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

被引：476

作者：

von Stackelberg, Arend ^{[1
]}

Locatelli, Franco ^{[7
,8
]}

Zugmaier, Gerhard ^{[2
]}

Handgretinger, Rupert ^{[3
]}

Trippett, Tanya M. ^{[14
]}

Rizzari, Carmelo ^{[9
]}

Bader, Peter ^{[4
]}

O'Brien, Maureen M. ^{[15
]}

Brethon, Benoit ^{[11
]}

Bhojwani, Deepa ^{[16
]}

Schlegel, Paul Gerhardt ^{[5
]}

Borkhardt, Arndt ^{[6
]}

Rheingold, Susan R. ^{[18
]}

Cooper, Todd Michael ^{[19
]}

Zwaan, Christian M. ^{[13
]}

Barnette, Phillip ^{[20
]}

Messina, Chiara ^{[10
]}

Michel, Gerard ^{[12
]}

DuBois, Steven G. ^{[21
,22
]}

Hu, Kuolung ^{[17
]}

Zhu, Min ^{[17
]}

Whitlock, James A. ^{[25
]}

Gore, Lia ^{[23
,24
]}

机构：

[1] Charite Campus Virchow, Berlin, Germany

[2] Amgen Res Munich, Munich, Germany

[3] Univ Tubingen, Tubingen, Germany

[4] Goethe Univ Frankfurt, Hosp Children & Adolescents 3, Frankfurt, Germany

[5] Univ Childrens Hosp Wurzburg, Wurzburg, Germany

[6] Univ Dusseldorf, Fac Med, Dusseldorf, Germany

[7] Osped Pediat Bambino Gesu, Rome, Italy

[8] Univ Pavia, Pavia, Italy

[9] Univ Milano Bicocca, San Gerardo Hosp, Monza, Italy

[10] Univ Padua, Clin Oncoematol Pediat, Padua, Italy

[11] Hop Robert Debre, Serv Hematol Immunol Pediat, Paris, France

[12] Hop Enfants La Timone, Marseille, France

[13] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Rotterdam, Netherlands

[14] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[15] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA

[16] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA

[17] Amgen Inc, Thousand Oaks, CA USA

[18] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[19] Seattle Childrens Hosp, Seattle, WA USA

[20] Primary Childrens Med Ctr, Salt Lake City, UT 84103 USA

[21] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA

[22] Harvard Med Sch, Boston, MA USA

[23] Univ Colorado, Sch Med, Aurora, CO USA

[24] Childrens Hosp Colorado, Aurora, CO USA

[25] Univ Toronto, Hosp Sick Children, Toronto, ON, Canada

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2016年 / 34卷 / 36期

关键词：

MINIMAL RESIDUAL DISEASE; TERM-FOLLOW-UP; T-CELLS; ANTIBODY; THERAPY; CD19; ACTIVATION; REMISSION; CHILDREN; RELAPSE;

D O I：

10.1200/JCO.2016.67.3301

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lympho-blasts. 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 mg/m(2)/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 mg/m2/d for the first 7 days, followed by 15 mg/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. (C) 2016 by American Society of Clinical Oncology

引用

页码：4381 / +

页数：11

共 31 条

[1] Extremely potent, rapid and costimulation-independent cytotoxic T-cell response against lymphoma cells catalyzed by a single-chain bispecific antibody [J].