Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening hyperinflammatory syndrome. It is increasingly recognized as a potential immune-mediated complication of T-cell engaging bispecific antibodies (bsAbs) used in hematologic malignancies. These bsAbs redirect T-cells to kill cancer cells, offering new hope for refractory leukemias and lymphomas. However, by powerfully activating T-cells, they also carry a risk of severe immune reactions. Towards the end of 2024, the U.S. Food and Drug Administration (FDA) flagged HLH as a potential safety signal associated with multiple bsAbs(U.S. Food and Drug Administration, 2024). Despite this alert, little real-world data exists quantifying how often HLH occurs with bsAb treatments or which patients are at risk. Clinical trials have limited numbers and may not capture rare events well, so real-world evidence from large databases is essential.

Objectives: This study aimed to (1) estimate the real-world incidence of HLH within 90 days of initiation of selected bsAbs - blinatumomab, glofitamab, teclistamab, talquetamab, epcoritamab, and elranatamab, (2) identify clinical predictors of HLH development and (3) Assess the impact of HLH occurrence on survival outcomes.

Methods: A retrospective cohort analysis was conducted using the TriNetX Global Network which included data from 202 healthcare organizations, accessed on July 8, 2025. The dataset included 4,260 adult patients (≥18 years) with hematologic malignancies who initiated bsAb therapy between January 1, 2022, and July 1, 2025. Patients with a prior diagnosis of HLH were excluded. The primary outcome was the occurrence of HLH within 90 days of bsAb initiation. Cohorts were defined based on HLH status, and baseline clinical and laboratory variables were balanced using 1:1 propensity score matching. Measure of Association analysis was used to compare outcome proportions between cohorts, estimating risk, risk difference, risk ratio, and odds ratio. Mortality outcomes (one year) were assessed using Kaplan-Meier Analysis.

Results: Among the 4,260 patients on bsAbs, 30 developed HLH within 90 days of bsAb initiation, corresponding to a cumulative incidence of 0.7%. After matching, each cohort included 30 patients. HLH-positive patients had a significantly higher risk of death compared to HLH-negative patients (66.7% vs. 33.3%, p=0.01), with a hazard ratio for death of 2.53 (95% CI: 0.89–7.21). Severe sepsis (33.3% vs. 2%, p<0.001), bacterial pneumonia (33.3% vs. 1.0%, p<0.001), elevated ferritin levels >500 ng/mL (33.3% vs. 13%, p=0.001), Elevated Lactate dehydrogenase (LDH) >225 U/L (66.7% vs. 45.4%, p=0.02 ), Neutropenia (Neutrophil <0.5 x 10^3/µL) (33.3% vs. 17.3%, p=0.021) , Anemia (Hb <9 g/dL) (66.7% vs. 41.1%, p=0.005) and Thrombocytopenia (Platelet <100 x 10^3/µL) (66.7% vs. 43.1%, p=0.009) were significantly more common in HLH-positive patients, suggesting potential clinical associations that warrants further investigation.

Conclusions: In this large, real-world cohort of patients with hematologic malignancies treated with bsAbs, HLH occurred in approximately 1 in 140 patients within 90 days of therapy initiation. HLH was associated with markedly increased mortality during the one-year period following therapy. History of severe Infections prior to initiation of bsAbs therapy and baseline laboratory markers such as hyperferritinemia, Elevated LDH, Neutropenia, Anemia and Thrombocytopenia were associated with HLH. These findings support the FDA's ongoing safety signal evaluation. Development of risk stratification tools and proactive monitoring strategies is warranted to mitigate this serious complication. In summary, while HLH is rare in bsAb-treated patients, it carries a high risk of death. Our findings underscore the importance of early detection and intervention for HLH and provide a foundation for targeted risk-based monitoring strategies to mitigate this serious complication.

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2025
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