Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia

John C. Byrd, Bonnie Harrington, Susan O'Brien, Jeffrey A. Jones, Anna Schuh, Steve Devereux, Jorge Chaves, William G. Wierda, Farrukh T. Awan, Jennifer R. Brown, Peter Hillmen, Deborah M. Stephens, Paolo Ghia, Jacqueline C. Barrientos, John M. Pagel, Jennifer Woyach, Dave Johnson, Jane Huang, Xiaolin Wang, Allard Kaptein & 10 others Brian J. Lannutti, Todd Covey, Maria Fardis, Jesse McGreivy, Ahmed Hamdy, Wayne Rothbaum, Raquel Izumi, Thomas G. Diacovo, Amy J. Johnson, Richard R. Furman

Research output: Contribution to journalArticle

310 Citations (Scopus)

Abstract

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 followup 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. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.)

Original languageEnglish
Pages (from-to)323-332
Number of pages10
JournalNew England Journal of Medicine
Volume374
Issue number4
DOIs
Publication statusPublished - Jan 28 2016

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B-Cell Chronic Lymphocytic Leukemia
Chromosome Deletion
Safety
Immunoglobulin Heavy Chain Genes
Lymphocytosis
acalabrutinib
Poisons
Therapeutics
Multicenter Studies
Headache
Diarrhea
Lymphoma
Phosphotransferases
Pharmacokinetics
Weights and Measures
Agammaglobulinaemia tyrosine kinase

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Byrd, J. C., Harrington, B., O'Brien, S., Jones, J. A., Schuh, A., Devereux, S., ... Furman, R. R. (2016). Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. New England Journal of Medicine, 374(4), 323-332. https://doi.org/10.1056/NEJMoa1509981

Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. / Byrd, John C.; Harrington, Bonnie; O'Brien, Susan; Jones, Jeffrey A.; Schuh, Anna; Devereux, Steve; Chaves, Jorge; Wierda, William G.; Awan, Farrukh T.; Brown, Jennifer R.; Hillmen, Peter; Stephens, Deborah M.; Ghia, Paolo; Barrientos, Jacqueline C.; Pagel, John M.; Woyach, Jennifer; Johnson, Dave; Huang, Jane; Wang, Xiaolin; Kaptein, Allard; Lannutti, Brian J.; Covey, Todd; Fardis, Maria; McGreivy, Jesse; Hamdy, Ahmed; Rothbaum, Wayne; Izumi, Raquel; Diacovo, Thomas G.; Johnson, Amy J.; Furman, Richard R.

In: New England Journal of Medicine, Vol. 374, No. 4, 28.01.2016, p. 323-332.

Research output: Contribution to journalArticle

Byrd, JC, Harrington, B, O'Brien, S, Jones, JA, Schuh, A, Devereux, S, Chaves, J, Wierda, WG, Awan, FT, Brown, JR, Hillmen, P, Stephens, DM, Ghia, P, Barrientos, JC, Pagel, JM, Woyach, J, Johnson, D, Huang, J, Wang, X, Kaptein, A, Lannutti, BJ, Covey, T, Fardis, M, McGreivy, J, Hamdy, A, Rothbaum, W, Izumi, R, Diacovo, TG, Johnson, AJ & Furman, RR 2016, 'Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia', New England Journal of Medicine, vol. 374, no. 4, pp. 323-332. https://doi.org/10.1056/NEJMoa1509981
Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. New England Journal of Medicine. 2016 Jan 28;374(4):323-332. https://doi.org/10.1056/NEJMoa1509981
Byrd, John C. ; Harrington, Bonnie ; O'Brien, Susan ; Jones, Jeffrey A. ; Schuh, Anna ; Devereux, Steve ; Chaves, Jorge ; Wierda, William G. ; Awan, Farrukh T. ; Brown, Jennifer R. ; Hillmen, Peter ; Stephens, Deborah M. ; Ghia, Paolo ; Barrientos, Jacqueline C. ; Pagel, John M. ; Woyach, Jennifer ; Johnson, Dave ; Huang, Jane ; Wang, Xiaolin ; Kaptein, Allard ; Lannutti, Brian J. ; Covey, Todd ; Fardis, Maria ; McGreivy, Jesse ; Hamdy, Ahmed ; Rothbaum, Wayne ; Izumi, Raquel ; Diacovo, Thomas G. ; Johnson, Amy J. ; Furman, Richard R. / Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. In: New England Journal of Medicine. 2016 ; Vol. 374, No. 4. pp. 323-332.
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abstract = "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 followup 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. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.)",
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T1 - Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia

AU - Byrd, John C.

AU - Harrington, Bonnie

AU - O'Brien, Susan

AU - Jones, Jeffrey A.

AU - Schuh, Anna

AU - Devereux, Steve

AU - Chaves, Jorge

AU - Wierda, William G.

AU - Awan, Farrukh T.

AU - Brown, Jennifer R.

AU - Hillmen, Peter

AU - Stephens, Deborah M.

AU - Ghia, Paolo

AU - Barrientos, Jacqueline C.

AU - Pagel, John M.

AU - Woyach, Jennifer

AU - Johnson, Dave

AU - Huang, Jane

AU - Wang, Xiaolin

AU - Kaptein, Allard

AU - Lannutti, Brian J.

AU - Covey, Todd

AU - Fardis, Maria

AU - McGreivy, Jesse

AU - Hamdy, Ahmed

AU - Rothbaum, Wayne

AU - Izumi, Raquel

AU - Diacovo, Thomas G.

AU - Johnson, Amy J.

AU - Furman, Richard R.

PY - 2016/1/28

Y1 - 2016/1/28

N2 - 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 followup 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. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.)

AB - 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 followup 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. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.)

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