Nicolas Delanoy1, Jean-Marie Michot2, Thibault Comont3, Nora Kramkimel4, Julien Lazarovici5, Romain Dupont3, Stéphane Champiat1, Claude Chahine5, Caroline Robert6, Charles Herbaux7, Benjamin Besse6, Aude Guillemin8, Christine Mateus6, Patricia Pautier6, Philippe Saïag9, Emanuela Madonna5, Marie Maerevoet10, Jean-Christophe Bout11, Charlotte Leduc12, Pascal Biscay13, Gilles Quere14, Charlée Nardin15, Mikael Ebbo16, Laurence Albigès6, Grégoire Marret17, Virginie Levrat18, Cécile Dujon19, Jacques Vargaftig20, Salim Laghouati21, Laure Croisille22, Anne-Laure Voisin21, Bertrand Godeau23, Christophe Massard1, Vincent Ribrag1, Aurélien Marabelle1, Marc Michel23, Olivier Lambotte24. 1. Département des Innovations Thérapeutiques et Essais Précoces, Gustave Roussy, Université Paris-Saclay, Villejuif, France. 2. Département des Innovations Thérapeutiques et Essais Précoces, Gustave Roussy, Université Paris-Saclay, Villejuif, France; Service de Médecine Interne and Immunologie Clinique, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France. Electronic address: jean-marie.michot@gustaveroussy.fr. 3. Service de Médecine Interne et d'Immunopathologie, Institut Universitaire du Cancer, Toulouse, France. 4. Service de Dermatologie et Vénérologie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France. 5. Département d'Hématologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France. 6. Département de Médecine Oncologique, Gustave Roussy, Université Paris-Saclay, Villejuif, France. 7. Service d'Hématologie, Centre Hospitalier Régional Universitaire de Lille, Lille, France. 8. Service d'Oncologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France. 9. Service des Cancers Cutanés, Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France. 10. Department of Haematology, Institute Jules Bordet, Brussels, Belgium. 11. Centre Médical de L'Archipel, Saint-Brieuc, France. 12. Service d'Oncologie Thoracique, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. 13. Service de Médecine Interne, Clinique Mutualiste de Pessac, Pessac, France. 14. Service de Pneumologie, Hôpital Morvan Centre Hospitalier Régional Universitaire de Brest, Brest, France. 15. Service de Dermatologie, Centre Hospitalier Régional Universitaire Jean Minjoz, Besançon, France. 16. Service de Médecine Interne, Hôpital de la Timone, Aix Marseille Université, Assistance Publique Hôpitaux de Marseille, Marseille, France. 17. Service d'Oncologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France. 18. Service de Pneumologie, Centre Hospitalier de La Rochelle, La Rochelle, France. 19. Service de Pneumologie, Hôpital André Mignot, Centre Hospitalier Universitaire de Versailles, Le Chesnay, France. 20. Service d'Hématologie, René Huguenin Hospital-Curie Institute, Saint-Cloud, France. 21. Unité de Pharmacovigilance, Gustave Roussy, Université Paris-Saclay, Villejuif, France. 22. Laboratoire HLA-ILP, Etablissement Français du Sang, Créteil, France. 23. Service de Médecine Interne, Centre de Référence des Cytopénies Auto-Immunes de l'Adulte, Assistance Publique-Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France. 24. Service de Médecine Interne and Immunologie Clinique, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France; Université Paris Sud, Centre de Recherche en Immunologie des Infections Virales et des Maladies Auto-Immunes, INSERM, Le Kremlin-Bicêtre, France; Division d'Immunovirologie, Commissariat à l'Energie Atomique et aux Energies Alternatives, Fontenay-aux-Roses, France.
Abstract
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.
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.
Authors: Rebecca Karp Leaf; Christopher Ferreri; Deepa Rangachari; James Mier; Wesley Witteles; George Ansstas; Theodora Anagnostou; Leyre Zubiri; Zofia Piotrowska; Thein H Oo; David Iberri; Mark Yarchoan; April K S Salama; Douglas B Johnson; Andrew D Leavitt; Osama E Rahma; Kerry L Reynolds; David E Leaf Journal: Am J Hematol Date: 2019-03-13 Impact factor: 13.265
Authors: Julie R Brahmer; Hamzah Abu-Sbeih; Paolo Antonio Ascierto; Jill Brufsky; Laura C Cappelli; Frank B Cortazar; David E Gerber; Lamya Hamad; Eric Hansen; Douglas B Johnson; Mario E Lacouture; Gregory A Masters; Jarushka Naidoo; Michele Nanni; Miguel-Angel Perales; Igor Puzanov; Bianca D Santomasso; Satish P Shanbhag; Rajeev Sharma; Dimitra Skondra; Jeffrey A Sosman; Michelle Turner; Marc S Ernstoff Journal: J Immunother Cancer Date: 2021-06 Impact factor: 13.751