Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion

A multicentre, open-label, phase 2 study

Stephan Stilgenbauer, Barbara Eichhorst, Johannes Schetelig, Steven Coutre, John F. Seymour, Talha Munir, Soham D Puvvada, Clemens Martin Wendtner, Andrew W. Roberts, Wojciech Jurczak, Stephen P. Mulligan, Sebastian Böttcher, Mehrdad Mobasher, Ming Zhu, Monali Desai, Brenda Chyla, Maria Verdugo, Sari Heitner Enschede, Elisa Cerri, Rod Humerickhouse & 3 others Gary Gordon, Michael Hallek, William G. Wierda

Research output: Contribution to journalArticle

328 Citations (Scopus)

Abstract

Background: Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. Methods: In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. Findings: Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). Interpretation: Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. Funding: AbbVie and Genentech.

Original languageEnglish (US)
JournalThe Lancet Oncology
DOIs
StateAccepted/In press - 2016

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B-Cell Chronic Lymphocytic Leukemia
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide
Disease Progression
Therapeutics
Safety
Autoimmune Hemolytic Anemia
Febrile Neutropenia
Chromosome Deletion
Architectural Accessibility
Advisory Committees
Poland
Neutropenia
Thrombocytopenia
Immunotherapy
Multicenter Studies
Canada
Germany
Anemia
Pneumonia
Appointments and Schedules

ASJC Scopus subject areas

  • Oncology

Cite this

Stilgenbauer, S., Eichhorst, B., Schetelig, J., Coutre, S., Seymour, J. F., Munir, T., ... Wierda, W. G. (Accepted/In press). Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: A multicentre, open-label, phase 2 study. The Lancet Oncology. https://doi.org/10.1016/S1470-2045(16)30019-5

Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion : A multicentre, open-label, phase 2 study. / Stilgenbauer, Stephan; Eichhorst, Barbara; Schetelig, Johannes; Coutre, Steven; Seymour, John F.; Munir, Talha; Puvvada, Soham D; Wendtner, Clemens Martin; Roberts, Andrew W.; Jurczak, Wojciech; Mulligan, Stephen P.; Böttcher, Sebastian; Mobasher, Mehrdad; Zhu, Ming; Desai, Monali; Chyla, Brenda; Verdugo, Maria; Enschede, Sari Heitner; Cerri, Elisa; Humerickhouse, Rod; Gordon, Gary; Hallek, Michael; Wierda, William G.

In: The Lancet Oncology, 2016.

Research output: Contribution to journalArticle

Stilgenbauer, S, Eichhorst, B, Schetelig, J, Coutre, S, Seymour, JF, Munir, T, Puvvada, SD, Wendtner, CM, Roberts, AW, Jurczak, W, Mulligan, SP, Böttcher, S, Mobasher, M, Zhu, M, Desai, M, Chyla, B, Verdugo, M, Enschede, SH, Cerri, E, Humerickhouse, R, Gordon, G, Hallek, M & Wierda, WG 2016, 'Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: A multicentre, open-label, phase 2 study', The Lancet Oncology. https://doi.org/10.1016/S1470-2045(16)30019-5
Stilgenbauer, Stephan ; Eichhorst, Barbara ; Schetelig, Johannes ; Coutre, Steven ; Seymour, John F. ; Munir, Talha ; Puvvada, Soham D ; Wendtner, Clemens Martin ; Roberts, Andrew W. ; Jurczak, Wojciech ; Mulligan, Stephen P. ; Böttcher, Sebastian ; Mobasher, Mehrdad ; Zhu, Ming ; Desai, Monali ; Chyla, Brenda ; Verdugo, Maria ; Enschede, Sari Heitner ; Cerri, Elisa ; Humerickhouse, Rod ; Gordon, Gary ; Hallek, Michael ; Wierda, William G. / Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion : A multicentre, open-label, phase 2 study. In: The Lancet Oncology. 2016.
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title = "Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: A multicentre, open-label, phase 2 study",
abstract = "Background: Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77{\%} of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. Methods: In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. Findings: Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4{\%}; 95{\%} CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40{\%}]), infection (21 [20{\%}]), anaemia (19 [18{\%}]), and thrombocytopenia (16 [15{\%}]). Serious adverse events occurred in 59 (55{\%}) patients, irrespective of their relationship to treatment, with the most common (≥5{\%} of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7{\%}] each), pneumonia (six [6{\%}]), and febrile neutropenia (five [5{\%}]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). Interpretation: Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. Funding: AbbVie and Genentech.",
author = "Stephan Stilgenbauer and Barbara Eichhorst and Johannes Schetelig and Steven Coutre and Seymour, {John F.} and Talha Munir and Puvvada, {Soham D} and Wendtner, {Clemens Martin} and Roberts, {Andrew W.} and Wojciech Jurczak and Mulligan, {Stephen P.} and Sebastian B{\"o}ttcher and Mehrdad Mobasher and Ming Zhu and Monali Desai and Brenda Chyla and Maria Verdugo and Enschede, {Sari Heitner} and Elisa Cerri and Rod Humerickhouse and Gary Gordon and Michael Hallek and Wierda, {William G.}",
year = "2016",
doi = "10.1016/S1470-2045(16)30019-5",
language = "English (US)",
journal = "The Lancet Oncology",
issn = "1470-2045",
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TY - JOUR

T1 - Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion

T2 - A multicentre, open-label, phase 2 study

AU - Stilgenbauer, Stephan

AU - Eichhorst, Barbara

AU - Schetelig, Johannes

AU - Coutre, Steven

AU - Seymour, John F.

AU - Munir, Talha

AU - Puvvada, Soham D

AU - Wendtner, Clemens Martin

AU - Roberts, Andrew W.

AU - Jurczak, Wojciech

AU - Mulligan, Stephen P.

AU - Böttcher, Sebastian

AU - Mobasher, Mehrdad

AU - Zhu, Ming

AU - Desai, Monali

AU - Chyla, Brenda

AU - Verdugo, Maria

AU - Enschede, Sari Heitner

AU - Cerri, Elisa

AU - Humerickhouse, Rod

AU - Gordon, Gary

AU - Hallek, Michael

AU - Wierda, William G.

PY - 2016

Y1 - 2016

N2 - Background: Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. Methods: In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. Findings: Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). Interpretation: Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. Funding: AbbVie and Genentech.

AB - Background: Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. Methods: In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. Findings: Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). Interpretation: Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. Funding: AbbVie and Genentech.

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SN - 1470-2045

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