A large-scale pharmacovigilance analysis of temozolomide (TMZ) has revealed both expected and unexpected adverse events associated with this standard glioblastoma treatment, providing critical insights for optimizing patient safety in real-world clinical settings. The study, which analyzed 13,608 TMZ-related adverse events from the FDA Adverse Event Reporting System (FAERS) database spanning 2004 to 2023, identified significant safety signals that may warrant updates to current clinical monitoring guidelines.
Hematologic Toxicities Dominate Safety Profile
The analysis confirmed that hematologic toxicities represent the most prominent safety concern with TMZ therapy. Blood and lymphatic system disorders showed the strongest safety signal with a relative odds ratio (ROR) of 5.94 (95% CI: 5.73-6.15) and proportional reporting ratio (PRR) of 5.48 (95% CI: 5.27-5.7). Specific hematologic adverse events included platelet count decreased (ROR 8.61), febrile neutropenia (ROR 7.40), and myelodysplastic syndrome (ROR 5.77).
These findings align with TMZ's known alkylating mechanism, which disrupts DNA replication in rapidly dividing cells, including hematopoietic precursors. The identification of myelodysplastic syndrome as a significant adverse event raises particular concerns about long-term clonal hematopoiesis risks associated with alkylating agent therapy.
Unexpected Thromboembolic and Infectious Complications
The study uncovered unexpected adverse events that may require enhanced clinical vigilance. Pulmonary embolism emerged as a significant safety signal with an ROR of 4.96 (95% CI: 4.44-5.53), with 323 reported cases. Notably, 102 cases (31.6%) occurred in patients with a Khorana score of 1, suggesting that even patients with lower thrombotic risk scores may benefit from prophylactic anticoagulation during TMZ treatment.
Pneumocystis jirovecii pneumonia (PjP) also showed a strong safety signal (ROR 7.09, 95% CI: 5.18-9.72) with 39 reported cases. Among these, 17 cases (43.6%) involved concurrent dexamethasone use at daily doses ≥2 mg for ≥1 week, suggesting that PjP risk may emerge with lower corticosteroid doses or shorter durations than currently recommended in clinical guidelines.
Neurological and Metabolic Concerns
The analysis identified significant associations between TMZ and neurotoxic adverse events, including hemiparesis (ROR 9.36, 95% CI: 7.78-11.27) and seizures (ROR 6.19). While these events may reflect disease progression in glioma patients, the study authors note that TMZ's ability to cross the blood-brain barrier and potentially induce direct neuronal toxicity cannot be discounted.
Renal and metabolic disorders, including hypernatremia and hyperchloremia, were also identified as significant safety signals. These may be linked to TMZ's interaction with osmotic agents like mannitol, often co-administered to reduce cerebral edema in glioma patients.
Clinical Implications and Recommendations
Based on these findings, the researchers recommend several updates to clinical monitoring practices. For thromboprophylaxis, the data suggest considering prophylactic anticoagulation in patients with a Khorana score ≥1, rather than the current NCCN Guidelines threshold of ≥2. For PjP prophylaxis, the findings support initiating prevention when TMZ is combined with dexamethasone ≥2 mg/day for ≥1 week, lower than the current ESMO guideline recommendation of ≥4 mg/day for ≥2 weeks.
Study Characteristics and Limitations
The analysis included reports from 48,766,547 adverse drug reactions in the FAERS database, with TMZ-related cases predominantly involving males (53.66%) and patients aged 45 years and older. The majority of reports originated from the United States (50.44%), with hospitalization being the most common outcome (35.76%), followed by death (22.79%) and other serious adverse events (34.24%).
The researchers acknowledge several limitations, including potential underreporting and reporting bias inherent in FAERS data, as well as the lack of detailed clinical information such as TMZ dosing schedules and concomitant medications. The study's focus on disproportionality analysis does not establish causality, emphasizing the need for prospective pharmacovigilance initiatives to confirm these signals.
Future Research Directions
The findings underscore the need for mechanistic studies to elucidate TMZ's role in neurotoxicity and renal dysfunction, as well as randomized trials evaluating risk mitigation strategies. The researchers emphasize that integrating real-world data with preclinical models could help refine TMZ's safety profile and improve outcomes for glioma patients.
This comprehensive analysis reinforces the importance of vigilant monitoring in TMZ-treated patients, particularly for hematologic, thromboembolic, and opportunistic infection-related complications, while highlighting the value of real-world pharmacovigilance data in identifying previously unrecognized safety signals.
