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PD-1/PD-L1 inhibitor-induced immune thrombocytopenia: A pharmacovigilance study and systematic review
Donald C Moore1, Joseph B Elmes2, Justin R Arnall3
1Clinical Oncology Pharmacy Manager, Levine Cancer Institute, Atrium Health, Department of Pharmacy, 1021 Morehead Medical Drive, Charlotte, NC 28204, USA.
Introduction:
Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) are used for a variety of cancers and are associated with a risk of developing immune-related adverse events, most commonly dermatitis, colitis, hepatitis, and pneumonitis. Immune-mediated hematologic toxicities have been reported, but are less well-described in the literature. Immune thrombocytopenia (ITP) is a rare autoimmune, hematologic adverse event that has been reported with PD-1/PD-L1 inhibitors.
Methods:
We performed a retrospective observational analysis of the United States Food and Drug Administration Adverse Event Reporting System (FAERS) data. We searched for cases of ITP reported with exposure to PD-1/PD-L1 inhibitors from initial FDA approval for each agent to September 30, 2022. Disproportionality signal analysis was done by calculating the reporting odds ratio (ROR). Oxaliplatin was used as a positive control for sensitivity analysis as it is an anticancer therapy that has been associated with drug-induced ITP. A systematic review of the PubMed database was also conducted to identify published cases of PD-1/PD-L1 inhibitor-induced ITP.
Results:
There were 329 reports of ITP with ICIs in the FAERS database that were reviewed for a disproportionality signal, including atezolizumab (n = 27), durvalumab (n = 17), nivolumab (n = 160), and pembrolizumab (n = 125). The ROR was significant for atezolizumab (ROR 5.39, 95 % CI 3.69-7.87), avelumab (ROR 10.32, 95 % CI 4.91-21.69), durvalumab (ROR 7.91, 95 % CI 4.91-12.75), nivolumab (ROR 9.76, 95 % CI 8.34-11.43), and pembrolizumab (ROR 12.6, 95 % CI 10.55-15.06). In our systematic review, we summated 57 cases of ICI-induced ITP. Nivolumab and pembrolizumab had the most reported cases of ITP in the literature. Most cases reported (53 %) included ITP-directed therapies beyond corticosteroids for the management of ICI-induced ITP.
Conclusion:
There is a significant reporting signal of ITP with several ICI agents. Clinicians should be aware of and monitor for signs of this potentially serious adverse event.
Insights
Immune thrombocytopenia (ITP) is a rare but serious adverse event associated with programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs). This study found a significant reporting signal for ITP with several ICI agents, highlighting the need for clinical awareness.
Area of Science:
- Oncology
- Immunology
- Pharmacovigilance
Background:
- Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) are widely used in cancer therapy.
- While generally safe, ICIs can cause immune-related adverse events, including less common hematologic toxicities like immune thrombocytopenia (ITP).
Approach:
- A retrospective analysis of the US FDA Adverse Event Reporting System (FAERS) database was conducted for ITP cases linked to PD-1/PD-L1 inhibitors up to September 2022.
- Disproportionality analysis using the reporting odds ratio (ROR) identified significant associations between specific ICIs and ITP.
- A systematic literature review supplemented the FAERS data to identify and summarize published cases of ICI-induced ITP.
Key Points:
- The FAERS database contained 329 reports of ITP associated with ICIs, with significant reporting signals for atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab.
- The reporting odds ratios (RORs) indicated a heightened risk of ITP with these agents, with pembrolizumab showing the highest ROR (12.6).
- A systematic review identified 57 published cases of ICI-induced ITP, with nivolumab and pembrolizumab being the most frequently implicated agents. Over half of these cases required ITP-specific therapies beyond corticosteroids.
Conclusions:
- A significant reporting signal for immune thrombocytopenia (ITP) exists for several immune checkpoint inhibitor (ICI) agents.
- Clinicians must remain vigilant for and monitor patients for signs of ITP during ICI therapy.
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