Abstract
Background: Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 have transformed cancer therapy. However, their expanding use is associated with immune-related adverse events (irAEs), including a less characterized subset of hematologic toxicities. Autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), aplastic anemia, and pancytopenia are potentially life-threatening manifestations, but current knowledge is limited to case reports and small series. These events are often underreported in clinical trials due to rarity and limited follow-up. Large-scale pharmacovigilance is needed to better defined their incidence and risk profile.
Methods: We conducted a retrospective pharmacovigilance analysis using the FDA Adverse Event Reporting System (FAERS) from Q1 2014 through Q1 2025. Hematologic cytopenias were identified using MedDRA preferred terms of pancytopenia, neutropenia, thrombocytopenia, aplastic anemia, AIHA, ITP, agranulocytosis, and hemolysis. ICIs were identified by both generic and brand names. Disproportionality was assessed using reporting odds ratios (RORs) and 95% confidence intervals, comparing ICI-associated cytopenia reports to all other FAERS reports. Regimen complexity was determined using FAERS therapy-sequence metadata to classify reports as monotherapy or combination. Time trends in cytopenia reporting were visualized across the study period.
Results: Among 294,685 cytopenia reports, 13,847 (4.7%) involved at least one ICI. Nivolumab, pembrolizumab, and atezolizumab accounted for over 85% of these cases. Disproportionality analysis revealed the highest signal was seen with atezolizumab and AIHA (ROR 24.8, 95% CI: 22.8–27.0). Other notable signals included durvalumab with pancytopenia (ROR 1.67), ipilimumab with thrombocytopenia (ROR 1.43), and pembrolizumab with AIHA (ROR 1.74). Combination regimens accounted for 73.3% of ICI-related cytopenia reports, 6.9% occurred with monotherapy, and 19.8% had incomplete regimen data. Temporal trends showed a steep rise in ICI-associated cytopenias beginning in 2016, peaking between 2021–2023, mirroring ICI adoption across cancer types.
Conclusions: In this decade-long pharmacovigilance analysis, hematologic irAEs, particularly AIHA and ITP, were disproportionately associated with ICIs, most notably anti–PD-L1 agents. Most occurred with combination regimens, but monotherapy regimenss were not exempt. Our findings emphasize the importance of early recognition, diagnostic evaluation, and multidisciplinary management of new-onset cytopenias during immunotherapy. These real-world data complement clinical trial findings and support enhanced risk stratification and safety monitoring in oncologic practice. Further prospective and mechanistic studies are warranted to guide prevention strategies as ICI use continues to expand.
