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Summary Introduction Immune checkpoint inhibitor-induced diabetes mellitus (ICI-DM) is an immune-related adverse drug reaction (irADR). Hyperglycemia can be linked to endogenous insulin deficiency with ketoacidosis or associated with preserved beta-cell function. Objectives We aimed to identify the characteristics of both types of ICI-DM (type 1 and type 2 DM), to improve our understanding of this irADR and its management. Methods Data for ICI-DM recorded in the French Pharmacovigilance Database from 2015 to October 2019 were analyzed according to the French causality assessment. Results In total, 60 subjects were included. Anti-PD1/PDL1 pathway blockade therapy (nivolumab: 61.7% + 3.3% in association with ipilimumab pembrolizumab: 28.3%) was most frequently implicated in ICI-DM, but some reports involved anti-CTLA4 drug (ipilimumab: 6.7% + 3.3% in association with nivolumab). One third of reports occurred within one month of the initiation of immunotherapy. Decreased insulin secretion (defined by the presence of ketone bodies) were confirmed in 80% of reports. Among them, 54% of patients met the diagnostic criteria for fulminant diabetes. Overall, 17.7% of the reports had pre-existing type 2 diabetes T2D. Four deaths due to hyperglycemia were declared, with altered insulin secretion in only two of these reports. BMI was lower in the insulinopenic group (23.4 ± 0.7 vs. 27.9 ± 1.6, P = 0.004) and other irADRs were more frequently observed in patients with persistent insulin secretion (66.7 vs. 18.8%, P = 0.02). We found no difference in age, indication or cumulative ICI dose between the two groups (with and without insulinopenia). The presence of GAD antibodies was associated with a shorter time to diabetes onset (42.6 ± 6.1 vs. 208.1 ± 41.6 days, P = 0.029). Conclusions ICI-DM is a rare but serious irADR triggered by all classes of immunotherapy. The observation period for ICI-DM can be shortened for patients positive for anti-GAD antibodies. Endogenous insulin deficiency did not appear to be the only mechanism involved in ICI-DM, as beta-cell function was preserved in 20% of reports. Improvements in our understanding of this complication will be required for its prevention.

As ibrutinib has become a standard of care in B-cell malignancies in monotherapy or in combination with other agents, definition of its safety profile appears essential. The aim of this study was to further characterize the safety profile of ibrutinib through the identification of potential safety signals in a large-scale pharmacovigilance database. All serious individual case safety reports (ICSRs) in patients aged ≥18 years involving ibrutinib suspected in the occurrence of serious adverse drug reactions or drug interacting from November 13th, 2013 to December 31st, 2020 were extracted from VigiBase, the World Health Organization global safety database. Disproportionality reporting was assessed using the information component (IC) and the proportional reporting ratio (PRR), with all other anticancer drugs used as the reference group. To mitigate the confounding of age, two subgroups were considered: patients aged

Trastuzumab is a monoclonal antibody targeted against the Human Epidermal Growth Factor Receptor 2 (HER2) overexpressed in some breast cancer. This targeted therapy significantly improves the prognosis of these cancers. Recently an anti-HER2 antibodydrug conjugate was shaped in order to facilitate the targeted delivery of potent cytotoxic drug to cancer cells and to reduce resistance. This formulation, called trastuzumab emtansine (T-DM1), consists of the monoclonal antibody trastuzumab linked to a cytotoxic drug (a derivative of maytansine) via a chemical linker. Little is known about adverse reactions due to this new formulation. Herein we described the case of a woman suffering from a HER2-positive breast cancer, treated with trastuzumab for 30 months followed by T-DM1 monotherapy. After 12 months of T-DM1 treatment, a nodular regenerative hyperplasia confirmed by liver biopsy occurred. T-DM1 was stopped and medical imagery showed a resolution of the nodular regenerative hyperplasia. Unfortunately, hepatic metastasis progressed. Few cases of nodular regenerative hyperplasia induced by T-DM1 have been described so far. Further studies are needed to explore pathogenesis of nodular regenerative hyperplasia with this new antibody-drug conjugate treatment.

International audience

BackgroundSafety of rechallenge of immune checkpoint inhibitor (ICI) after grade ≥2 immune-related adverse events (irAEs) leading to ICI discontinuation remains unclear.MethodsAll adverse drug reactions involving at least one ICI reported up to December 31, 2019 were extracted from the French pharmacovigilance database. Patients were included if they experienced at least one grade ≥2 irAE resulting in ICI discontinuation, with subsequent ICI rechallenge. The primary outcome was the recurrence of at least one grade ≥2 irAE in these patients after ICI rechallenge.ResultsWe included 180 patients: 61.1% were men (median age of 66 years), 43.9% had melanoma and 78.9% were receiving anti-programmed cell death 1. First ICI discontinuation was related to 191 irAEs. After ICI rechallenge, 38.9% of the patients experienced at least one grade ≥2 irAE. Among them, 70.0% experienced the same irAE, 25.7% a distinct irAE, and 4.3% both the same and a distinct irAE. Lower recurrence rates of irAEs were associated with rechallenge with the same ICI treatment (p=0.02) or first endocrine irAEs (p=0.003). Gastrointestinal irAEs were more likely to recur (p=0.007). The median duration from ICI discontinuation to rechallenge and the severity of the initial irAE did not predict recurrent irAEs after ICI rechallenge (p=0.53 and p=0.40, respectively).ConclusionsIn this study, 61.1% of the patients who discontinued ICI treatment for grade ≥2 irAEs experienced no recurrent grade ≥2 irAEs after ICI rechallenge. Although ICI rechallenge appears to be safe under close monitoring, it should always be discussed balancing usefulness of rechallenge, patient comorbidities and risk of recurrence of first irAE(s). Due to inherent bias associated with pharmacovigilance studies, further prospective studies are needed to assess risk factors that may influence patient outcomes after ICI rechallenge.

Aims To provide real-life data on patterns of use and safety of ibrutinib. Methods A cohort study including all patients initiating ibrutinib between 21 November 2014 and 21 November 2018, and followed for 1 year was conducted. Patient characteristics, ibrutinib use and adverse drug reactions (ADRs) were collected from medical records. Kaplan-Meier analysis estimated the probability of developing ibrutinib-associated serious ADRs (SADRs) with a 95% confidence interval (CI). A Cox proportional hazards model was used to investigate factors associated with SADR occurrence. Results In total, 102 patients were included in the study. The median age was 70.3 years (interquartile range 64.7-75.6), the male/female gender ratio was 2.9. Almost half the patients (47.1%) were prescribed ibrutinib for chronic lymphocytic leukaemia (CLL). Forty-three patients (42.1%) permanently discontinued ibrutinib in the first year, mostly for progression (51.2%) or ADRs (32.6%). Forty-eight patients (47.1%) experienced at least one ibrutinib-associated SADR. Haematological, infectious and vascular disorders were the most frequent SADRs. The probability of developing ibrutinib-associated SADR was 35.1% (95% CI 26.3-45.7%) at 3 months, 44.8% (35.2%; 55.8%) at 6 months and 54.3% (44.0%; 65.2%) at 12 months. Age ≥80 years (hazard ratio [HR] 2.03; 95% CI 1.02-4.05) and CLL (HR 1.81; 95% CI 1.01-3.25) were significantly associated with a higher risk of SADR occurrence. Conclusion This study found a high cumulative incidence of ibrutinib-associated SADRs within the first year of treatment. In view of the risk of SADR, patients aged ≥80 years or treated for CLL deserve special attention.

International audience

International audience; BACKGROUND:Several clusters of encephalopathy occurred after the market change from Holoxan® (ifosfamide lyophilized powder) to Ifosfamide EG® (liquid formulation) and justified a formal survey in 2015. In June 2016, the regulatory authority decided to apply a precautionary measure in reducing the shelf life of Ifosfamide EG® at 7 months. One-year study from spontaneous reports lead to suspect a potential residual risk. Due to the many limitations associated with spontaneous notifications, we performed a multicentric observational study, aiming to better explore this pharmacovigilance signal.METHODS:We performed a case-control study in pediatric oncology Departments of 25 university hospitals between July 1st, 2016 and July 1st, 2018. All children (

Background Although antituberculosis drug-associated drug reaction with eosinophilia and systemic symptoms (DRESS) is rarely reported, its diagnosis should not be dismissed. Its management implies an early withdrawal of suspected drugs. Objective The objective of this study was to describe the characteristics of antituberculosis drug-associated DRESS and to identify the most likely involved drugs. Methods We searched for potential cases of DRESS with rifampicin, isoniazid, pyrazinamide, and ethambutol reported from January 1, 2005, to July 30, 2015, in the French pharmacovigilance database. A literature review was also performed. Results Sixty-seven cases of antituberculosis drug-associated DRESS were analyzed (40 women and 27 men, median age of 61 years). Liver and kidneys were the most frequently involved organs. Two patients died from DRESS. Skin tests were performed in 11 patients and were positive in 8 cases. Discrepancies between epicutaneous tests and reintroduction of the culprit drugs were observed for 2 patients with a premature reintroduction of antituberculosis drugs in 1 case. Antituberculosis drugs were the only suspects in 20 cases. As for the literature data, rifampicin was the most suspected drug because of its larger indications, but in case of tuberculosis infections, isoniazid was the most suspected drug. Conclusions We described the largest case series of first-line antituberculosis drug-associated DRESS in the literature. All antituberculosis drugs pose a risk of DRESS. An early withdrawal of the culprit drugs is essential. A drug allergy evaluation must be performed to optimize the second-line treatment of tuberculosis infection.