Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia

被引：755

作者：

Byrd, John C. ^{[1
]}

Harrington, Bonnie ^{[2
]}

O'Brien, Susan ^{[3
]}

Jones, Jeffrey A. ^{[1
]}

Schuh, Anna ^{[4
]}

Devereux, Steve ^{[5
]}

Chaves, Jorge ^{[7
]}

Wierda, William G. ^{[9
,10
]}

Awan, Farrukh T. ^{[1
]}

Brown, Jennifer R. ^{[11
]}

Hillmen, Peter ^{[6
]}

Stephens, Deborah M. ^{[12
]}

Ghia, Paolo ^{[13
,14
]}

Barrientos, Jacqueline C. ^{[15
]}

Pagel, John M. ^{[8
]}

Woyach, Jennifer ^{[1
]}

Johnson, Dave ^{[18
]}

Huang, Jane ^{[18
]}

Wang, Xiaolin ^{[18
]}

Kaptein, Allard ^{[18
]}

Lannutti, Brian J. ^{[18
]}

Covey, Todd ^{[18
]}

Fardis, Maria ^{[18
]}

McGreivy, Jesse ^{[18
]}

Hamdy, Ahmed ^{[18
]}

Rothbaum, Wayne ^{[18
]}

Izumi, Raquel ^{[18
]}

Diacovo, Thomas G. ^{[16
]}

Johnson, Amy J. ^{[1
]}

Furman, Richard R. ^{[17
]}

机构：

[1] Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA

[2] Coll Vet Med, Dept Vet Biosci, Columbus, OH USA

[3] Univ Calif Irvine, UC Irvine Hlth Chao Family Comprehens Canc Ctr, Orange, CA USA

[4] Univ Oxford, Oxford, England

[5] Kings Coll Hosp London, NHS Fdn Trust, London, England

[6] St James Univ Hosp, Dept Haematol, Leeds, W Yorkshire, England

[7] Northwest Med Specialties, Tacoma, WA USA

[8] Swedish Canc Inst, Seattle, WA USA

[9] Univ Texas Houston, Div Canc Med, Dept Leukemia, Houston, TX USA

[10] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[11] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[12] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA

[13] Univ Vita Salute San Raffaele, Milan, Italy

[14] Ist Sci San Raffaele, Milan, Italy

[15] Hofstra North Shore LIJ Sch Med, Chron Lymphocyt Leukemia Res & Treatment Ctr, Lake Success, NY USA

[16] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY USA

[17] Weill Cornell Med Ctr, New York Presbyterian, New York, NY USA

[18] Acerta Pharma, Oss, Netherlands

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2016年 / 374卷 / 04期

关键词：

TYROSINE KINASE INHIBITOR; B-CELL RECEPTOR; X-LINKED AGAMMAGLOBULINEMIA; OPEN-LABEL; IN-VIVO; IBRUTINIB; BTK; PCI-32765; ACTIVATION; LYMPHOMA;

D O I：

10.1056/NEJMoa1509981

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Irreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors. METHODS In this uncontrolled, phase 1-2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with acalabrutinib at a dose of 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion. RESULTS The median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy-chain variable genes. No dose-limiting toxic effects occurred during the dose-escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter's transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred. CONCLUSIONS In this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 deletion.

引用

页码：323 / 332

页数：10

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