Hematological immune-related adverse events associated with checkpoint inhibitors.

Immune-related hematologic adverse events in the context of immune checkpoint inhibitor therapy.

Immune-Related Hematologic Adverse Events in the Context of Checkpoint Inhibitors

Hematologic Immune-Related Adverse Events from Immune Checkpoint Inhibitors: A Systematic Review of Case-Reports and Case-Series

Immune checkpoint inhibitor–associated cytopenias: A decade of real-world signal detection from faers (2014–2025)

2642 Background: The effectiveness of immunotherapy is often hindered by the development of immune-related adverse events (IrAE). Racial minorities were under-represented in the key clinical trials that led to the approval of different immune checkpoint inhibitors (ICI). In this study, we explore the side effect profile of immune checkpoint inhibitors in our patient population that comprises almost entirely of minorities, mostly African Americans (AA) and Hispanics. We hypothesize that due to race-based differences in immune milieu of the body and disease susceptibility, the timing and severity of immunotherapy-related IrAE would be different in AA and Hispanics compared to Caucasians. This can translate into a difference in clinical outcomes as well. There have been some suggestions of a positive association of the development of IrAE with cancer survival, although the data is limited and heterogeneous. The purpose of our study is to study the frequency and severity of IrAEs in racial minority groups, compare them with previous clinical trials population, and add valuable real-world data in this underrepresented group of patients. Methods: A retrospective chart review was performed on adult patients with solid malignancies treated with any ICI between January 1, 2015 and April 30, 2022. Patients were classified according to age (greater/equal to 65y or younger), sex, race (self-identified), primary cancer, and type of immunotherapy received. Outcome data using type and severity of IrAE, time to development of IrAE, and any association with clinical outcomes was collected and analyzed using descriptive statistics as well as univariate analysis. Results: A total of 78 patients were included in the final analysis. The mean age was 68 years; 51% were males; 42.3% were Hispanics, 37% were AA, 19.7% were others, and 1% were Whites. Most common malignancy was lung cancer (65.5%). Most common ICI agent used was Pembrolizumab (n = 52) and 2 patients were treated with combination therapy using Ipilimumab and Nivolumab. 41 (52.5%) patients had IrAE of any grade while 9 (11.5%) patients experienced grade 3 side effects. None of the patients experienced grade 4 side effects. Most common IrAE of any grade was hypothyroidism (n = 14) while most common grade 3 side effect was colitis (n = 6). 31 patients were less than 65y of age. There was no significant difference in IrAE in patients less than 65 years of age vs ≥ 65 years (51.6% vs 53.1%) or grade 3 IrAE (9.6% vs 12.7%). Conclusions: In our study population consisting mostly of AA and Hispanics, the rate of IrAE of any grade as well as grade 3 or 4 IrAE with ICI therapy was comparable to what was seen in clinical trials involving these drugs. This data and its potential effects on survival outcomes need to be analyzed in prospective studies involving a larger number of patients.

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors.

Immune checkpoint inhibitors have recently emerged as important and effective advanced cancer treatment options. Programmed cell death receptor-1 (PD-1) antagonists such as pembrolizumab and nivolumab have been approved by the US Food and Drug Administration for treatment of many advanced cancers. As anti-PD-1 checkpoint inhibitor use has been increasing, previously unreported rare side effects emerge. These checkpoint inhibitors upregulate humoral and cellular immune responses to tumor antigens. Consequently, they can be associated with immune-related adverse events including hematological-related reactions such as autoimmune hemolytic anemia, immune thrombocytopenia, neutropenia and pancytopenia. However, pure red cell aplasia (PRCA) induced by anti-PD-1 checkpoint inhibitors is rarely reported in the literature. We herein report cases of two patients who developed PRCA during treatment with anti-PD-1 checkpoint inhibitors. In both cases, a peripheral blood smear examination demonstrated reticulocytopenia. Bone marrow biopsies revealed severe erythroid hypoplasia with maturation arrest at the proerythroblast stage, relative granulocytic hyperplasia and lymphocytosis. Flow cytometry and immunohistochemistry revealed that the lymphocytes were predominantly CD8+ T cells. T lymphocytosis, especially in one of the two patients, mimicked a T-cell lymphoproliferative disorder; lack of clonality indicated a reactive process. Our findings, in addition to data presented in the literature, suggest that T cells play a critical role in the pathogenesis of immune-related PRCA. PRCA is an under-recognized immune-mediated adverse event that does not manifest during the clinical trial phase. It is a potentially life-threatening complication, which should be considered in the differential diagnosis of anemia in patients treated with anti-PD-1 checkpoint inhibitors.

Clinical Features of Immune Checkpoint Inhibitor-Associated Autoimmune Hemolytic Anemia: A Series of 14 Cases

e14128 Background: Immune checkpoint inhibitors (ICIs) are changing the landscape of treatment in oncology. The use of ICIs is growing rapidly as the indications for these medications broaden and new ICIs become approved. Given the rapid growth and relative infancy of the use of ICIs, much information stands to be gained on their use in the clinical practice setting, especially regarding toxicity. Methods: The primary objective of this project was to examine the incidence and severity of immune-related adverse events (irAEs), after treatment with single-agent or combination ICIs at a multi-site community cancer center. A retrospective chart review was conducted on all patients who had received ipilimumab, nivolumab, pembrolizumab, atezolizumab, or ipilimumab plus nivolumab from May 1, 2011 to June 30, 2017. Data collected included patient demographics, disease state, treatment information, preexisting autoimmune disease, previous immunotherapy, and adverse event details. The results were analyzed using descriptive statistics. Results: Data was collected on 383 patients. Dermatologic irAEs were common across single agent ICIs (overall incidence 23%). Diarrhea and/or colitis incidence was highest with CTLA-4 inhibitor ipilimumab (26% at 3 mg/kg and 22% at 10 mg/kg) versus the other monotherapy PD-1/PDL-1 inhibitors. Endocrinopathies were most common with ipilimumab 10 mg/kg (55%) and pneumonitis incidence was highest with nivolumab (6%). ICI toxicity occurred in 63% of patients with preexisting autoimmune disease versus 54% of those without a baseline autoimmune disease. Incidence of hospitalization and treatment holds due to irAEs was higher with combination therapy (57% and 66%, respectively) than with monotherapy (10% and 24%, respectively). Conclusions: Overall, there was increased incidence in ICI toxicity in patients at this oncology institution versus what has been reported in clinical trials. Patients with preexisting autoimmune diseases appeared to have mainly low-grade toxicities with slightly increased incidence of irAE compared with those without pre-existing autoimmune disease. Treatment holds and hospitalizations were higher in patients treated with combination therapy ICIs compared to monotherapy ICIs.

The landscape of cancer treatment has been dramatically transformed by the advent of immune checkpoint inhibitors (ICIs), particularly in the management of advanced melanoma. However, despite their revolutionary success, the use of ICIs is often complicated by immune-related adverse events (irAEs), which can range from mild symptoms to severe, life-threatening conditions. Understanding the underlying mechanisms of these toxicities is crucial to enhancing the safety and effectiveness of immunotherapy [1]. In a recent study published in Nature Cancer, Dimitriou et al. [2] provide novel insights into the immunological processes driving irAEs in melanoma patients treated with ICIs. The researchers identified a significant increase in interleukin-17A (IL-17A) expressing CD4+ T cells at the onset of irAEs, pointing to a type III immune response as a key factor in these adverse events. This discovery not only deepens our understanding of irAEs but also suggests a potential therapeutic target for mitigating these toxicities without compromising the antitumor efficacy of ICIs. What sets these findings apart is their contribution to a broader understanding of the mechanisms behind ICIs’ AEs compared to primary autoimmune diseases. While irAEs share certain immune mechanisms with autoimmune diseases, such as rheumatoid arthritis or psoriasis, the immunological context of ICIs is distinct because of the pharmacological disruption of immune checkpoints [3]. The study highlights the difference between irAEs and primary autoimmune disease by showing that IL-17A expressing CD4+ T cells are particularly implicated in ICI-induced toxicity, which is not a prominent feature of many primary autoimmune conditions. The study utilized a comprehensive approach, including proteomic analyses, multiplex cytokine and chemokine assays, and flow cytometry, to examine the immune profiles of melanoma patients undergoing ICI therapy. A critical finding was the consistent upregulation of IL-17A, along with other type I and III cytokines, at the onset of irAEs. These results were corroborated by the observation that IL-17A expressing CD4+ T cells were significantly elevated in patients experiencing irAEs compared to those who did not. Importantly, the authors provided proof-of-principle evidence for the therapeutic potential of targeting IL-17A in managing irAEs. In a small cohort of patients with severe, corticosteroid-refractory irAEs, treatment with the anti-IL-17A monoclonal antibody secukinumab led to a resolution of symptoms. Secukinumab, primarily used in the treatment of psoriasis, where IL-17A plays a well-established pathogenic role, offers a novel therapeutic option for managing irAEs [4]. Its efficacy in these patients not only underscores the importance of IL-17A in both conditions but also suggests that treatment strategies from autoimmune diseases can be successfully repurposed for irAEs in cancer immunotherapy. This outcome suggests that IL-17A blockade could be a viable strategy for controlling irAEs, offering a new avenue for improving the safety profile of ICIs in melanoma treatment. These findings are particularly relevant given the expanding use of ICIs across various cancers. The ability to identify patients at risk for severe irAEs through biomarkers like IL-17A could enable more personalized treatment approaches. Moreover, the successful use of secukinumab in this context opens the door to broader clinical trials aimed at validating IL-17A as a therapeutic target, potentially leading to the development of new protocols for managing irAEs. The implications of this study extend beyond melanoma. The mechanisms of irAEs are likely to be similar across different cancers treated with ICIs, suggesting that these findings could have broader applicability. As such, researchers and clinicians should consider exploring the role of IL-17A and type III immune responses in other oncological contexts, with the goal of developing more effective and personalized immunotherapy strategies. In conclusion, this study marks a significant advancement in the field of cancer immunotherapy. By identifying IL-17A expressing CD4+ T cells as a central player in irAE development, the study not only enhances our understanding of these toxicities but also provides a promising new target for therapeutic intervention. As the use of ICIs continues to grow, these findings offer a path forward for improving patient outcomes by balancing the benefits of immunotherapy with the need to manage its associated risks effectively. Kai Huang drafted and revised the manuscript. Not applicable. The author declares no conflict of interest. This work is funded by National Natural Science Foundation of China (No. 82103209) and Taishan Schorlar of Shandong Province (tsqn202103174). Not applicable. Not applicable.

Clinical Spectrum, Evolution and Management of Autoimmune Cytopenia Associated with Angioimmunoblastic T-Cell Lymphoma: A Retrospective, Multicenter Study

Immune checkpoint inhibitors have improved outcomes for patients with numerous hematological and solid cancers. Hematologic toxicities have been described, but the spectrum, timing, and clinical presentation of these complications are not well understood. We used the World Health Organization's pharmacovigilance database of individual-case-safety-reports (ICSRs) of adverse drug reactions, VigiBase, to identify cases of hematologic toxicities complicating immune checkpoint inhibitor therapy. We identified 168 ICSRs of immune thrombocytopenic purpura (ITP), hemolytic anemia (HA), hemophagocytic lymphohistiocytosis, aplastic anemia, and pure red cell aplasia in 164 ICSRs. ITP (n = 68) and HA (n = 57) were the most common of these toxicities and occurred concomitantly in four patients. These events occurred early on treatment (median 40 days) and were associated with fatal outcome in 12% of cases. Ipilimumab-based therapy (monotherapy or combination with anti-programmed death-1 [PD-1]) was associated with earlier onset (median 23 vs. 47.5 days, p = .006) than anti-PD-1/programmed death ligand-1 monotherapy. Reporting of hematologic toxicities has increased over the past 2 years (98 cases between January 2017 and March 2018 vs. 70 cases before 2017), possibly because of increased use of checkpoint inhibitors and improved recognition of toxicities. Future studies should evaluate incidence of hematologic toxicities, elucidate risk factors, and determine the most effective treatment algorithms. KEY POINTS: Immune-mediated hematologic toxicities are a potential side effect of immune checkpoint inhibitors (ICIs).Providers should monitor complete blood counts during treatment with ICIs.Corticosteroids are the mainstay of treatment for immune-mediated hematologic toxicities.Further research is needed to define patient-specific risk factors and optimal management strategies for hematologic toxicities.

Immune checkpoint inhibitors (ICIs) have improved survival in patients with advanced melanoma but can be associated with a spectrum of immune-related adverse events (AEs), including both autoimmune-related AEs and other immune-related inflammatory AEs. These associations have primarily been evaluated in clinical trials that include highly selected patients, with older adults often underrepresented. To evaluate the association between use of ICIs and immune-related AEs (autoimmune and other immune related) among older patients with cutaneous melanoma. A population-based cohort study was conducted from January 1, 2011, to December 31, 2015. Data were analyzed from January 31 to May 31, 2021. With use of a linked database of Medicare claims and Surveillance, Epidemiology, and End Results (SEER) Program population-based cancer registries, patients of White race diagnosed with stages II-IV or unknown (American Joint Committee on Cancer, AJCC Cancer Staging Manual 6th edition) first primary cutaneous melanoma during 2011-2015, as reported to SEER, and followed up through December 31, 2015, were identified. Immune checkpoint inhibitors for treatment of melanoma. The association between ICIs and immune-related AEs ascertained from Medicare claims data was estimated using multivariable Cox regression with hazard ratios (HRs) and 95% CIs and with cumulative incidence accounting for competing risk of death. The study included 4489 patients of White race with first primary melanoma (3002 men [66.9%]; median age, 74.9 [range, 66.0-84.9] years). During follow-up (median, 1.4 [range, 0-5.0] years), 1576 patients (35.1%) had an immune-related AE on a Medicare claim. Use of ICIs (reported for 418 patients) was associated with autoimmune-related AEs (HR, 2.5; 95% CI, 1.6-4.0), including primary adrenal insufficiency (HR, 9.9; 95% CI, 4.5-21.5) and ulcerative colitis (HR, 8.6; 95% CI, 2.8-26.3). Immune checkpoint inhibitors also were associated with other immune-related AEs (HR, 2.2; 95% CI, 1.7-2.8), including Cushing syndrome (HR, 11.8; 95% CI, 1.4-97.2), hyperthyroidism (HR, 6.3; 95% CI, 2.0-19.5), hypothyroidism (HR, 3.8; 95% CI, 2.4-6.1), hypopituitarism (HR, 19.8; 95% CI, 5.4-72.9), other pituitary gland disorders (HR, 6.0; 95% CI, 1.2-30.2), diarrhea (HR, 3.5; 95% CI, 2.5-4.9), and sepsis or septicemia (HR, 2.2; 95% CI, 1.4-3.3). Most associations were pronounced within 6 months following the first ICI claim and comparable with or without a baseline history of autoimmune disease. The cumulative incidence at 6 months following the first ICI claim was 13.7% (95% CI, 9.7%-18.3%) for autoimmune-related AEs and 46.8% (95% CI, 40.7%-52.7%) for other immune-related AEs. In this cohort study of older adults with melanoma, ICIs were associated with autoimmune-related AEs and other immune-related AEs. Although some findings were consistent with clinical trials of ICIs, others warrant further investigation. As ICI use continues to expand rapidly, ongoing investigation of the spectrum of immune-related AEs may optimize management of disease in patients.

Cancer specific risk and mortality due to autoimmune hemolytic anemia (AIHA) associated with immune checkpoint inhibitors (ICI)

Background There are conflicting data regarding the vulnerability of cancer patients receiving immune checkpoint inhibitors (ICIs) to COVID-19 infection.1–3 In addition, immune-related adverse events (irAEs) driven in part by cytokine...