case approach in the management of patients with immune-related adverse events (irAEs). Experimental design The ImmunoTOX assessment board was set up in 2016 at Gustave Roussy in France. It meets every 2 weeks to discuss the case-by-case management of patients presenting with irAEs. Here, we describe the ImmunoTOX board's activities between 2016 and 2019. Results Over study period, 398 requests (concerning 356 patients) were submitted to the ImmunoTOX board. Most of the requests concerned the putative causal link between immunotherapy and the irAE (n = 148, 37%), followed by possible retreatment after temporary withdrawal because of an adverse event (n = 109, 27%), the clinical management of complex situations (n = 100, 25%) and the initiation of immunotherapy in patients with pre-existing comorbidities (n = 41, 10%). The ImmunoTOX board discerned 273 irAEs. The five organ systems most frequently involved by irAEs were lung (n = 58, 21%), gastrointestinal tract (n = 36, 13%), liver or biliary tract (n = 33, 12%), musculoskeletal system (n = 27, 10%), and nervous system (n = 23, 8%). The time to occurrence was shorter for severe irAEs (grade III and VI) than for mild irAEs (grades I and II), with medians of 47 and 91 days, respectively (p = 0.0216). Conclusion The main medical needs in the management of irAEs involved the lung organ. Severe irAEs were expected to occur earlier than mild irAEs. This real-life study can help to better estimate medical needs and therefore help to assess the management of irAEs.

Aim The growing use of immune checkpoint inhibitors (ICIs) is associated with the occurrence of immune-related adverse events (irAEs). Few data are published on systemic, immunohaematological and rheumatic irAEs. In a pharmacovigilance database analysis, we screened for these irAEs and calculated their prevalence. Patients and methods Participants were recruited via Registre des Effets Indesirables Severes des Anticorps Monoclonaux Immunomodulateurs en Cancerologie (REISAMIC) 1 a French registry of grade ≥2 irAEs occurring in ICI-treated patients. The pathologies of interest were systemic autoimmune and inflammatory diseases, rheumatic diseases and immune cytopenia. Results Out of 908 patients treated with anti-Programmed cell Death 1 (PD1)/anti-Programmed cell Death-Ligand 1 (PD-L1) agents (together with an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) agent in 40 cases) between December 2012 and December 2016 at a single centre, 21 patients experienced systemic irAEs. The types and the prevalence of irAEs were as follows: immune thrombocytopenia (0.2%), Sjogren syndrome (0.3%), rheumatoid arthritis (0.2%), polymyalgia rheumatica (0.2%), psoriatic arthritis (0.2%), seronegative polyarthritis (0.7%) and sarcoidosis (0.2%). Patients with Sjogren syndrome or seronegative polyarthritis were more likely to have received combination therapy with ipilimumab (2.5% for both). We described these 21 cases, together with nine additional cases from five other centres. Most irAE were moderately severe (grade 2, 63%). The median time to onset was 57°days (interquartile range (IQR) 24–117). The ICI was withdrawn in 12 cases, 25 patients (83%) received corticosteroids, and five patients (17%) received immunosuppressant/immunomodulatory agents. The irAEs resolved fully or partially in 28 cases (93%). Conclusion Although systemic, immunohaematological and rheumatic diseases are rarely associated with ICI use, the prevalence is higher when two ICIs are combined. Corticosteroids are often effective and may enable the continued administration of ICIs. Studies designed to identify at-risk patients are warranted.

The use of immune checkpoint inhibitors (ICI) in melanoma and non-small cell lung cancer patients is associated with the onset of vitiligo. However, previous studies have suggested conflicting results on the conditions of occurrence of ICI-induced vitiligo. The aim of this study was to describe the occurrences and outcomes of several cases of ICI-induced vitiligo. A retrospective study was carried out using the French Pharmacovigilance Database (FPD) between the beginning of the commercialization of ICI in France and 1 January 2019, selecting for analysis the vitiligo reactions of patients due to treatment with ICI. Among the 95 case patients identified in the FPD, the median times to onset of vitiligo after the start of pembrolizumab, nivolumab and ipilimumab therapies were 5.4, 5.0, and 3.8 months, respectively. Furthermore, 37 patients (45%) discontinued ICI treatment due to disease progression. The median follow-up time of all patients was 33 months (interquartile range 2–56). This study provided an overall picture of ICI-induced vitiligo in daily medical practice on a large number of pharmacovigilance observations of case patients. Among the observations of ICI-induced vitiligo, the diagnosed cancer was melanoma for almost all patients. Most patients in the study experienced other associated adverse drug reactions (ADRs), such as colitis, pruritus, hypothyroidism, hyperthyroidism, thyroiditis, pancreatitis, and gastritis. Furthermore, our data suggest that the resolution of pembrolizumab- or nivolumab-induced vitiligo could be a marker of disease progression. Future studies evaluating vitiligo outcomes are warranted.

Purpose Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein 1 (PD-1), or its ligand PD-L1, are the mainstay of metastatic cancer treatment. Patients receiving these treatments may develop immune-related adverse events (irAEs). This study aimed to estimate the prevalence and describe the clinical patterns of moderate-to-severe ocular irAEs-associated with anti-PD-(L)1 treatment. Design Prospective case series. Methods This study included patients recruited via (1) a single-center prospective cohort and (2) a national pharmacovigilance registry between June 2014 and March 2018, and focused on patients with moderate-to-severe ocular irAEs following anti-PD-(L)1. All patients underwent a comprehensive ophthalmologic assessment. The main outcome measure was the prevalence of moderate-to-severe ocular irAEs. Results Of a total of 745 patients included in the prospective cohort, 3 developed moderate-to-severe ocular irAEs, providing a prevalence of 0.4% and an incidence of 0.7 per 1000 patient-months of treatment. An additional 5 cases of moderate-to-severe ocular irAEs were reported through the national registry. From these 8 patients, 5 presented with intraocular inflammation, 2 with ocular surface disease, and 1 with orbital myopathy. Five patients (62.5%) experienced additional extraophthalmologic irAEs. Ocular irAEs led to permanent discontinuation of anti-PD-(L)1 in 4 patients. Treatment by local and/or systemic corticosteroids allowed resolution or control of the ocular symptoms in 7 of 8 patients. Conclusion Although uncommon, anti-PD-(L)1-associated ocular complications may be sight-threatening and lead to discontinuation of anti-PD-(L)1 treatments. Patients complaining of eye problems while receiving ICI treatment should immediately be seen by an ophthalmologist.

Importance Although immune checkpoint inhibitors (ICIs), such as anti–PD-1 (programmed cell death 1) or anti–PD-L1 (programmed cell death 1 ligand 1), have proved effective in treating many cancers, patients receiving ICIs may experience immune-related adverse events (irAEs). Little evidence exists on the safety of resuming these treatments after an irAE. Objective To investigate the safety of a rechallenge with anti–PD-1 or anti–PD-L1 immunotherapies after an irAE. Design, Setting, and Participants This cohort study of the safety of an ICI rechallenge involved consecutive adult patients (n = 93) who were referred to the ImmunoTOX assessment board at the Gustave Roussy cancer center in Villejuif, France, between August 1, 2015, and December 31, 2017. Data were analyzed from May 28 to November 25, 2018. Main Outcomes and Measures Incidence of a second irAE in patients who had a readministration of an anti–PD-1 or anti–PD-L1 inhibitor after an initial grade 2 or higher irAE. Characteristics of the patients and the irAEs were reviewed, and the primary end point was the rate of occurrence of second irAEs. Results A total of 93 patients were included, among whom 48 (52%) were female, and the median (range) age was 62.5 (33-85) years. The main cancer types or tumor sites were melanoma (31 [33%]), lung (15 [16%]), colorectal (8 [9%]), and lymphoma (8 [9%]). For the initial irAE, 43 grade 2 events (46%), 36 grade 3 events (39%), and 14 grade 4 events (15%) were found, presenting primarily as hepatitis (17 [18%]), skin toxic effect (14 [15%]), pneumonitis (13 [14%]), colitis (11 [12%]), or arthralgia (7 [7.5%]). Forty patients (43%) were rechallenged with the same anti–PD-1 or anti–PD-L1 agent. The rechallenged and non-rechallenged groups did not differ in terms of median (range) age (61 [34-84] years vs 63 [33-85] years;P = .37), time to initial irAE (5 [1-40] treatment cycles vs 3 [1-22] treatment cycles;P = .32), irAE severity (grade 2: 18 [47.5%] vs 27 [51%]; grades 3-4: 22 [52.5%] vs 26 [49%];P = .70), or steroid use (17 [42.5%] vs 32 [60%];P = .09). With a median follow-up period of 14 months, the same irAE or a different irAE occurred in 22 patients (55%). Shorter time to the initial irAE was linked to the occurrence of a second irAE (9 vs 15 weeks;P = .04). The second irAEs were not found to be more severe than the first. Conclusions and Relevance The risk-reward ratio for an anti–PD-1 or anti–PD-L1 rechallenge appears to be acceptable, although these patients require close monitoring; further investigation into rechallenge conditions through a prospective clinical trial is needed.

Additional file 2: Table S2. Antitumor response rates in patients with a pre-existing PNS (cohort 1).

International audience; BACKGROUND:Paraneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy.METHODS:We included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively.FINDINGS:Of the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45-88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1-2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1.INTERPRETATION:Our results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.

Background: Although immunotherapy is globally better tolerated than chemotherapy, immune checkpoint inhibitors may be associated with immune-related adverse events (irAEs) characterized by their diversity, unpredictability, and corticosteroid responsiveness. We investigate the ImmunoTOX meeting's activities, a multidisciplinary real life and case-by-case approach to manage irAEs, to capture the salient medical needs in the management immunological toxicities. Methods: The ImmunoTOX assessment board is an academic, multidisciplinary group of oncologists and organ specialists that was set up in April 2016 at Gustave Roussy cancer centre in France. It meets every two weeks to discuss the case-by-case management of patients presenting with irAEs. This report describes ImmunoTOX's meeting activities between April 6th, 2016, and January 2nd, 2019. Findings: Over the 32 months of study period, 398 requests concerning 356 patients were submitted to the ImmunoTOX board. The most common tumour types of patients were thoracic cancers (n=105, 29%), skin cancers (n=82, 23%), and renal carcinomas (n=28, 8%). The requests most frequently asked were causal link between immunotherapy and adverse event, (n=148, 37%), the possibility for retreatment after hold due to previous adverse event (n=109, 27%), the clinical management of complex situation (n=100, 25%), and the initiation of immunotherapy in patients with pre-existing comorbidities (n=41, 10%). The ImmunoTOX board found a relationship between immunotherapy and adverse event in 273 (77%) of the 356 patients. The organ systems most frequently involved by irAEs were the lung (n=58, 21%), gastrointestinal tract (n=36, 13%), liver or biliary tract (n=33, 12%), musculoskeletal system (n=27, 10%) and nervous system (n=23, 8%). The retreatment by immunotherapy after holding due to previous adverse event and the initiation of immunotherapy in patients with pre-existing autoimmune comorbidities, were assessed as precaution for use and not formally contraindication in 65% and 93% of the cases, respectively. Interpretation: The medical needs in the management of immune-related adverse events involve five salient organ systems, namely the lung, gastrointestinal, liver and biliary tract, musculoskeletal and nervous systems. Retreatment after holding due to previous adverse events and immunotherapy initiation in patients with autoimmune comorbidities were mostly assessed as precaution for use and not formal contraindication. A multidisciplinary and case by case approach can be helpful and complementary of general guidelines in the management of immunological toxicities. Clinical Registration Number: The study was registered with the French National Data Protection Commission (Commission Nationale de l’Informatique et des Libertes; reference: 2098694v0). Funding Statement: Gustave Roussy and the Gustave Roussy Immunotherapy Programme. Ethical Approval Statement: All the patients gave their verbal, informed consent to the publication of their anonymized data, and the study was approved by the institutional review board at Gustave Roussy (Villejuif, France).

Introduction La toxicite pulmonaire touche 3 a 7% des patients traites par immunotherapie et le traitement repose classiquement sur l’utilisation d’une corticotherapie orale. Toutefois, il existe peu de donnees detaillees portant sur les benefices de ce traitement. Methodes Etude monocentrique retrospective de patients traites par Ac anti-PD1 ou anti-PD-L1 avec toxicite pulmonaire ≥ grade2. Description des donnees cliniques, fonctionnelles et scanographiques avant/apres corticotherapie. Resultats Entre novembre 2016 et octobre 2019, 26 patients traites par immunotherapies ont presente une toxicite pulmonaire de grade ≥ 2 justifiant une corticotherapie orale. Parmi eux, 16 (62%) etaient des hommes et l’âge median etait de 65 [58–73] ans. Soixante-seize pour cent etaient exposes a un tabagisme. Les cancers faisant porter l’indication d’immunotherapie etaient principalement pulmonaires et melanomes metastatiques dans 11 (42%) et 6 (22%) des cas respectivement. La nature de l’immunotherapie etait un anti-PD1 en monotherapie dans 17 (65%). Les grades de toxicite etaient 2, 3 et 4 dans 22 (86%), 2 (7%) et 2 (7%), respectivement avec un delai moyen de survenue de 3,8 [2,4–8,4] apres l’institution de l’immunotherapie. Les motifs scanographiques dominants etaient consolidation, n = 12 (46%), verre depoli, n = 6 (23%) et infiltrats non specifiques, n = 8 (31%). La dose mediane de corticotherapie etait de 0,75 [0,5–1] mg/kg/j pour une duree mediane de 74 [51–150] jours. L’evaluation de la reponse au traitement montrait une resolution dans 12 (46%) cas, une amelioration dans 11 (42%) cas, une stabilite dans 1 (4%) cas et une aggravation chez 2 (8%) patients. Les donnees principales des epreuves fonctionnelles respiratoires montraient les evolutions suivantes : CVF passant de 3090 ± 660 mL a 3208 ± 1079 mL (p = 0,28) et DLCO passant de 54 ± 14% a 63 ± 17% (p = 0,03). Les plus grands benefices d’amelioration des parametres respiratoires etaient observes dans la population des patients avec consolidation (p = 0,007). Une reprise du traitement etait realisee chez 8 (32%) des patients, emaillee d’une recidive de toxicite dans 1 (12%) cas. Conclusion Le traitement des toxicites pulmonaires d’immunotherapie s’accompagne dans la grande majorite des cas d’une resolution ou d’une amelioration de l’atteinte. La DLCO apparait etre un outil pertinent de suivi. Les patients avec consolidation au scanner semblent les plus repondeurs au traitement, soulevant la question d’un raccourcissement de la duree du traitement dans ce sous-groupe.

Although treatment with immune checkpoint inhibitors (ICIs) is associated with better survival in many cancer settings, these therapeutics can induce immune-related adverse events (IrAEs).1 ,2 REISAMICi is a French, prospective, multicentre, academic registry sponsored by the Gustave Roussy Institute cancer centre. The objective is to better detect, document and manage IrAEs. Connective tissue diseases (CTD) have not previously been reported in patients treated with anti-PD1/PDL-1 agents. The REISAMIC registry was screened for reports of CTD. Of the 447 patients supervised in the REISAMIC registry, three have developed CTD: two cases of Sjogren's syndrome and one case of cryoglobulinemic vasculitis as a complication of suspected Sjogren's syndrome (table 1). A case of ANA+ myositis registered in REISAMIC by another investigating centre …

Background Patients (pts) living with cancer are exposed to higher risk for thrombotic event (TE). The thrombotic risk (TR) is related to cancer disease and could also be associated with anti-cancer drugs such as antiangiogenic (AA). AA are currently being used more and more widely, alone or in combination (combo) with anti-PD(L)1 immunotherapies. It isn’t known whether combining anti-PD1 or PD-L1 with AA drug could increase the risk of TE. This study aimed at evaluating the TR in patients receiving a combo of AA and anti-PD1 or PD-L1. Methods Observational study conducted from January 2017 to September 2019 and retrospectively investigated all consecutive adults pts with cancer treated with a combo of AA plus anti-PD(L)1. All TE (venous and arterial) occurring following investigated treatment(s) and Khorana scores (KS) were analyzed. The TR was assessed in pts receiving the combo and compared with pts treated with single anti-PD(L)1. For the single anti-PD(L)1 cohort, data were collected from the pharmacovigilance Register of Severe Adverse Effects of Immunomodulatory Monoclonal Antibody in Cancer (REISAMIC). Data were compared between the combo and REISAMIC cohort using the Fisher’s exact and CHI2 tests (α = 5%). Results Overall, 83 pts receiving a combo of anti-PD(L)1 plus AA and 484 pts treated with anti-PD(L)1 were included. Both cohorts were similar for baseline characteristics: sex ratio, age, weight. Main tumor types in single anti-PD(L)1 vs combo were (in %): renal cell carcinoma, 5 vs 37; urothelial carcinoma, 3 vs 4; thoracic (lung or mesothelioma), 45 vs 32; gynecologic, 1 vs 8. The KS score was heterogeneous. It found 334/484 (69%) pts at intermediary or high risk of TE in the REISAMIC cohort and 70/83 (84%) in combo cohort (p = 0.006). In REISAMIC cohort, TE incidence was 7% compared to 18% in the combo cohort (p value=0.0006). Conclusion These results suggest that pts treated with combo AA plus anti-PD(L)1 seem to be more at risk of developing TE compare to single therapy anti-PD(L)1, according to a KS higher in this cohort. Further prospective study're warranted to investigate the risk of TE in pts receiving AA plus anti-PD(L)1 and to investigate the benefit of preventive anticoagulants therapy. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

We read with interest the study of Kostine et al describing rheumatic immune-related adverse events (irAE), which occur in 6.6% of patients treated for cancer by anti-programmed death-(ligand) 1 (PDL1).1 These new adverse effects pose significant challenges to patient care in terms of optimal management of these autoimmune damaging toxicities, while allowing effective antitumor therapy to continue. The PD(L)1 pathway is involved in the maintenance of immune tolerance, and the blockage of this axis by anticancer immunotherapy could trigger autoimmune diseases and especially lupus.2 3 We then searched in the pharmacovigilance register of our institution—the ‘ Registre des Effets Indesirables Severes des Anticorps Monoclonaux Immunomodulateurs en Cancerologie (REISAMIC)’—whether cases of drug-induced lupus erythematosus (DI-LE) were reported following anti-PD(L)1 immunotherapies. Between October 2013 and July 2017, five cases of DI-LE were recorded in REISAMIC. Given the number of patients having received anti-PD(L)1 during the same period (n=1044), the estimated incidence of DI-LE was 0.48%. All patients gave their written informed consent for the use of their data in this …

Background. Anti-programmed death (ligand) 1 (PD-(L)1) antibodies are novel immunotherapies for cancer. Anti-PD(L)1 can induce immune-related adverse events (irAEs), which most frequently affect the skin, endocrine glands, lung, liver and digestive tract, however all organs including the hematopoietic system can potentially be involved. Hematologic irAEs (hem-irAEs) have not yet been extensively characterized. This study based on a pharmacovigilance academic registry aims to provide a comprehensive report of hem-irAEs. Patients and methods. All grade 2 or higher hem-irAEs recorded in pharmacovigilance databases were recorded in this study over the period 2013-2018. Pharmacovilance database included REISAMIC (Registre des Effets Indesirables Severes des Anticorps Monoclonaux Immunomodulateurs en Cancerologie) and ImmunoTOX committee of Gustave Roussy, and the French nationwide CeReCAI registry (Centre de Reference des Cytopenies Auto-Immunes de l'adulte). Prevalence of hem-irAE was calculated in the prospective REISAMIC registry. The hem-irAE's severity was assessed according to the Common Terminology Criteria for Adverse Events (version 4.03). Results. Thirty-five patients (21 men and 14 women) with hem-irAEs related to anti-PD(L)1s were recorded. The prevalence of grade ≥2 hem-irAEs among patients treated with anti-PD(L)1s was estimated to 0.54%. The patients' median age was 65 years (range: 30-90), tumor types were melanoma (n=15), non-small-cell lung carcinoma (n=12), lymphoma (n=4), and other types (n=4). A concomitant medical history of chronic lymphocytic leukemia was found in 3 (9%) patients. The hem-irAEs were classified as neutropenia (n=9; 26%), auto-immune hemolytic anemia (n=9; 26%), immune thrombocytopenia (IT) (n=9; 26%), pancytopenia or aplastic anemia (n=5; 14%), bicytopenia (n=2; 6%) and pure-red cell aplasia (n=1; 3%). The maximum grade of severity reported was grade 2 in 3 (9%) patients, grade 3 in 8 (23%) patients and grade 4 in 24 (69%) patients. Two patients (6%) had a poor outcome and died in the course of the hem-irAE. Treatments given for the hem-irAE were steroids in 31 (89%) patients, granulocyte colony-stimulating factor in 13 (37%) patients, intravenous immunoglobulins in 6 (17%) patients and rituximab in 2 (6%) patients. The median time to onset from anti-PD(L)1 initiation was 10.1 weeks (range 0.9 - 198.0). With a median follow-up of 19 (range 2-180) weeks, the rate of resolution of hem-irAE was 67% (78% for IT and 40% for aplastic anemia patients, p=0.524). After resolution, 6/35 (17%) patients were rechallenged and 3 of them (50%) recurred the same hem-irAE. Conclusion. The clinical spectrum of hematologic irAE is wide and dominated by neutropenia, hemolytic anemia and immune thrombocytopenia. Aplastic anemia is rarer and present as a life-threatening condition. The prevalence of grade ≥2 hematologic irAEs following anti-PD(L)1 was 0.54%. The recurrence rate after rechallenge was 50%. Further prospective investigations are warranted to better detect and manage hematologic immune-related adverse events. Funding: This academic study was supported by Gustave Roussy Declaration of Interest: Nicolas Delanoy: none, Jean-Marie Michot: Advisory board: Bristol-Myers Squibb, Thibaut Comont: none, Nora Kramkimel: none, Julien Lazarovici : none, Romain Dupont : none, Stephane Champiat : none, Caroline Robert: Advisory board: Bristol-Myers Squibb, Charles Herbaux: none, Benjamin Besse : none, Claude Chahine : none, Aude Guillemin : none, Christine Mateus : none Ethical Approval: The REISAMIC registry was approved by ethical committee and the institutional review board of Gustave Roussy.

Background The use of immune checkpoint inhibitors (ICI) has revealed a new panel of tumor response and adverse events. Immune-related sarcoidosis-like reactions is frequently misdiagnosed as progressive or recurrent disease. This study aims to decipher the diagnosis hallmark of immune-related sarcoidosis-like reactions as well as its association with patients’ outcome. Methods From August 2014 and December 2018, in a centralized single center review, we retrospectively included all patients with histologically proven immune-related sarcoidosis-like reaction during a treatment with ICI in monotherapy or combination. 54 variables were retrospectively recorded: clinical (n = 17), biological (n = 11) and radiological (n = 26), as well as the objective response to treatment using the best overall response according to iRECIST. Results Out of 3,200 patients treated with ICI, a total of 18 histologically proven sarcoidosis were diagnosed. The majority were female patients (n = 11/18) treated for melanoma (n = 14/18) or clear renal cell carcinoma (n = 3/18). The median [range] time to diagnosis of a sarcoidosis-like reaction was 30 [5-126] weeks after ICI treatment initiation. On CT-scans, the most common radiological findings were: absence of radiographical progression of the primary tumor per RECIST1.1 (100%), bilateral symmetrical mediastinal lymphadenopathy (100%), symmetrical hilar lymphadenopathy (84%), and micronodules with lymphatic distribution (15%). On PET-CT, an extrathoracic glucose uptake was observed in 65% of patients. The sites involved were pleural involvement, abdominal lymph nodes, liver, and spleen. Patients with immune-related sarcoidosis-like reactions were objective responders according to iRECIST in 84% (n = 15/18) of patients, while only 15% had stable disease. Conclusions Immune-related sarcoidosis is characterized by the appearance of new mediastinal and/or pulmonary lesions, usually at 30 weeks after initiation of treatment, with stability of baseline target lesions. PET/CT demonstrated extrathoracic uptake in 65% of patients. This should not be misinterpreted as disease progressive since 84% of patients will show an objective response to ICI. Legal entity responsible for the study Ammari Sami. Funding Has not received any funding. Disclosure S. Champiat: Advisory / Consultancy: Astrazenaca; Advisory / Consultancy: BMS; Advisory / Consultancy: Janssen; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche. J. Michot: Advisory / Consultancy: BMS. All other authors have declared no conflicts of interest.

Objective Patients with autoimmune or inflammatory disease (AID) are susceptible to immune-related adverse events (irAEs) when treated with immune check-point inhibitors (ICIs). We decided to analyse the safety and effectiveness of anti-PD-1 antibodies in AID patients and look for an association between the presence of pre-existing AID and the clinical outcome. Methods In a prospective study of the REISAMIC registry of grade ≥2 irAEs occurring in ICI-treated patients, we studied the associations between pre-existing AID on one hand and irAE-free survival, overall survival and best objective response rate on the other. Results We identified 45 patients with 53 AIDs in REISAMIC. The cancer diagnoses included melanoma (n = 36), non–small-cell lung cancer (n = 6) and others (n = 3). The most frequent pre-existing AIDs were vitiligo (n = 17), psoriasis (n = 12), thyroiditis (n = 7), Sjogren syndrome (n = 4) and rheumatoid arthritis (n = 2). Twenty patients (44.4%) presented with at least one irAE: eleven of these were associated with a pre-existing AID (‘AID flare’). Treatment with anti-PD-1 antibodies was maintained in 15 of the 20 patients with an irAE. The IrAE-free survival time was significantly shorter in AID patients (median: 5.4 months) than in AID-free patients (median: 13 months, p = 2.1 × 10−4). The AID and AID-free groups did not differ significantly with regard to the overall survival time and objective response rate (p = 0.38 and 0.098, respectively). Conclusion In patients treated with anti-PD-1 antibody, pre-existing AID was associated with a significantly increased risk of irAEs. Our results indicate that cancer treatments with anti-PD-1 antibodies are just as effective in AID patients as they are in AID-free patients.

Introduction Les anti-programmed cell death 1 (anti-PD-1) sont actuellement utilises pour de nombreux types de cancer, et leur profil d’innocuite est domine par les evenements indesirables lies a l’immunite (ei-li). La description de leur tolerance dans les etudes cliniques actuelles contient la frequence et la gravite de chaque evenement indesirable individuellement, mais ne tient pas compte de l’effet cumulatif des toxicites. Le but de cette etude est d’evaluer les toxicites cumulees des patients traites par anti-PD-1 ou anti-PD-L1. Patients et methodes La toxicite multiple (multitox) a ete definie comme la survenue chez un meme patient de plus de 2 evenements indesirables lies a l’immunite de grade superieur ou egal a 2, selon la CTCAE v4,03. Les donnees analysees proviennent du registre REISAMIC qui enregistre prospectivement les donnees de pharmacovigilance de tous les patients traites par anti-PD-1 ou anti-PD-L1 donne comme traitement standard sur la periode janvier 2015 a decembre 2017 a Gustave Roussy, Villejuif, France. Resultats Parmi les six cent quarante-trois patients (pts) inclus dans REISAMIC, cinquante-huit (9 %) patients presentaient une multitox apres le debut du traitement anti-PD-1. Les patients ayant un multitox avaient un âge moyen de 62,7 ans et 54 % des patients etaient des femmes. L’indication de l’anti-PD-1 etait le melanome (n = 49), le cancer du poumon non a petites cellules (n = 7), autre types de tumeur (n = 2). Les patients recevaient l’anti-PD-1 pembrolizumab (n = 38) ou nivolumab (n = 14). La duree totale d’exposition au traitement anti-PD-1 etait de 31,3 [15,1–54,0] semaines. Le premier ei-li et le second ei-li se sont produits dans un delai median de 8 et 18 semaines apres la premiere administration de l’anti-PD-1, respectivement. Le nombre moyen d’ei-li par patient etait de 2,43 [2–5]. La distribution de l’organe affecte par le premier ei-li etait cutanee (n = 42 pts), suivi de la thyroide (20 pts), gastro-intestinal (14 pts), pancreas (11 pts), foie (10 pts), rhumatologique (8 pts), rein (3), ophtalmique (2 pts) ou pulmonaire (1 pt). Vingt-huit (48 %) pts ont du arreter l’anti-PD-1 pour cause de toxicite et quatorze (24 %) pour une maladie tumorale progressive. Sept patients (12 %) ont arrete leur traitement anti-PD-1 en situation de reponse complete oncologique. Les symptomes relatifs a l’ei-li ont disparu spontanement chez 30 patients. Vingt-deux pts ont recu des corticosteroides systemiques et 6 patients ont recu un traitement immunosuppresseur ou immunomodulateur par inhibiteurs du TNF alpha (n = 3 pts), methotrexate (n = 2 pts) ou hydroxychloroquine (n = 1 pt). Au cours du suivi des patients ayant eu une multitox, dix-sept deces sont survenus dont un en lien avec le traitement anti-PD-1. Le taux de reponse global anti tumorale etait de 67 % et la duree moyenne de reponse etait de 16 mois [1,3–30] au cours de la periode de suivi de 517 jours [IQR 98-945]. Conclusion La toxicite multiple liee a l’immunite est un evenement survenant chez 9 % des patients traites par anti-PD-1. La multi-toxicite pourrait etre consideree comme un nouveau marqueur pour evaluer la tolerance des anti-PD-1.

Introduction Les anticorps anti-programmed cell death 1 (PD-1) et anti-programmed cell death ligand (PD-L1) sont de nouvelles immunotherapies contre le cancer pouvant induire des evenements indesirables lies a l’immunite (eili). Les eili miment des reactions auto-immunes et peuvent impliquer theoriquement tous les organes, y compris le systeme hematopoietique. Jusqu’a present, les effets indesirables hematologiques lies a l’immunite (hem-eili) n’ont pas ete caracterises de maniere extensive. Cette etude vise a fournir une frequence et une description clinique des cytopenies induites par anti-PD-1 ou anti-PD-L1. Patients et methodes Les criteres d’eligibilite etaient tous les patients consecutifs adultes ayant presente un hem-eili de grade superieur ou egal a 2, induit par les anti-PD-1 ou anti-PD-L1 et enregistres dans les bases de donnees francaises de pharmacovigilance sur la periode oct. 2013–jun. 2018. Les bases de donnees de pharmacovilance etaient celles de REISAMIC (Registre des effets indesirables severes des anticorps monoclonaux immunomodulateurs en cancerologie), du comite ImmunoTOX de Gustave Roussy et du registre CeReCAI (Centre de reference des cytopenies auto-immunes de l’adulte). Le critere d’evaluation principal etait la description clinique avec la frequence des hem-eili. Resultats Sur les 948 patients depistes (745 dans REISAMIC, 190 chez ImmunoTOX et 13 chez CeReCAI), trente-cinq patients (21 hommes et 14 femmes) ont ete retenus avec un hem-eili en lien avec un anti-PD-1 ou PD-L1. Quatre des 745 patients suivis de maniere prospective dans le registre REISAMIC presentaient un hem-eili, ce qui conduisait a une estimation de la frequence de grade ≥ 2 hem-eili a 0,54 %. Parmi les 35 patients ayant un hem-eili, l’âge median etait de 65 ans (extremes : 30-90), les types de tumeurs etaient : melanomes (n = 15), carcinomes pulmonaires non a petites cellules (n = 12), lymphomes (n = 4) et autres types (n = 4). Des antecedents medicaux concomitants de leucemie lymphoide chronique ont ete observes chez 3 (9 %) des 35 patients. Les hem-eili parmi les 35 patients etaient repartis en neutropenie (n = 9, 26 %), anemie hemolytique auto-immune (n = 9, 26 %), thrombocytemie immunologique (n = 9, 26 %), pancytopenie ou aplasie medullaire (n = 5, 14 %), bi-cytopenie (n = 2, 5 %) et erythroblastopenie (n = 1, 3 %). Deux patients sont decedes d’une neutropenie febrile en cours de traitement par anti-PD-1. Le delai median d’apparition de l’hem-eili a partir de l’initiation l’anti-PD-1 ou anti-PD-L1 etait de 10,1 semaines (intervalle de 0,9 a 198,0). Une resolution de l’hem-eili etait observee chez 21 (60 %) des 35 patients. Conclusion Les evenements indesirables hematologiques lies a l’immunite induits par les anti-PD-1 ou les anti-PD-L1 sont des evenements rares et potentiellement severes. La neutropenie, l’anemie hemolytique auto-immune, la thrombocytemie immunologique et l’aplasie medullaire dominent le tableau clinique. De futures etudes sont necessaires pour etudier leur detection plus precoce et une meilleure prise en charge.

Immune checkpoints (ICPs) as PD-1, CTLA4, constitute one of the most important mechanisms for regulating activation of the immune system. Immune checkpoints have a major role in infectious disease because they help to limit harmful inflammatory responses (as notably seen in tuberculosis). However, ICP overexpression favours an immunosuppressive microenvironment, in various cancers and in chronic infections. Thus, ICPs inhibitors (ICPIs) as anti-PD-1 agents constitute a valuable means of boosting pathogen-specific immune responses or countering an immunosuppressive microenvironment. The effectiveness of this strategy has been widely demonstrated in oncology where impressive overall survival rates have been observed for a growing number of metastatic cancers. However, infections have been reported in patients taking ICPIs. These infections can be favoured by steroids given to treat immune-related adverse events which are the main safety concern of ICPI use. Moreover, we show in this report reactivation of tuberculosis in patients treated with anti-PD-1. We discuss the mechanisms involved and suggest an immune reactivation syndrome. Cancer patients treated with ICPIs are likely to receive corticosteroids and immunosuppressants with a risk of infectious complications. Although tuberculosis seems to be rare, its reactivation may be favoured by the specific action of anti PD-1 agents. Considering an IGRA test before initiation of an ICPI in all subjects, and specifically proposing it as a mandatory measure for all subjects with lymphoma, lung cancer and/or medical history of exposure to tuberculosis could be valuable.

Objectives Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have demonstrated improved survival for multiple cancers. However, these new drug classes have led to increased immune-related adverse events (IrAE). Rheumatic IrAEs have not been well described in clinical trials. We report here cases of rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI treatment. Methods This was a retrospective study of patients receiving an ICI in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of RA or PMR. Results In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression. Conclusions This is the first description of RA occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.

Antiprogrammed death-1 (anti-PD1) and antiprogrammed death ligand-1 (anti-PD-L1) antibodies are effective checkpoint inhibitors that stimulate the immune system against many types of cancers. The flip side of these immunotherapies is the generation of immune-related adverse events, which can theoretically affect all organs. Among these side effects, lipase increase is frequently observed; however the meaning of this biological abnormality remains poorly understood. We investigate in this case study all the lipase increases greater or equal to grade 2 that occurred in patients receiving anti-PD-1 or anti-PD-L1 treatments, to determine their biological and clinical significance. Twenty-one patients were retained with lipase increase related to the immune checkpoint inhibitor. Most of them (71%) were treated for a metastatic melanoma. The peak of lipase increase was observed at a median of 2.8 (range, 0.4-11.4) months after the initiation of the anti-PD1 or anti-PD-L1 treatment, which correlates with cycle 5 of treatment. Three of 21 patients (14%) had a clinical or radiologic immune-related pancreatitis that led to a permanent discontinuation of the treatment. In 15 of 21 (71%) patients, the lipase increase was not considered as clinically significant, and the treatment was continued without complications. The 3 remaining patients discontinued the treatment for progressive disease. These data indicate that lipase increase related to anti-PD1 or anti-PD-L1 is not associated with a significant clinical event in most cases. On the basis of these data, we propose that lipase increase in an asymptomatic patient and without radiographic abnormalities of the pancreas can be reasonably regarded as a not clinically significant event, allowing the continuation of the anti-PD-1 or anti-PD-L1 treatment.

Background The adverse events generated by immunotherapies are characterized by their wide diversity, unpredictability and reversibility by steroid used, and requires a delicate management. A collaborative organization of immunological toxicology management called ImmunoTOX (iTox) has been set up at Gustave Roussy to support physicians in their routine practice. Methods Descriptive study of all consecutive advice given by the ImmunoTOX committee at Gustave Roussy from Apr 6, 2016 to Jan 2, 2019. The iTox committee organizes a multidisciplinary meeting twice a month with organs specialists, oncologists, pharmacovigilants, radiologists, around prescribing physicians facing difficult to manage or unusual immune related adverse events (irAEs). Results The iTox committee delivered 398 pieces of advice for 356 patients (207 men and 149 women) receiving immunotherapies. Patients received anti-PD1 (55%) or anti-PDL1 (6%) given in monotherapy, or in combination with anti-CTLA4 (11%), or in combination with targeted therapy (11%), or another immunotherapy regimen (17%). The queries patterns for advices questioned the causal link (37%), rechallenge over G ≥ 3 (27%), or a complex clinical management (25%) or the possibility of initiating immunotherapy in a patient with comorbidities (10%). The iTox committee retained a causal link between the adverse event and immunotherapy in 273 of the 356 patients (77%). Of these 273 patients with irAEs, the grade of maximum severity was grade 1-2 in 112 (41%), grade 3-4 in 148 patients (54%), and irAE ultimately resulted in death in 13 (5%) patients. The organ categories mostly involved by requests were lung (21%), gastrointestinal (13%), liver (12%), musculoskeletal (10%) and neurological (8%). Over the study period, the 273 patients with irAEs led to 313 requests for advice that recommended systemic corticosteroids (n = 193, 62%) or a second immunomodulatory agents (n = 45, 14%). Conclusions These results should help cancer hospitals to further appreciate the current medical needs in their management of irAEs. By a specific management, patients with autoimmune comorbidities and rechallenge over G ≥ 3 could be regarded as precautions for use and not absolute contraindications. Clinical trial identification Commission Nationale de l’Informatique et des Libertes N°2098694v0. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure J. Michot: Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Cellgene; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (institution): Abbvie; Honoraria (institution): Xencor. J. Soria: Full / Part-time employment: MedImmune. C. Massard: Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (institution), Advisory / Consultancy, Leadership role: Lilly. All other authors have declared no conflicts of interest.

Introduction Les patients atteints de maladies auto-immunes ou inflammatoires (MAI) traitees par des inhibiteurs de check-points immunitaires (ICI) pour la prise en charge d’un cancer metastatique ou localement avance sont intrinsequement susceptibles de developper des effets indesirables immunologiques (irAE). Nous avons mene cette etude pour decrire et analyser la tolerance et l’efficacite des ICI chez les patients atteints de MAI. Patients et methodes Nous avons mene une etude prospective decrivant et analysant l’efficacite et la tolerance des ICI chez les patients atteints de MAI inclus dans le registre REISAMIC (« Registre des evenements indesirables severes des anticorps monoclonaux immunomodulateurs en oncologie ») entre le 1er juin 2014 et le 31 decembre 2016. Nous avons compare les survies sans irAE et globale ainsi que les taux de reponses objectives des patients ayant une MAI par rapport a des patients controles sans MAI. Resultats Nous avons decrit 54 patients atteints de MAI traites par ICI et analyse 45 d’entre eux inclus dans REISAMIC, qui ont ete compares a 397 patients controles sans MAI. Les patients etaient atteints de melanome dans 40 cas (74,1 %), de cancer pulmonaire dans 10 cas (22,2 %) et d’autre cancer dans 4 cas. Les MAI preexistantes etaient du vitiligo (n = 17, 31,5 %), du psoriasis cutane (n = 13, 32,5 %), des thyroidites auto-immunes (n = 8, 20 %), des syndromes de Sjogren (n = 4, 10 %), des polyarthrites rhumatoides (n = 4, 10 %), des cytopenies auto-immunes (n = 3, 17,5 %), des spondyloarthrites (n = 2, 5 %), des scleroses en plaques (n = 2, 5 %) des maladies de Verneuil (n = 2, 5 %), et chacune dans un cas : une myasthenie, une pseudopolyarthrite rhizomelique, une polyarterite noueuse, une sarcoidose, un lupus cutane chronique, un diabete de type 1, un syndrome nephrotique idiopathique, une nephrite tubulo-interstitielle aigue et un syndrome des abces aseptiques. Dans 23 cas (42,6 %), les patients ont presente, au moins, un irAE de grade 2. Treize irAE (57 %) etaient des poussees de la MAI preexistantes : nous avons observe des augmentations de psoriasis cutane, le developpement d’une polyarthrite psoriasique avec un psoriasis cutanee pustuleux, des extensions de vitiligo, des hyperthyroidies, des exacerbations de syndrome de Sjogren, une crise de myasthenie, une polyarthrite et une colite severe avec abces mesenteriques. Onze patients ont developpe des irAE qui n’etaient pas evocatrices de la MAI preexistante. Trente-trois patients (61,1 %) etaient vivants lors du dernier suivi avec un delai median de 6,3 mois (intervalle 4,1–9,7 mois). Dix-neuf patients (35,2 %) poursuivaient l’ICI au dernier suivi avec un temps median de 4,9 mois (intervalle 3,4–7 mois). La survie sans irAE etait plus courte chez les patients atteints de MAI (mediane = 5,4 mois) par rapport aux patients sans MAI (mediane = 13 mois, p = 2,1,10–4). La survie globale chez les patients atteints de MAI n’etait pas differente de celle observee chez les patients sans MAI (p = 0,38). Nous n’avons pas observe de difference significative entre les taux de reponse objective chez les patients atteints de MAI (38 %) par rapport aux controles (28 %) (OR = 0,51, IC 95 % [−1,54–0,077] ; p = 0,098). Conclusion L’administration d’un anticorps monoclonal inhibiteur de check-points immunitaires a des patients atteints de MAI est associee a un sur-risque d’effets indesirables immunologiques. Cependant, dans cette etude la survie globale des patients atteints d’une MAI, ainsi que le taux de reponse objective aux traitements n’etaient pas differents de ceux des patients controles. Ces elements soulignent l’importance des reseaux de collaborations entre les medecins oncologues, specialistes des organes et internistes pour ameliorer la qualite des soins des patients.

Background. Anti-programmed death (ligand) 1 (PD-(L)1) antibodies are novel immunotherapies for cancer. Anti-PD(L)1 can induce immune-related adverse events (irAEs), which most frequently affect the skin, endocrine glands, lung, liver and digestive tract, however all organs including the hematopoietic system can potentially be involved. Hematologic irAEs (hem-irAEs) have not yet been extensively characterized. This study based on a pharmacovigilance academic registry aims to provide a comprehensive report of hem-irAEs. Patients and methods. All grade 2 or higher hem-irAEs recorded in pharmacovigilance databases were recorded in this study over the period 2013-2018. Pharmacovilance database included REISAMIC (Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie) and ImmunoTOX committee of Gustave Roussy, and the French nationwide CeReCAI registry (Centre de Référence des Cytopénies Auto-Immunes de l'adulte). Prevalence of hem-irAE was calculated in the prospective REISAMIC registry. The hem-irAE's severity was assessed according to the Common Terminology Criteria for Adverse Events (version 4.03). Results. Thirty-five patients (21 men and 14 women) with hem-irAEs related to anti-PD(L)1s were recorded. The prevalence of grade ≥2 hem-irAEs among patients treated with anti-PD(L)1s was estimated to 0.54%. The patients' median age was 65 years (range: 30-90), tumor types were melanoma (n=15), non-small-cell lung carcinoma (n=12), lymphoma (n=4), and other types (n=4). A concomitant medical history of chronic lymphocytic leukemia was found in 3 (9%) patients. The hem-irAEs were classified as neutropenia (n=9; 26%), auto-immune hemolytic anemia (n=9; 26%), immune thrombocytopenia (IT) (n=9; 26%), pancytopenia or aplastic anemia (n=5; 14%), bicytopenia (n=2; 6%) and pure-red cell aplasia (n=1; 3%). The maximum grade of severity reported was grade 2 in 3 (9%) patients, grade 3 in 8 (23%) patients and grade 4 in 24 (69%) patients. Two patients (6%) had a poor outcome and died in the course of the hem-irAE. Treatments given for the hem-irAE were steroids in 31 (89%) patients, granulocyte colony-stimulating factor in 13 (37%) patients, intravenous immunoglobulins in 6 (17%) patients and rituximab in 2 (6%) patients. The median time to onset from anti-PD(L)1 initiation was 10.1 weeks (range 0.9 - 198.0). With a median follow-up of 19 (range 2-180) weeks, the rate of resolution of hem-irAE was 67% (78% for IT and 40% for aplastic anemia patients, p=0.524). After resolution, 6/35 (17%) patients were rechallenged and 3 of them (50%) recurred the same hem-irAE. Conclusion. The clinical spectrum of hematologic irAE is wide and dominated by neutropenia, hemolytic anemia and immune thrombocytopenia. Aplastic anemia is rarer and present as a life-threatening condition. The prevalence of grade ≥2 hematologic irAEs following anti-PD(L)1 was 0.54%. The recurrence rate after rechallenge was 50%. Further prospective investigations are warranted to better detect and manage hematologic immune-related adverse events. Disclosures Herbaux: Gilead Sciences, Inc.: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Maerevoet:abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grant; roche: Other: travel grant; takeda: Membership on an entity's Board of Directors or advisory committees, Other: travel grant; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Ribrag:Servier: Consultancy, Honoraria; Amgen: Research Funding; BMS: Consultancy, Honoraria, Other: travel; Incyte Corporation: Consultancy; Infinity: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; MSD: Honoraria; Gilead: Consultancy, Honoraria; Roche: Honoraria, Other: travel; argenX: Research Funding; epizyme: Consultancy, Honoraria; pharmamar: Other: travel.

Introduction Les immune check-points inhibiteurs (ICPi), anticorps monoclonaux anti-CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), anti-PD-1 ( Program Death 1 ) et anti-PD-L1 ( Program Death Ligand 1 ) revolutionnent la prise en charge des patients atteints de cancer metastatiques ou d’hemopathies lymphoides. Des les essais therapeutiques precoces de l’ipilimumab (anti-CTLA-4) les cliniciens ont ete confrontes a des effets indesirables dit immun medie ou « immune related adverse events » (irAE), se manifestant par la survenue de toxicites evoquant des maladies auto-immunes ou inflammatoires (MAI 2 ). Les malades prealablement atteints de MAI 2 sont ainsi exclus des essais precoces mais le benefice des ICPi dans des pathologies cancereuses metastatiques incitera a proposer ces traitements a une large population de patients. Nous souhaitons etudier la tolerance et l’efficacite des ICPi chez des patients ayant un antecedent de MAI 2 . Patients et methodes Nous avons realise une etude retrospective observationnelle des patients ayant un antecedent de MAI 2 traites par ICPi inclus dans le registre REISAMIC (Registre des effets indesirables severes des anticorps monoclonaux immunomodulateurs en cancerologie) incluant 414 patients ou identifies par un appel a observations. Resultats Vingt-sept patients ont ete retenus parmi 53 identifies dans REISAMIC avec un antecedent de MAI 2 et un patient du CHU Pitie Salpetriere. Les MAI 2 retenues etaient un psoriasis cutane (7/27 patients), un rhumatisme inflammatoire chronique (5/27), un syndrome de Sjogren primaire (3/27), une thyroidite auto-immune (3/27), une cytopenie auto-immune (2/27), une sclerose en plaque (2/27), une myasthenie (1/27), un syndrome des abces aseptiques (1/27), une periarterite noueuse (1/27), un syndrome nephrotique idiopathique complique d’insuffisance renale terminale (1/27) et un vitiligo (1/27). L’indication de l’ICPi etait un melanome dans 15/27 cas, un cancer pulmonaire non a petite cellule dans 6/27, un carcinome epidermoide cutane dans 3/27 cas, un carcinome urothelial de vessie, un angiomyolipome renal et un carcinome de Merkel dans 1/27 cas. L’ICPi prescrit etait un anticorps monoclonal anti-PD-1 dans 20 cas (76,9 %), anti-CTLA-4 dans 4 cas (14,3 %) et anti-PD-L1 dans 3 cas (12 %). L’avis d’un medecin interniste ou specialiste d’organe a ete sollicite avant la prescription de l’ICPi chez 19/27 patients : il donnait des conseils concernant les modalites de surveillance (9/27), le maintien du traitement de la MAI 2 (5/27) et l’arret d’un traitement immunosuppresseur (1/28). Il n’a pas ete introduit de corticotherapie ou de traitement immunosuppresseur en prevision de l’ICPi. Le suivi median des patients apres la premiere administration de l’ICPi etait de 5,4 mois (0,7–56,4 mois). Huit patients (29,6 %) ont eu un benefice therapeutique sans toxicite. Le taux d’irAE etait de 8/27 cas (29,6 %) contre 98/388 cas (25,3 %) parmi les autres patients inclus dans REISAMIC. Les patients ayant presente un irAE avaient une MAI 2 symptomatique ou des manifestations cliniques dans l’annee precedant la premiere perfusion d’ICPi dans 50 % des cas versus 31,6 % chez ceux sans toxicite. Le delai median de survenue apres C1 etait de 2,2 mois (1–2,9). Les irAE etaient une aggravation de psoriasis cutanee dans 3 cas associee a l’apparition d’un rhumatisme inflammatoire de type psoriasique dans 2 cas et une hypophysite dans 1 cas, une ileite abcedee mortelle chez une patiente atteinte d’un syndrome des abces aseptique (1 cas), une colite aigue (1 cas), une colite lymphocytaire (1 cas), une nephrite tubulo-interstitielle aigue compliquant un syndrome de Sjogren (1 cas), et une crise myasthenique oculomotrice (1 cas). Le traitement de l’irAE consistait en une corticotherapie systemique dans 7/8 cas avec l’arret de l’ICPi dans 5/8 cas. Il n’a pas ete introduit de traitement immunosuppresseur. La mortalite globale etait de 50 % : 1/14 lie a un irAE, 12/14 lies a la progression de la maladie et 1/14 d’une cause non oncologique (AVC ischemique). Discussion Les patients atteints de MAI 2 ont probablement un risque plus important d’irAE. Il s’agit cependant de maladies tres heterogenes dont les mecanismes physiopathologiques ne sont pas superposables et pour lesquels les niveaux de risques d’irAE sont probablement differents. Le rapport benefice-risque de ces nouveaux traitements doit pouvoir etre evalue le plus precisement possible afin de beneficier a un maximum de malades. Conclusion Un registre plus large de patients atteints de MAI 2 est necessaire pour preciser leurs modalites d’utilisation.