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.
Prospective case series.
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.
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.
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.
•Prevalence of moderate-to-severe ocular complications of anti PD-(L)1 is 0.4% and incidence is 0.7 per 1000 patient-months.•Main clinical patterns include intraocular inflammation, ocular surface disease, and orbital myopathy.•Ocular complications usually start early after the onset of treatments but can be delayed.•Orbital myopathies may be associated with life-threatening myocarditis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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.
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.
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.
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.
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.
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), Sjögren 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).
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.
•In patients treated with anti-PD-1 antibodies, the presence of a pre-existing auto-immune or inflammatory disease is associated with a higher risk of immune-related adverse events.•Immunotherapies provide similar levels of effectiveness (overall survival) in patients with and without pre-existing auto-immune or inflammatory disease.•Half of these immune-related adverse events are flares or manifestations of the pre-existing autoimmune or inflammatory disease.•Anti-PD-1 antibodies can be maintained in 75% of the patients despite the immune-related adverse events.
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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.
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 the ICI discovery cohort (
= 37), SIP cut-off was 39.5%, 27% of patients were SIP
. In the ICI validation cohort (
= 46), SIP
status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%,
= 0.04), median progression-free survival (PFS) 1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months,
= 0.009 and median overall survival, OS 2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months,
= 0.02. SIP
status was significantly associated with circulating specific immunephenotypes,
lower CD8
T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population (
= 83), SIP
status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (
= 61), 11% of patients were SIP
. SIP status did not correlate with outcomes upon PCT.
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.
.
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.
•Incidence of grade ≥ II immune related adverse events (irAEs) is higher in older.•Older patients are more prone to having multiple irAEs.•Prescribers should monitor closely older patients during anti-PD(L)1 treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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.
•ICI readministration in ICI-related sarcoidosis was not specifically evaluated.•Patients with lung involvement of ICI-related sarcoidosis have a mild presentation.•No patient presented with extrathoracic involvement only.•There was no severe extrathoracic disease.•Stopping ICI in the setting of ICI-induced sarcoidosis is not always necessary.
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Checkpoints inhibitors anti-programmed death 1 (PD1) and anti-programmed death ligand 1 (PD-L1) restore immunity against tumour. By their mechanism of action, they could induce immune-related adverse ...events (irAEs) that can theoretically involve all organs. These irAEs, especially those that are rare, remain incompletely described. Immune-related eosinophilia has been described with ipilimumab and was interestingly associated with favourable response to immunotherapy. We report here the first series of patients who experienced immune-related eosinophilia due to anti-PDI or anti-PD-L1 antibodies. Immune-related eosinophilia is a new biological immune-related adverse effect with anti-PD-1 or anti-PD-Ll. To the best of our knowledge, we report here the first case series of immune-related eosinophilia with anti-PDl or anti-PD-Ll. Importantly, we show that kinetics of leukocyte changes was restricted to the eosinophil lineage. This immune-related eosinophilia was rare (estimated frequency of 2.9%), began at 3.0 months with a peak achieved at 6.4 months. Patients with immune-related eosinophilia remain asymptomatic. Larger prospective studies are required to search for a link with favourable anti-tumour response.
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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.
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.
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.
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.
•Infections were searched for in 200 records from patients treated with ICIs.•The infection rate was 18%, without any severe or opportunistic infection.•Twenty-one patients (58.3%) had a lung infection.•The occurrence of an infection was not associated with immunosuppressant use.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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.
Participants were recruited via Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC)11Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie, managed by the Gustave Roussy cancer centre (Villejuif, France). 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.
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%), Sjögren 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 Sjögren 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%).
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 prevalence of systemic immune-related adverse events (irAEs) associated with anti-Programmed Cell Death-1 (PD1)/anti-Programmed Cell Death Ligand-1 (PD-L1) use is low but increases with combination therapy.•Oncologists have to be able to recognise systemic irAEs associated with anti-PD1/anti-PD-L1 agents.•Systemic irAEs usually respond well to treatment with corticosteroids.•Biological profiling might help to identify patients at risk of developing systemic irAEs.
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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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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