Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma

Michael L. Wang, Simon Rule, Peter Martin, Andre Goy, Rebecca Auer, Brad S. Kahl Wojciech Jurczak, Ranjana H. Advani, Jorge E. Romaguera, Michael E. Williams, Jacqueline C. Barrientos, Ewa Chmielowska, John Radford, Stephan Stilgenbauer, Martin Dreyling, Wieslaw Wiktor Jedrzejczak, Peter Johnson, Stephen Spurgeon, Lei Li, Liang Zhang, Kate Newberry & 10 others Zhishuo Ou, Nancy Cheng, Bingliang Fang, Jesse McGreivy, Fong Clow, Joseph J. Buggy, Betty Y. Chang, Darrin M. Beaupre, Lori A. Kunkel, Kristie A. Blum

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Bruton's tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma. METHODS: In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety. RESULTS: The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progressionfree survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months. CONCLUSIONS: Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

Original languageEnglish (US)
Pages (from-to)507-516
Number of pages10
JournalNew England Journal of Medicine
Volume369
Issue number6
DOIs
StatePublished - 2013

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Mantle-Cell Lymphoma
Survival
B-Lymphocytes
Confidence Intervals
Therapeutics
Neutropenia
Thrombocytopenia
Non-Hodgkin's Lymphoma
Nausea
Disease-Free Survival
Fatigue
Agammaglobulinaemia tyrosine kinase
PCI 32765
Anemia
Diarrhea
Survival Rate
Safety
Bortezomib
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Wang, M. L., Rule, S., Martin, P., Goy, A., Auer, R., Kahl Wojciech Jurczak, B. S., ... Blum, K. A. (2013). Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. New England Journal of Medicine, 369(6), 507-516. https://doi.org/10.1056/NEJMoa1306220

Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. / Wang, Michael L.; Rule, Simon; Martin, Peter; Goy, Andre; Auer, Rebecca; Kahl Wojciech Jurczak, Brad S.; Advani, Ranjana H.; Romaguera, Jorge E.; Williams, Michael E.; Barrientos, Jacqueline C.; Chmielowska, Ewa; Radford, John; Stilgenbauer, Stephan; Dreyling, Martin; Jedrzejczak, Wieslaw Wiktor; Johnson, Peter; Spurgeon, Stephen; Li, Lei; Zhang, Liang; Newberry, Kate; Ou, Zhishuo; Cheng, Nancy; Fang, Bingliang; McGreivy, Jesse; Clow, Fong; Buggy, Joseph J.; Chang, Betty Y.; Beaupre, Darrin M.; Kunkel, Lori A.; Blum, Kristie A.

In: New England Journal of Medicine, Vol. 369, No. 6, 2013, p. 507-516.

Research output: Contribution to journalArticle

Wang, ML, Rule, S, Martin, P, Goy, A, Auer, R, Kahl Wojciech Jurczak, BS, Advani, RH, Romaguera, JE, Williams, ME, Barrientos, JC, Chmielowska, E, Radford, J, Stilgenbauer, S, Dreyling, M, Jedrzejczak, WW, Johnson, P, Spurgeon, S, Li, L, Zhang, L, Newberry, K, Ou, Z, Cheng, N, Fang, B, McGreivy, J, Clow, F, Buggy, JJ, Chang, BY, Beaupre, DM, Kunkel, LA & Blum, KA 2013, 'Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma', New England Journal of Medicine, vol. 369, no. 6, pp. 507-516. https://doi.org/10.1056/NEJMoa1306220
Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl Wojciech Jurczak BS et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. New England Journal of Medicine. 2013;369(6):507-516. https://doi.org/10.1056/NEJMoa1306220
Wang, Michael L. ; Rule, Simon ; Martin, Peter ; Goy, Andre ; Auer, Rebecca ; Kahl Wojciech Jurczak, Brad S. ; Advani, Ranjana H. ; Romaguera, Jorge E. ; Williams, Michael E. ; Barrientos, Jacqueline C. ; Chmielowska, Ewa ; Radford, John ; Stilgenbauer, Stephan ; Dreyling, Martin ; Jedrzejczak, Wieslaw Wiktor ; Johnson, Peter ; Spurgeon, Stephen ; Li, Lei ; Zhang, Liang ; Newberry, Kate ; Ou, Zhishuo ; Cheng, Nancy ; Fang, Bingliang ; McGreivy, Jesse ; Clow, Fong ; Buggy, Joseph J. ; Chang, Betty Y. ; Beaupre, Darrin M. ; Kunkel, Lori A. ; Blum, Kristie A. / Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. In: New England Journal of Medicine. 2013 ; Vol. 369, No. 6. pp. 507-516.
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title = "Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma",
abstract = "BACKGROUND: Bruton's tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma. METHODS: In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety. RESULTS: The median age was 68 years, and 86{\%} of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16{\%} of patients), thrombocytopenia (in 11{\%}), and anemia (in 10{\%}). A response rate of 68{\%} (75 patients) was observed, with a complete response rate of 21{\%} and a partial response rate of 47{\%}; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95{\%} confidence interval [CI], 15.8 to not reached), the estimated median progressionfree survival was 13.9 months (95{\%} CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58{\%} at 18 months. CONCLUSIONS: Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)",
author = "Wang, {Michael L.} and Simon Rule and Peter Martin and Andre Goy and Rebecca Auer and {Kahl Wojciech Jurczak}, {Brad S.} and Advani, {Ranjana H.} and Romaguera, {Jorge E.} and Williams, {Michael E.} and Barrientos, {Jacqueline C.} and Ewa Chmielowska and John Radford and Stephan Stilgenbauer and Martin Dreyling and Jedrzejczak, {Wieslaw Wiktor} and Peter Johnson and Stephen Spurgeon and Lei Li and Liang Zhang and Kate Newberry and Zhishuo Ou and Nancy Cheng and Bingliang Fang and Jesse McGreivy and Fong Clow and Buggy, {Joseph J.} and Chang, {Betty Y.} and Beaupre, {Darrin M.} and Kunkel, {Lori A.} and Blum, {Kristie A.}",
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TY - JOUR

T1 - Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma

AU - Wang, Michael L.

AU - Rule, Simon

AU - Martin, Peter

AU - Goy, Andre

AU - Auer, Rebecca

AU - Kahl Wojciech Jurczak, Brad S.

AU - Advani, Ranjana H.

AU - Romaguera, Jorge E.

AU - Williams, Michael E.

AU - Barrientos, Jacqueline C.

AU - Chmielowska, Ewa

AU - Radford, John

AU - Stilgenbauer, Stephan

AU - Dreyling, Martin

AU - Jedrzejczak, Wieslaw Wiktor

AU - Johnson, Peter

AU - Spurgeon, Stephen

AU - Li, Lei

AU - Zhang, Liang

AU - Newberry, Kate

AU - Ou, Zhishuo

AU - Cheng, Nancy

AU - Fang, Bingliang

AU - McGreivy, Jesse

AU - Clow, Fong

AU - Buggy, Joseph J.

AU - Chang, Betty Y.

AU - Beaupre, Darrin M.

AU - Kunkel, Lori A.

AU - Blum, Kristie A.

PY - 2013

Y1 - 2013

N2 - BACKGROUND: Bruton's tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma. METHODS: In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety. RESULTS: The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progressionfree survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months. CONCLUSIONS: Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

AB - BACKGROUND: Bruton's tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma. METHODS: In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety. RESULTS: The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progressionfree survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months. CONCLUSIONS: Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

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