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.
J Clin Oncol. 2016 Dec 20;34(36):4381-4389. doi: 10.1200/JCO.2016.67.3301. Epub 2016 Oct 31.
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.
目的：Blinatumomab 是一种双特异性 T 细胞衔接抗体构建体，靶向 B 细胞淋巴母细胞上的 CD19。我们评估了blinatumomab 在复发/难治性 B 细胞前体急性淋巴细胞白血病（BCP-ALL）儿童中的安全性、药代动力学、推荐剂量和疗效潜力。
方法：这项开放标签研究纳入了复发/难治性 BCP-ALL 儿童，分为 I 期剂量递增部分和 II 期部分，使用 6 周治疗周期。主要终点是最大耐受剂量（I 期）和前两个周期内的完全缓解率（II 期）。
结果：我们在 I 期治疗了 49 例患者，在 II 期治疗了 44 例患者。在第 1 周期中，4 例患者出现剂量限制毒性（I 期）。3 例发生 4 级细胞因子释放综合征（1 例归因于 5 级心力衰竭）；1 例发生致命性呼吸衰竭。最大耐受剂量为 15μg/m/d。blinatumomab 的药代动力学在剂量水平上呈线性，且在各年龄组中一致。基于 I 期数据，复发/难治性 ALL 患儿推荐的 blinatumomab 剂量为前 7 天 5μg/m/d，此后为 15μg/m/d。在接受推荐剂量的 70 例患者中，27 例（39%；95%CI，27%至 51%）在前两个周期内达到完全缓解，其中 14 例（52%）达到完全微小残留病缓解。最常见的≥3 级不良事件为贫血（36%）、血小板减少（21%）和低钾血症（17%）。3 例（4%）和 1 例（1%）患者分别发生 3 级和 4 级细胞因子释放综合征。2 例（3%）患者因 2 级癫痫发作而中断治疗。
结论：本试验是我们所知的首个儿科此类试验，证明了单药 blinatumomab 在复发/难治性 BCP-ALL 儿童中的抗白血病活性，并伴有完全微小残留病缓解。blinatumomab 可能是该治疗环境中的一个重要新治疗选择，需要进一步研究以确定其治愈适应证。
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