Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study.

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 Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (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 Référence des Cytopénies 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.

Auto bi-level with pressure relief during exhalation as a rescue therapy for optimally treated obstructive sleep apnoea patients with poor compliance to continuous positive airways pressure therapy--a pilot study.

BACKGROUND: Continuous positive airways pressure (CPAP) is the accepted therapy for obstructive sleep apnoea (OSA), but compliance is variable. We hypothesised that an auto bi-level device with pressure relief during exhalation (auto bi-level) would treat OSA as well as CPAP and that transitioning non-compliant CPAP patients without modifiable causes of poor compliance to this device would improve compliance and clinical outcomes. MATERIALS AND METHODS: OSA patient's on positive airways pressure therapy with compliance below 4 h of use on ≥70% of nights over the past 3 months despite having no modifiable causes of poor compliance were transitioned onto an auto bi-level device for 10 weeks. Patients completed an Epworth sleepiness scale and Functional Outcomes of Sleep Questionnaire (FOSQ) at 15 days and 10 weeks and had their compliance and therapy data downloaded. Additionally, patients underwent polysomnography on their auto bi-level device at week 10. RESULTS: Thirty-five patients were included. The apnoea-hypopnoea index, arousal index, sleep efficiency, total sleep time and sleep stage distribution were similar at baseline and week 10. Compliance, excessive daytime sleepiness and several FOSQ domains improved significantly at day 15 and week 10. Patients requiring an effective pressure ≥10 cmH(2)0 during the lead-in period on CPAP experienced greater significant improvements compliance than those requiring an effective pressure <10 cmH(2)0. CONCLUSIONS: Auto bi-level with pressure relief during exhalation treats OSA as effectively as CPAP without inducing additional arousals. Transitioning non-compliant CPAP patients without modifiable causes of poor compliance from their CPAP to this new device improves compliance and clinical outcomes over a 10-week period.