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J Clin Oncol. 2016 Dec 20;34(36):4381-4389. Epub 2016 Oct 31.

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

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Arend von Stackelberg, Charité Campus Virchow, Berlin; Gerhard Zugmaier, Amgen Research (Munich), Munich; Rupert Handgretinger, University of Tübingen, Tübingen; Peter Bader, Hospital for Children and Adolescents III, University of Frankfurt, Frankfurt; Paul Gerhardt Schlegel, University Children's Hospital Würzburg, Würzburg; Arndt Borkhardt, University of Düsseldorf Medical Faculty, Düsseldorf, Germany; Franco Locatelli, Ospedale Pediatrico Bambino Gesù, Rome, University of Pavia, Pavia; Carmelo Rizzari, San Gerardo Hospital, University of Milano-Bicocca, Monza; Chiara Messina, Clinica di Oncoematologia Pediatrica, Università degli Studi di Padova, Padova, Italy; Benoît Brethon, Hôpital Robert Debré, Service Hématologie-Immunologie Pédiatrique, Paris; Gérard Michel, Hôpital de la Timone, Marseille, France; Christian M. Zwaan, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, Netherlands; Tanya M. Trippett, Memorial Sloan Kettering Cancer Center, New York, NY; Maureen M. O'Brien, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Deepa Bhojwani, Children's Hospital of Los Angeles; Kuolung Hu and Min Zhu, Amgen, Thousand Oaks, CA; Susan R. Rheingold, Children's Hospital of Philadelphia, Philadelphia, PA; Todd Michael Cooper, Seattle Children's Hospital, Seattle, WA; Phillip Barnette, Primary Children's Medical Center, Salt Lake City, UT; Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Lia Gore, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO; and James A. Whitlock, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.


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/m2/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/m2/d for the first 7 days, followed by 15 µg/m2/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.


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