Impact of immunosuppressive agents on the management of immune-related adverse events of immune checkpoint blockers.

BACKGROUND: Immune checkpoint blockers (ICBs) can induce immune-related adverse events (irAEs) whose management is based on expert opinion and may require the prescription of steroids and/or immunosuppressants (ISs). Recent data suggest that these treatments can reduce the effectiveness of ICBs. OBJECTIVE: To investigate the relationship between the use of steroids and/or ISs and overall survival (OS) and progression-free survival (PFS) among ICB-treated patients with an irAE. METHODS: We prospectively collected data from the medical records of patients with solid tumors or lymphoma in the French REISAMIC cohort and who had been treated with ICBs between June 2014 and June 2020. RESULTS: 184 ICB-treated patients experienced at least one Common Terminology Criteria for Adverse Events grade ≥ 2 irAE. 107 (58.2%) were treated with steroids alone, 20 (10.9%) with steroids plus IS, 57 (31.0%) not received steroids or IS. The median OS was significantly shorter for patients treated with steroids alone (25.2 months [95% confidence interval (CI): 22.3-32.4] than for patients treated without steroids or IS (63 months [95%CI: 40.4-NA]) and those receiving an IS with steroids (53.4 months [95%CI: 47.3-NA]) (p < 0.001). The median PFS was significantly shorter for patients treated with steroids alone (17.0 months [95%CI: 11.7-22.9]) than for patients treated without steroids or IS (33.9 months [95%CI: 18.0-NA]) and those receiving an IS with steroids (41.1 months [95%CI: 26.2-NA]) (p = 0.006). There were no significant intergroup differences in the hospital admission and infection rates. CONCLUSION: In a prospective cohort of ICB-treated patients, the use of IS was not associated with worse OS or PFS, contrasting with the use of steroids for the management of irAEs.

Immunosuppressant mycophenolate mofetil for patients with steroid-refractory immune-related hepatitis induced by checkpoint inhibitors in oncology.

BACKGROUND: Immune-checkpoint inhibitor (ICI) hepatitis, which does not improve with steroids and requires additional immunosuppressant, is defined as steroid-refractory ICI hepatitis. The outcome of patients with steroid-refractory ICI hepatitis remains poorly determined. Herein, we investigated the incidence, clinical features, and outcome of patients treated with second-line immunosuppressant for steroid-refractory ICI hepatitis. METHODS: This is a retrospective analysis of patients who presented ICI hepatitis from 1st June 2016 to 30th September 2022. Steroid-refractory ICI hepatitis was defined as no clinical and biological improvement after systemic steroid therapy ≥1 mg/kg/d. Main objectives were to assess the frequency and risk factors associated with steroid-refractory ICI hepatitis and to evaluate the efficacy of second-line immunosuppressants. RESULTS: In total, 130 patients with grade ≥3 ICI hepatitis were screened, of them 60 (46.2%) were treated with systemic steroids. In total, 11/130 (8.5%) had steroid-refractory hepatitis. Statistically significant factors associated with steroid-refractory hepatitis included previous liver comorbidities (54.5% versus 11.6%; p < 0.01), hyperbilirubinemia (p < 0.001), and general symptoms (fever, jaundice, ascites, and/or encephalopathy) associated with hepatitis (72.7% versus 30.8%; p = 0.015). The 11 patients with steroid-refractory hepatitis were treated with mycophenolate mofetil. In total, resolution or return to grade ≤1 for hepatitis was observed in 81.8% (9/11) of patients. CONCLUSIONS: Steroid-refractory ICI hepatitis accounted for 8.5% of patients with grade ≥3 immune-related hepatitis and was statistically associated with previous liver comorbidities, hyperbilirubinemia, and general symptoms. Mycophenolate mofetil was a suitable option of therapy for steroid-refractory ICI hepatitis.

Protective effect of obesity on survival in cancers treated with immunotherapy vanishes when controlling for type of cancer, weight loss and reduced skeletal muscle.

INTRODUCTION: 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. METHODS: 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. RESULTS: In the univariable analysis of the entire population, overweight/obesity (BMI ≥ 25 kg/m2) was associated with longer survival (p < 0.01); however, this effect was limited to NSCLC (p < 0.01) and was absent in melanoma. Weight loss (WL) and reduced skeletal muscle mass were observed in patients within all BMI categories. WL was associated with shorter survival in multivariable analysis in both tumour sites (p < 0.01), and for NSCLC, BMI lost significance when WL was included (p = 0.13). In models further adjusted for CT-defined skeletal muscle mass, WL retained significance for both tumour types (p < 0.01), and reduced skeletal muscle only for NSCLC (p = 0.02) was associated with shorter survival. WL retained significance when biomarkers (lactate dehydrogenase enzyme, albumin and derived neutrophil to lymphocyte ratio) were added to the multivariable model. CONCLUSIONS: The 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).

Immune-related generalised oedema - A new category of adverse events with immune checkpoint inhibitors.

BACKGROUND: Generalised oedema was occasionally reported associated with immune checkpoint inhibitors (ICPIs). The purpose of this study is to investigate immune-related generalised oedema (ir-GE) drug related to ICPI, through frequency, clinical and pathological characteristics, and patient's outcome. PATIENTS AND METHODS: Objectives of the study were to report on ir-GE associated with ICPI to define frequency, associated signs and symptoms, pathological characteristics, severity, and response to corticosteroids. To be included in the study, adult patients had to have ir-GE related to ICPI with certain or likely link, without any other known causes of generalised oedema. The study design was observational, over the period 2014-2020, from pharmacovigilance databases in France, including the prospective Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC) registry. Calculation of the frequency of ir-GE was restricted to the prospective REISAMIC registry. RESULTS: Over 6633 screened patients, 20 had ir-GE confirmed drug related to ICPI. Based on the prospective REISAMIC registry, the frequency of ir-GE was 0.19% of ICPI-treated patients (3 cases out of 1598 screened patients). The 20 patients with ir-GE had a median (range) age of 62 (26-81) years, most frequent tumour types were melanoma (n = 9; 45%) and lung cancer (n = 6; 30%). The most frequent localisations of oedema were peripheral (n = 17; 85%), pleural (n = 13; 65%), and peritoneal (n = 10; 50%). Polyserositis was observed in 11 (55%) patients. The median (range) weight gain per patient was 9 (2-30) kg. Associated signs and symptoms met criteria for capillary leak syndrome (n = 4; 20%), sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) (n = 3; 15%), or subcutaneous autoimmune syndrome (n = 2; 10%). Corticosteroids were administered to 15 patients; of them, 10 (67%) improved clinically after corticosteroids. Based on CTCAEV5.0, the highest severity of ir-GE was grade ≥4 in 11 (55%) patients and four (20%) patients died due to ir-GE. CONCLUSIONS: Generalised immune system-related oedema is a new category of adverse event with immune checkpoint inhibitors and is often associated with a life-threatening condition. The pathophysiology may in some cases be related to endothelial dysfunctions, such as SOS/VOD or capillary leak syndrome.

The determinants of very severe immune-related adverse events associated with immune checkpoint inhibitors: A prospective study of the French REISAMIC registry.

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 Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (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.

Infant feeding practices and sleep at 1 year of age in the nationwide ELFE cohort.

Sleep problems reported by parents affect 20% to 30% of infants. Few studies focused on the longitudinal association between infant feeding practices and sleep, especially in France. Analyses were based on 8,696 infants from the French national birth cohort ELFE. Collection of feeding practices from birth to 10 months allowed for the identification of trajectories of use of baby cereals and thickened formula by group-based trajectory modelling and calculation of duration of any breastfeeding (BF) and age at complementary feeding introduction (CFI) excluding baby cereals. Total sleep duration (TSD), night waking (NW) and sleep onset difficulties (SOD) were reported at age 1. Associations between feeding and sleep were tested by multinomial logistic regressions. BF duration ≥6 months was associated with parent-reported frequent NW, SOD and TSD ≤ 12 h/24 h at age 1. For TSD and SOD, this association was no longer significant after accounting for parental sleep-related practices. Early use of baby cereals (≤5 months) was associated with poor sleep. Early CFI (<4 months) was associated with shorter TSD and SOD but not NW. Early use of thickened formula (only <6 months) was related to poor sleep at age 1 (NW and SOD), whereas late (around 6 months) use of thickened formula was associated with better sleep. BF duration ≥6 months was related to poor sleep at age 1 but not after adjustment on 1-year parental sleep-related practices except for NW. The use of baby cereals or early CFI was not related to better sleep at age 1.

Sleep habits and sleep characteristics at age one year in the ELFE birth cohort study.

OBJECTIVE: Infant sleep plays a critical role in normal development. Sleep problems, including sleep onset difficulties (SODs) and night waking (NW), range from 20% to 30% in infants and young children and can be persistent over time up to adulthood. Young French children seem to have longer sleep durations and less sleep troubles than their counterparts worldwide. Here, we aimed at describing infant sleep characteristics (total sleep time (TST)/24 h, NW, and SODs) and associated sleep habits in infants at age one year from the French nationwide birth cohort Etude Longitudinale Française depuis l'Enfance (ELFE). METHODS: This study included 11,783 infants with information on both sleep characteristics and sleep habits (parental presence when falling asleep, eating to fall asleep, sucking a pacifier or finger to sleep and sleep arrangement and location). Associations were studied by multinomial logistic regression analyses adjusted for familial and infant characteristics. RESULTS: Mean TST was 13 h36 min including 2 h54 min of naps; 20% of the infants had TST ≤12 h/24 h. About 46% did not present SOD or NW, 16% had frequent SODs and 22% had NW > 1 night in 2. Parental presence, feeding to fall asleep and infant sleep arrangements were frequent in infants with short sleep duration (≤12 h/24 h), NW and SODs. Non-nutritive sucking was associated with risk of NW, SOD and TST >14 h/24 h. Parental room sharing was associated with NW. CONCLUSION: This work provides new information on infant sleep arrangements and non-nutritive sucking that should be accounted for when considering sleep behaviors. In addition, most identified sleep habits associated with poor sleep characteristics may be amenable to change.

Infant feeding practices and sleep development in pre-schoolers from the EDEN mother-child cohort.

Sleep problems affect 20%-30% of toddlers and preschoolers. Few longitudinal studies focused on the impact of infant feeding practices on sleep. We aimed to study the associations between feeding practices up to 8 months and trajectories of sleep quantity or quality from 2 to 5-6 years. Analyses included 1,028 children from the EDEN mother-child cohort. Data were collected by self-administered questionnaires. Associations between feeding practices (breastfeeding, complementary feeding, use of thickened infant formula, night feeding) and sleep trajectories (sleep-onset difficulties, night waking, nighttime in bed) were analysed by multiple logistic regressions. Predominant breastfeeding for more than 4 months was associated with lower risk for belonging to the persistent sleep-onset difficulties trajectory. Night feeding at 4 months or at 2 years old was associated with higher risk for belonging to the persistent sleep-onset difficulties trajectory, and night feeding at 8 months was associated with higher risk for night waking and higher risk for short nighttime in bed. Early introduction (< 4 months) to complementary foods (excluding baby cereals) was related to lower risk for short nighttime in bed. Use of baby cereals or thickened infant formula was related neither to sleep quality nor to sleep quantity. In conclusion, infant feeding practices are associated with sleep trajectories in preschoolers, with notably a potential protective role of breastfeeding. Further researches are needed to clarify the mechanisms of these relationships.