Margaux Lafaurie

Summary: Bruton's tyrosine kinase inhibitors (BTKi) are widely used in B‐cell malignancies. Ibrutinib is associated with atrial fibrillation (AF), but comparative real‐world evidence on AF risk across BTKi remains limited. We conducted a nationwide new‐user population study using the French national health insurance database (2015–2024). Adults initiating ibrutinib, acalabrutinib, zanubrutinib or venetoclax were included, excluding those with prior AF or non‐overlapping BTKi indications. The primary outcome was AF requiring hospitalization. Hazard ratios (HRs) were estimated using Cox models with inverse probability of treatment weighting (IPTW). Among 26 393 patients, median follow‐up ranged from 167 days in the zanubrutinib cohort to 526 days in the ibrutinib cohort. One‐year incidence of hospitalized AF was highest with ibrutinib (2.3%) versus acalabrutinib (0.9%), zanubrutinib (0.7%) and venetoclax (0.5%). Ibrutinib was associated with a significantly higher AF risk versus acalabrutinib (HR 3.03, 95% confidence interval [CI] 1.84–5.00), zanubrutinib (HR 7.58, 95% CI 2.05–28.06) and venetoclax (HR 9.04, 95% CI 5.81–14.04). No significant differences in AF risk were observed between second‐generation BTKi and venetoclax. Ibrutinib was associated with a substantially higher risk of hospitalized AF than second‐generation BTKi, supporting closer cardiac monitoring in ibrutinib‐treated patients.

Context: Bispecific antibodies (bsAbs) recently reshaped the treatment landscape of multiple myeloma (MM). Rare cases of progressive multifocal leukoencephalopathy (PML) have been reported in MM patients, and more recently in bsAbs-treated patients. Objectives: We aimed to investigate a potential safety signal for PML in patients with MM treated with bsAbs. Methods: We included all patients with MM treated with bsAbs identified in the French prospective registry of JC polyomavirus infections of the central nervous system and/or from the French pharmacovigilance database (FPVD). We also performed a systematic review. We then assessed whether a disproportionality signal for PML reporting exists, comparing bsAbs and other MM therapies in VigiBase®, the world pharmacovigilance database. Results: In the registry-FPVD cohort, 14 patients were included; all had at least triple-refractory MM, with a median disease duration of 13 years (IQR, 10-14) and were exposed to BCMA-targeting bsAbs (median time to PML diagnosis: 22 months, IQR, 12-24); 10 (71%) were in complete response. Main clinical manifestations included motor deficit, cognitive impairment and visual symptoms (8/14 patients each, 57%). Twelve (86%) had died from PML by month 12. Similar features and outcomes were observed in the systematic review (n=14 cases). PML reporting was significantly higher with bsAbs than with other MM therapies (Reporting Odds Ratio 17.7; 95% CI, 12.1-26.1). Interpretation: PML may represent an emerging complication in patients with MM receiving bsAbs. Vigilant monitoring and rapid assessment of new neurological deficits are critical in this population.

Le purpura thrombopénique immunologique (PTI) est une maladie auto-immune rare avec un risque de saignement spontané, mais aussi de thrombose dont la prise en charge est particulièrement difficile. Le traitement de première intention repose sur les corticoïdes, plus ou moins les immunoglobulines intraveineuses (IgIV). Les agonistes du récepteur de la thrombopoïétine (AR-TPO ; eltrombopag et romiplostim) sont les médicaments privilégiés en deuxième ligne. Nous avons sélectionné trois questions pharmacoépidémiologiques pour mieux comprendre la maladie et sa prise en charge. Dès les études précliniques, un risque de survenue de cataracte associé à l'exposition à l'eltrombopag a été évoqué, alors que le risque est inconnu chez les patients en vie réelle. Les AR-TPO ainsi que les corticoïdes et les IgIV sont suspectés d'augmenter le risque de thrombose, ce qui n'a pas été mesuré en vie réelle et ajusté sur les autres facteurs de risque. Enfin, à l'instar d'autres maladies auto-immunes, le risque de PTI après une vaccination est débattu, notamment après le vaccin contre la grippe. Nos travaux de thèse avaient pour objectif de répondre à ces trois questions importantes pour la pratique clinique. Nous avons utilisé une approche pharmacoépidémiologique basée sur la cohorte FAITH (NCT03429660) incluant tous les patients adultes présentant un PTI primaire incident depuis 2009 (n=9885), construite sur la base du Système des Données de Santé (SNDS) ; trois études ont été menées avec des méthodes spécifiques pour chacune des questions. Dans une étude cas-témoins nichée, nous n'avons trouvé aucune association entre l'exposition à l'eltrombopag et la survenue d'une chirurgie de cataracte après ajustement sur les facteurs de risque de cataracte tels que le diabète et l'exposition aux corticostéroïdes (Lafaurie et al., Br J Haematol, 2020). L'exposition aux AR-TPO était associée à la survenue d'hospitalisation pour thrombose veineuse et artérielle après ajustement pour les facteurs de risque individuels et les autres traitements prothrombotiques du PTI (corticoïdes, IgIV et splénectomie) dans une étude de cohorte utilisant des expositions variables dans le temps (Lafaurie et al. Br J Haematol, 2021). En utilisant des méthodes autocontrôlées (self-controlled case series et case crossover) et une méthode cas-témoins (témoins issus de la population générale), nous n'avons pas trouvé d'association entre la vaccination contre la grippe et la survenue du PTI (Lafaurie et al., JAMA Intern Med, 2022). Ainsi, ces travaux de thèse ont fourni des résultats importants pour la pratique clinique sur des questions controversées.

Autoimmune hemolytic anemia (AIHA) is a rare and sometimes life-threatening disease. Infections are frequent and often severe during the course of AIHA. Rituximab is commonly used to treat patients with AIHA. This study aimed to assess the risk of hospitalization with infection after rituximab in patients with primary AIHA. We selected all adult patients newly diagnosed for primary AIHA and treated with rituximab between 2012 and 2018 in the French national health database. Patients were considered exposed to rituximab within 6 months after the first infusion. The main outcome was hospitalization with infection, identified by a discharge diagnosis of infection during the rituximab exposure. The cohort consisted of 959 patients (mean age of 67 years, standard deviation of 17.8 years; 60.5% of women). The 6-month cumulative incidence of hospitalization with infection was 17.6% (95% confidence interval [CI], 15.2-20.0). The most frequently characterized infections were pulmonary (40.2%). Opportunistic infections were observed in 28 (16.6%) patients, including 11 cases of pneumocystosis. All cases of pneumocystosis occurred in patients concomitantly exposed to corticosteroids, none of them had prophylaxis and all but 2 were aged ≥70 years. Overall, the main factors associated with hospitalization with infection were an age ≥70 years and the exposure to corticosteroids. The 30-day overall mortality after hospitalization with infection was 12.5% (95% CI, 8.0-18.0). In conclusion, the incidence of hospitalizations with infection, including opportunistic infections, as well as the subsequent mortality, are high in adult patients with primary AIHA treated with rituximab. Pneumocystosis prophylaxis should be encouraged in older patients exposed to corticosteroids.

More than 130 drugs have been suspected to induce immune hemolytic anemia. Comparative studies measuring the risk of drug-induced immune hemolytic anemia (DIIHA) are lacking. We aimed (1) to detect new signals of DIIHA, excluding vaccines, and (2) to assess the association between all suspected drugs and the occurrence of immune hemolytic anemia in a nationwide comparative study. The new signals were identified using a disproportionality study (case/noncase design) in the World Pharmacovigilance Database, Vigibase, among the cases of adverse drug reactions reported up to February 2020 (>20 million). We then conducted a comparative study in the French National health database that links sociodemographic, out-of-hospital, and hospital data for the entire population (67 million individuals). Associations between exposure to drugs (those already reported as DIIHA, plus new signals identified in Vigibase) and incident cases of immune hemolytic anemia (D59.0 and D59.1 diagnosis codes of the International Classification of Diseases, version 10) from 2012 to 2018 were assessed with case-control and case-crossover designs. In Vigibase, 3371 cases of DIIHA were recorded. Fifty-nine new signals were identified resulting in a final list of 112 drugs marketed in France and measurable in the nationwide cohort (n = 4746 patients with incident immune hemolytic anemia included in the case-control analysis matched with 22 447 controls from the general population). We identified an association between immune hemolytic anemia occurrence and some antibiotics, antifungal drugs, ibuprofen, acetaminophen, furosemide, azathioprine, and iomeprol.

Summary: Primary autoimmune haemolytic anaemia (AIHA) causes the destruction of red blood cells and a subsequent pro‐thrombotic state, potentially increasing the risk of ischaemic stroke. We investigated the risk of ischaemic stroke in patients with AIHA in a binational study. We used prospectively collected data from nationwide registers in Denmark and France to identify cohorts of patients with primary AIHA and age‐ and sex‐matched general population comparators. We followed the patient and comparison cohorts for up to 5 years, with the first hospitalization of a stroke during follow‐up as the main outcome. We estimated cumulative incidence, cause‐specific hazard ratios (csHR) and adjusted for comorbidity and exposure to selected medications. The combined AIHA cohorts from both countries comprised 5994 patients and the 81 525 comparators. There were 130 ischaemic strokes in the AIHA cohort and 1821 among the comparators. Country‐specific estimates were comparable, and the overall adjusted csHR was 1.36 [95% CI: 1.13–1.65], p = 0.001; the higher rate was limited to the first year after AIHA diagnosis (csHR 2.29 [95% CI: 1.77–2.97], p < 10 ⁻⁹ ) and decreased thereafter (csHR 0.89 [95% CI: 0.66–1.20], p = 0.45) ( p ‐interaction < 10 ⁻⁵ ). The findings indicate that patients diagnosed with primary AIHA are at higher risk of ischaemic stroke in the first year after diagnosis.

OffLabel Disclosure:. Michel:Alexion: Consultancy; Novartis: Consultancy; Sobi: Consultancy; Sanofi: Consultancy; argenx: Honoraria; UCB: Honoraria. Moulis:Grif

Aims: Pharmacovigilance signals of heart failure (HF) following exposure to protein kinase inhibitors (PKIs) have been detected in recent years. Our aim was to identify the PKIs most frequently associated with the development of HF.Methods: Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalization diagnosis and long‐term HF‐related disease codes were used to identify HF patients. HF incidence rate ratios (IRRs) were measured and adjusted hazard ratios (aHRs) were estimated using a Cox model. Sensitivity analyses were performed to limit the potential indication and competitive risk bias.Results: Thirteen PKIs were studied. Among the 49 714 new PKI users registered during the study period, the mean IRR of HF was 3.38 per 100 person‐years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for six medicinal products: pazopanib (aHR = 2.42, 95% confidence interval [CI] 1.67‐3.52), dasatinib (aHR = 2.22, 95% CI 1.42‐3.44), ruxolitinib (aHR = 2.11, 95% CI 1.69‐2.64), crizotinib (aHR = 1.71, 95% CI 1.07‐2.72), everolimus (aHR = 1.45, 95% CI 1.26‐1.67) and vemurafenib (aHR = 1.37, 95% CI 1.01‐1.86). Sensitivity analyses were consistent with our primary analysis.Conclusions: The current study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two medicinal products with results slightly above the significance threshold, namely, crizotinib and vemurafenib, in our sensitivity analyses.