Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

Abstract

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m/d for the first 7 days, followed by 15 µg/m/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

“…Four BSA‐based dose regimens were tested on the basis of results in adults: 5, 15, 30, and 15–30 μg/m 2 /d. Stepwise dosing of 5 μg/m 2 /d for 7 days, then 15 μg/m 2 /d for weeks 2–4 of cycle 1, and 15 μg/m 2 /d for subsequent cycles, was selected for phase II because of the positive efficacy signal and favorable safety profile; there were no incidences of cytokine release syndrome or Grade 3 central nervous system (CNS)‐related events for this dosing regimen in the phase I/II study 77. A total of 44 pediatric patients from <2–17 years, including two infants, were enrolled in phase II of the study.…”

Perspectives of Fc engineered antibodies in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia

“…Blinatumomab proved highly efficient in adult BCP-ALL and B-cell lymphoma patients as well as in pediatric BCP-ALL. 2 , 21 , 22 It has been approved by the FDA for the treatment of relapsed or refractory adult and pediatric ALL patients and current trials are in planning employing blinatumomab in the upfront non-relapsed setting in pediatric ALL also. Likewise, impressive effects in both adults and children were achieved by administration of genetically modified T cells which express a CD19 specific CAR consisting typically of a CD19 scFv fused to intracellular signal transduction domain of CD3ζ for activation and at least one costimulatory domain, e.g.…”

“…2 , 21 , 24 , 27 These toxicities include cytokine release syndrome (CRS), seizures and encephalopathy. In addition, CD19 CAR T cell therapy may be associated with long-term B cell aplasia.…”

Új és hagyományos irányok a gyermekkori akut lymphoblastos leukaemia biológiájában és ellátásában

“…Idetartozik a blinatumomab, amelynek anti-CD19-karja a leukaemiás B-sejteket, anti-CD3-karja pedig a normális érett T-sejteket köti, kialakítva ezáltal egy szerkezetileg megfelelő immunológiai szinapszist a CD19 + targetsejtek apoptózisára, illetve lízisére [42,51]. A blinatumomab hatékonynak bizonyult Ph-negatív refrakter vagy relabált prekurzor B-ALL-es gyermekeknél [52]. Más fejlesztések során egyéb targetekhez kötődő immunglobulin-alegységek-hez kémiailag kapcsoltak baktériumtoxint (DT2219; 2. ábra), citotoxikus ágenst (inotuzumab-ozogamicin) és radioizotópot ( 90 Y-ibritumomab-tiuxetán,…”