Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

被引：3841

作者：

Maude, S. L. ^{[1
,4
,5
]}

Laetsch, T. W. ^{[6
]}

Buechner, J. ^{[7
]}

Rives, S. ^{[8
]}

Boyer, M. ^{[9
]}

Bittencourt, H. ^{[10
,11
,12
]}

Bader, P. ^{[14
]}

Verneris, M. R. ^{[15
]}

Stefanski, H. E. ^{[15
]}

Myers, G. D. ^{[16
]}

Qayed, M. ^{[17
]}

De Moerloose, B. ^{[18
,19
]}

Hiramatsu, H. ^{[20
]}

Schlis, K. ^{[21
]}

Davis, K. L. ^{[21
]}

Martin, P. L. ^{[23
]}

Nemecek, E. R. ^{[24
]}

Yanik, G. A. ^{[25
]}

Peters, C. ^{[26
]}

Baruchel, A. ^{[27
,28
]}

Boissel, N. ^{[28
,29
]}

Mechinaud, F. ^{[30
]}

Balduzzi, A. ^{[31
]}

Krueger, J. ^{[13
]}

June, C. H. ^{[2
,3
]}

Levine, B. L. ^{[2
,3
]}

Wood, P. ^{[32
]}

Taran, T. ^{[32
]}

Leung, M. ^{[32
]}

Mueller, K. T. ^{[33
]}

Zhang, Y. ^{[32
]}

Sen, K. ^{[32
]}

Lebwohl, D. ^{[32
]}

Pulsipher, M. A. ^{[22
]}

Grupp, S. A. ^{[1
,4
,5
]}

机构：

[1] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA

[2] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[3] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA

[4] Childrens Hosp Philadelphia, Div Oncol, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA

[5] Childrens Hosp Philadelphia, Canc Immunotherapy Program, Philadelphia, PA 19104 USA

[6] Univ Texas Dallas, Southwestern Med Ctr, Dept Pediat, Dallas, TX USA

[7] Oslo Univ Hosp, Dept Pediat Hematol & Oncol, Oslo, Norway

[8] Hosp St Joan Deu Barcelona, Dept Pediat Hematol & Oncol, Barcelona, Spain

[9] Univ Utah, Dept Pediat & Internal Med, Salt Lake City, UT USA

[10] Univ Montreal, Dept Pediat, Fac Med, Montreal, PQ, Canada

[11] CHU Sainte Justine, Res Ctr, Hematol Oncol Div, Montreal, PQ, Canada

[12] CHU Sainte Justine, Res Ctr, Charles Bruneau Canc Ctr, Montreal, PQ, Canada

[13] Hosp Sick Children, Div Haematol Oncol Bone Marrow Transplantat, Toronto, ON, Canada

[14] Univ Hosp Frankfurt, Hosp Children & Adolescents, Div Stem Cell Transplantat & Immunol, Frankfurt, Germany

[15] Univ Minnesota, Div Pediat Blood & Marrow Transplant, Minneapolis, MN USA

[16] Childrens Mercy Hosp & Clin, Kansas City, MO USA

[17] Emory Univ, Aflac Canc & Blood Disorders Ctr, Atlanta, GA 30322 USA

[18] Ghent Univ Hosp, Dept Pediat Hematol Oncol & Stem Cell Transplanta, Ghent, Belgium

[19] CRIG, Ghent, Belgium

[20] Kyoto Univ, Grad Sch Med, Dept Pediat, Kyoto, Japan

[21] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA

[22] USC Keck Sch Med, Childrens Hosp Los Angeles, Div Hematol Oncol Blood & Marrow Transplant, Los Angeles, CA USA

[23] Duke Univ, Med Ctr, Div Pediat Blood & Marrow Transplant, Durham, NC USA

[24] Oregon Hlth & Sci Univ, Portland, OR 97201 USA

[25] CS Mott Childrens Hosp, Ann Arbor, MI USA

[26] St Anna Childrens Hosp, Stem Cell Transplantat Unit, Vienna, Austria

[27] Univ Hosp Robert Debre, Paris, France

[28] Univ Paris Diderot, Paris, France

[29] St Louis Hop, Paris, France

[30] Royal Childrens Hosp, Melbourne, Vic, Australia

[31] Univ Milano Bicocca, Clin Pediat, Monza, Italy

[32] Novartis Pharmaceut, E Hanover, NJ USA

[33] Novartis Inst Biomed Res, E Hanover, NJ USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2018年 / 378卷 / 05期

关键词：

CAR-T-CELLS; PEDIATRIC-PATIENTS;

D O I：

10.1056/NEJMoa1709866

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849.)

引用

页码：439 / 448

页数：10

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