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

von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, O'Brien MM, Brethon B, Bhojwani D, Schlegel PG, Borkhardt A, Rheingold SR, Cooper TM, Zwaan CM, Barnette P, Messina C, Michel G, DuBois SG, Hu K, Zhu M, Whitlock JA, Gore L
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017; 34362016Dec20: 4381-4389


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.

Zugehörigkeit: 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.

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