Drug‐induced autoimmune hemolytic anemias related to immune checkpoint inhibitors, therapeutic management, and outcome

Autoimmune hemolytic anemia (AIHA) is defined as augmented destruction of erythrocytes by autoimmune mechanisms, usually mediated by autoantibodies against erythrocyte surface antigens.1 Drug-induced hemolytic anemia is distinct cause of AIHA and is generally mediated by immunological mechanisms.1 Immune checkpoint inhibitors (ICIs) that are used to treat cancer, in particular PD-1 inhibitors, can induce AIHA.1, 2 The hematopoietic system and red blood cells could be occasionally involved as immune-related adverse events triggered by ICI with a frequency estimated to be around 0.5% of treated patients.3 ICI-AIHAs have only been reported in few patients in cases-series,2, 3 and data remain scarce about AIHA subtype distributions (warm vs. cold) and outcome of patients including mortality associated with AIHA and treatment efficacy. Management of patients with ICI-AIHA is based on corticosteroids and eventually rituximab,2, 3 and safety and efficacy data are not fully reported. We report here the management and therapeutic outcome of patients treated for ICI-AIHA in a tertiary academic anticancer center. The study design was an observational retrospective study of adult patients with ICI-AIHA in France. Immune checkpoint inhibitors considered for the study included anti-programmed death cell 1 (PD-1), anti-programmed death cell ligand 1 (PD-L1), and anti-CTLA4. Eligibility criteria were patients aged ≥18 years, with ICI-AIHA who were registered in the pharmacovigilance registry REISAMIC (Registry of Severe Adverse Reactions to Immunomodulatory Monoclonal Antibodies in Cancer)4 and those referred to the Gustave Roussy Immunotoxicity board5 over the period from June 27, 2014, to April 29, 2022, and those referred to the centers belonging to the French Reference Centers for Adult' Autoimmune Cytopenias (CeReCAI) network from 2014 to 2022 (Figure 1). The AIHA criteria and definitions for this study followed the 2020 first international consensus criteria for AIHA management.6 Study objectives, data collection information, statistical analysis, and ethical considerations are detailed in the Appendix S1. Between June 27, 2014, and April 29, 2022, 21 patients with confirmed ICI-AIHA were included in analysis (Figure 1). Among 2775 patients prospectively included in the REISAMIC registry of Gustave Roussy Centre, two patients have developed ICI-AIHA, and the rate of ICI-AIHA was 0.07% (two out of 2775 ICI-treated patients). Among the 21 patients diagnosed with ICI-AIHA; median age at onset of ICI-AIHA was 70 years (ranging from 29 to 88 years); sex ratio was 2.0 (14 men and 7 women); and tumor types were non-small cell lung carcinoma (n = 8; 38%), melanoma (n = 7; 33%), renal cancer (n = 3; 14%), Hodgkin lymphoma (n = 1; 5%), and other tumor types (n = 2; 10%). Patients with ICI-AIHA mostly received anti-PD-1 immunotherapy (n = 17; 81% of cases) and developed ICI-AIHA after a median time of 28 days (ranging from 11 to 1060 days) (Table S1). A medical history of lymphoproliferative disorder was found in 9/21 patients (43%), and a pre-existing autoimmune or inflammatory disease was known for three patients (14%). The lymphoproliferative disorders were chronic lymphocytic leukemia (n = 3 patients), marginal zone lymphoma (n = 2 patients), Hodgkin lymphoma (n = 2 patients), Waldenstrom disease (n = 1 patient), and monoclonal gammopathy of undetermined significance (n = 1 patient) (Table S1). Among these nine patients with lymphoproliferative disorder, only one patient had a previously known lymphoproliferative disorder (patient with Hodgkin lymphoma, treated with anti-PD1), the other eight patients had no known history of lymphoproliferative disorder, and the diagnosis of lymphoproliferative disorder was performed and revealed at the same time of ICI-AIHA. Nadir of hemoglobin was 6.9 g/dL (range 4.2–9.6 g/dL), and 14 patients (71%) required red blood cell transfusions for anemia management, with a median of four packed red cell units per patient (range 1–8). Mortality related to ICI-AIHA was observed in two (10%) patients (Table S2). According to common terminology criteria for adverse events (CTCAEV5), severity of anemia was grade ≥3 in 18 (86%) patients, and the severity of anemia was observed and distributed according to each ICI-AIHA subtype (Figure 1). All patients had direct antiglobulin test (DAT) performed, and 19 (90%) had a positive test, with an IgG pattern for 11 (52%) and qualified as warm ICI-AIHA, five (24%) were positive for IgM and qualified as cold ICI-AIHA, and three (14%) had a mixed profile and qualified as mixed ICI-AIHA. Two patients (10%) had a negative DAT (Table S1). Fourteen (66%) patients received corticosteroids alone, and six (29%) patients received corticosteroids and rituximab (Tables S2 and S3). One patient received only palliative therapies without specific treatment for ICI-AIHA and died due to cancer progression before receiving any specific treatment for ICI-AIHA. Overall complete response to corticosteroids was 36% (5/14 patients treated) (Table S2). The efficacy of corticosteroids was observed only in the warm-AIHA subtype (details of therapeutic responses by subtypes of ICI-AIHA are available in Tables S2 and S4). Six (29%) patients received rituximab for ICI-AIHA. The response rate to rituximab was 50% (3/6 patients treated) (Table S2). The efficacy of rituximab was 1/3 and 2/2 of treated patients in the warm-AIHA and cold-AIHA subtypes, respectively. Remission of ICI-AIHA was achieved in 19 of the 21 patients (90%), and treatment outcomes were complete response in eight (38%) patients and partial response in 11 (52%) patients, with similar response rates among patients treated with corticosteroids or with corticosteroids plus rituximab (Table S2). Evolution of hemoglobin after ICI-AIHA treatments according to corticosteroid or corticosteroid plus rituximab was similar as depicted in Figure 1. Although hemoglobin concentration at ICI-AIHA diagnosis timepoints tended to be lower in patients treated with corticosteroids plus rituximab as compared to corticosteroids alone (Hb 5.8 g/dL vs. 7.3 g/dL; p = .10; Table S3), the hemoglobin recovery at 6 months was similar (Figure 1). After ICI-AIHA diagnosis, immune checkpoint inhibitor therapy was permanently discontinued in 19 patients (90%). Two (9.5%) of the 21 patients were rechallenged with same ICI after obtaining durable complete remission of ICI-AIHA (Table S2). The two rechallenged patients were treated with corticosteroids alone, and in these two patients, no recurrence of ICI-AIHA was observed with a period after ICI rechallenge of 24 months. Finally, our study reports a case series of 21 patients diagnosed with ICI-AIHA delineating the subtypes of ICI-AIHA that appears to be mainly warm-AIHA (52%) and cold-AIHA (24%). DAT-negative ICI-AIHA was reported in 10% of cases, which seems to confirm that ICI-AIHA could be more frequently associated with negative DAT (DAT-negative AIHA is thought to be present in <5% of patients in the setting of AIHA outside of ICI1). Leaf et al.2 reported in the ICI-AIHA case series from the USA a negative DAT rate of 28%. Our study was able to estimate that ICI-AIHA is a rare complication associated with immunotherapy with an incidence rate of 0.07%. The mortality associated with ICI-AIHA was 10% of patients in our study, which indicates that ICI-AIHA was a severe and potential life-threatening complication of immunotherapy. In all patients in the study, corticosteroids or corticosteroids plus rituximab produced similar results on hemoglobin recovery, with remission of ICI-AIHA in 90% of patients. Overall, our results indicate that ICI-AIHA treatment should consider the AIHA subtypes; warm ICI-AIHA is to be treated with corticosteroids, with addition of rituximab in cases of insufficient response to corticosteroids. In patients with cold ICI-AIHA, corticosteroids do not seem to be effective, and the treatment should be based on rituximab. In our study, ICI-AIHA was associated with an underlying lymphoproliferative disorder in 43% of patients. Leaf et al.,2 in another report of ICI-AIHA, found an associated lymphoproliferative syndrome (most often chronic lymphocytic leukemia or indolent lymphoma) in 29% of their patients. We could discuss the causal factor of AIHA between the immunotherapy treatment or the natural evolution of the underlying lymphoproliferative syndrome, or the conjunction of the two. In conclusion, main ICI-AIHA subtypes included both warm-AIHA and cold-AIHA. An associated underlying lymphoproliferative disorder was frequently observed and should be recommended to look for. Our study suggests that ICI-AIHA treatment should consider AIHA subtypes: corticosteroids ± rituximab for warm-AIHA and rituximab alone for cold-AIHA. Marion Plaçais, Jean-Marie Michot, and Olivier Lambotte contributed to conception and design. Olivier Lambotte, Sabine Messayke, Jean-Marie Michot, Kaissa Ouali, Thibault Comont, Nora Kramkimel, Alexandre Thibault Jacques Maria, Laetitia Coutte, Charlee Nardin, Guillaume Manson, Ariane Laparra, and Audrey Perret contributed to provision of study materials or patients. Marion Plaçais, Kaissa Ouali, and Jean-Marie Michot collected and assembled the data. Marion Plaçais, Jean-Marie Michot, Ariane Laparra, Marc Michel, and Olivier Lambotte helped in data analysis and interpretation. All authors wrote and approved the final version of the manuscript. Data were collected by investigators and site personnel and analyzed in collaboration with senior academic authors. We thank the patients and their families and all investigators and site personnel. The authors thank Tina-Marie Zaarour for his assistance with copyediting. We thank the CeReCAI (Centre de Référence des Cytopénies Auto-Immunes de l'adulte) and the sites belonging to the CeReCAI in France. JMM and KO disclosed conflicts of interest outside of the submitted work: Institution received funding for clinical trials, and they both were principal/sub-investigator of clinical trials for Abbvie, Agios, Amgen, Argen-x, Astex, AstraZeneca, Beigene, Blueprint, BMS, Boehringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Seattle Genetics, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, and Xencor. JMM reported advisory board for Ideogen and Gilead and for Mallinckrodt Pharmaceuticals, steering committee member for Regeneron, and expert testimony fees for MSD; travel grant was paid by GSK. NK reported disclosed conflicts of interest outside of the submitted work with consultancy fees for BMS, and travel grant was paid by BMS. CN disclosed conflicts of interest outside of the submitted work: CN reported consultancy fees for BMS, Novartis, and MSD. ATJM disclosed conflicts of interest outside of the submitted work: consultancy fees for BMS, Astra Zeneca, MSD, Roche, and Sanofi. OL disclosed conflicts of interest outside of the submitted work: OL reported expert testimony and consultancy fees from Bristol-Myers Squibb France, MSD, and AstraZeneca, consultancy fees from Boehringer, and expert testimony fees from Abbvie. The other authors declare they have no conflicts of interest related to this study. The authors declare that the data presented in this article are available as raw data available from the corresponding author upon reasonable request. Appendix S1. Supporting information. Table S1. Characteristics of patients with immunotherapy-induced autoimmune hemolytic anemia. Table S2. Therapies administered and outcome in patients with immunotherapy-induced autoimmune hemolytic anemia. Table S3. Clinical characteristics and outcome of patients, according to treatment administered for immunotherapy-induced autoimmune hemolytic anemia. Table S4. Complete response to treatment of immunotherapy-induced autoimmune hemolytic anemia, according to each anemia subtype. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.