A comprehensive real-world analysis of antibody-drug conjugate (ADC) safety has revealed dramatic differences in neutropenia risk across commonly used agents, providing critical insights for clinical decision-making and patient monitoring strategies.
The retrospective study, presented by Dr. Miranda Chen at MASCC 2025, analyzed data from over 1,500 patients treated with ADCs across five University of California hospitals between November 2017 and June 2024. The research examined the incidence and predictors of grade ≥3 neutropenia following treatment with ten commonly used ADCs.
Drug-Specific Risk Profiles Emerge
The analysis revealed striking variations in hematologic toxicity risk among different ADC agents. Gemtuzumab ozogamicin emerged as the highest-risk agent, with an odds ratio of 60.50 (95% CI: 9.89–376.00, p<0.01) for severe neutropenia. Inotuzumab ozogamicin also posed significant risk with an odds ratio of 16.90 (95% CI: 2.87–101.00, p<0.01).
In contrast, certain ADCs demonstrated favorable safety profiles. Fam-trastuzumab deruxtecan and ado-trastuzumab emtansine were associated with significantly lower neutropenia risk, with odds ratios of 0.31 and 0.01, respectively.
Patient-Related Risk Factors Identified
Beyond drug-specific factors, the study identified several patient characteristics that independently increased neutropenia risk. Pre-existing anemia emerged as the strongest predictor with an odds ratio of 6.29, followed by breast malignancy (OR=3.68), baseline liver dysfunction (OR=2.38), and immunodeficiency disorders (OR=1.92).
"Understanding which patients are most at risk for these adverse effects is crucial for optimizing safety, maintaining dose intensity, and improving treatment outcomes," the researchers noted.
Clinical Implications for Practice
The findings have immediate implications for clinical practice, particularly for high-risk ADCs like gemtuzumab and inotuzumab ozogamicin. The research suggests that closer monitoring, prophylactic growth factor use, or treatment modification may be warranted in patients with identified risk factors.
The identification of modifiable risk factors, such as pre-treatment anemia and liver dysfunction, opens opportunities for prehabilitation strategies to improve patient resilience before ADC initiation. This approach aligns with broader precision supportive care efforts in oncology.
Notably, while neutropenia was a common and measurable toxicity, no variables were significantly associated with hospitalization in this study. This suggests that while neutropenia occurs frequently, it may not necessarily translate to hospital-level complications, possibly due to effective supportive care protocols.
Broader Context of ADC Toxicity
The findings complement broader research on ADC safety profiles. Recent analyses have shown that 89-93% of patients receiving ADCs experience treatment-related adverse events of any grade, with 46-58% experiencing grade ≥3 toxicities. Common adverse events across ADC therapies include fatigue, hematologic toxicities, nausea and vomiting, ophthalmologic toxicity, and neuropathy.
The heterogeneity in toxicity profiles across ADC agents reflects the complex interplay of various components including the target antigen, antibody structure, linker chemistry, payload characteristics, and drug-to-antibody ratio. This complexity underscores the importance of understanding both drug-specific and patient-related factors when selecting ADC therapy.
Future Directions
The research team suggests that future studies should explore the integration of biomarkers such as pharmacogenomic or immune profiling, evaluate the impact of dose modification strategies or prophylactic interventions, and assess real-world outcomes including treatment delays, dose reductions, and infection-related events.
As ADC use continues to expand across cancer types, these findings emphasize the need for predictive models that integrate clinical data, drug pharmacology, and patient comorbidities to optimize treatment selection and monitoring strategies.
