L. G. and C. B. contributed equally. Background: Blinatumomab is a bispecific T-cell engager (CD3/CD19) and the first target-specific immunotherapy moving to first-line treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Previously it was used in relapsed or refractory disease with a dose-finding study in 2014. The standard pediatric regimen escalates to a maximum of 15μg/m²/day, whereas adults receive doses up to 30μg/m²/day. Dose limiting toxicity in pediatrics consisted of severe cytokine release syndrome (CRS), partly associated with concurrent infections. Nowadays, clinical management and risk-assessment at start of blinatumomab have been improved over a decade. Therefore, higher doses have been applied to individual patients with very high risk ALL. We conducted a retrospective analysis comparing standard-dose vs high-dose blinatumomab (30μg/m²/day) in pediatric B-ALL and related B-lineage malignancies to evaluate safety and efficacy.

Methods:

Eighteen pediatric patients with relapsed/refractory B-ALL or a related B-lymphoid malignancy (including one in lymphoid blast crisis of CML) were retrospectively analyzed from a single center. Patients received blinatumomab at either the standard dose (up to 15μg/m²/day) or with escalation to 30μg/m²/day in at least one cycle. Escalation to 30μg/m²/day was an individual clinical decision based on line of treatment and relapse risk of ALL and thereby anticipated poor prognosis. In total, 42 cycles were evaluated (28 standard-dose and 14 high-dose cycles). Adverse events (AEs) were graded according to CTCAE v5.0, and a cumulative therapeutic burden (TB) score captured overall toxicity. Minimal residual disease (MRD) was assessed before and after each cycle using the most sensitive available method (PCR, flow cytometry, or morphology). Statistical tests were applied to compare toxicity and response outcomes between dosing groups.

Results: High-dose blinatumomab did not increase overall toxicity. The therapeutic burden was similar to that of standard dosing, and rates of grade ≥3 AEs were comparable between groups. CRS occurred in 32% of standard-dose cycles vs 29% of high-dose cycles; notably, no grade ≥3 CRS was observed in any high-dose cycle (whereas 7% of standard-dose cycles had grade ≥3 CRS). The most common grade ≥3 toxicities with 30 μg/m²/day were hematologic (cytopenias, e.g., neutropenia in 68% of high-dose cycles, anemia in 79%), likely reflecting the underlying disease burden. An MRD reduction was achieved in 32% of standard-dose cycles compared to 36% of high-dose cycles. Of note, patients receiving 30μg/m²/day had more advanced, refractory disease (often multiple relapses or post-transplant relapse). Despite their higher-risk profiles, these patients achieved MRD responses comparable to those with standard dosing.

Conclusions: Escalating the blinatumomab dose to 30μg/m²/day in pediatric B-ALL appears safe and did not increase toxicity or CRS severity relative to the standard dose. Even in children with high-risk or refractory disease, high-dose blinatumomab produced MRD responses similar to standard dosing. Changing pediatric standard dosing in the future will require prospective controlled clinical trials. However, these findings suggest that 30μg/m²/day is a feasible, well-tolerated dose that may offer an efficacy benefit in poor-prognosis B-ALL, supporting further optimization of pediatric dosing regimens.

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2025
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