TY - JOUR
T1 - Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib
T2 - an interim analysis of a multicentre, open-label, phase 2 trial
AU - Jones, Jeffrey A.
AU - Mato, Anthony R.
AU - Wierda, William G.
AU - Davids, Matthew S.
AU - Choi, Michael
AU - Cheson, Bruce D.
AU - Furman, Richard R.
AU - Lamanna, Nicole
AU - Barr, Paul M.
AU - Zhou, Lang
AU - Chyla, Brenda
AU - Salem, Ahmed Hamed
AU - Verdugo, Maria
AU - Humerickhouse, Rod A.
AU - Potluri, Jalaja
AU - Coutre, Steven
AU - Woyach, Jennifer
AU - Byrd, John C.
N1 - Funding Information:
JAJ is an advisory board member for, and reports institutional research funding from, Genentech, AbbVie, and Pharmacyclics. ARM reports institutional research funding from Pharmacyclics, Gilead, AbbVie, TG Therapeutics, and Acerta, and is a consultant for Pharmacyclics, AbbVie, and Janssen. WGW reports research funding from AbbVie and Genentech, and is a consultant and speaker bureau for Genentech. MSD is an advisory board member for Genentech, Pharmacyclics, TG Therapeutics, Gilead, and Incyte; reports institutional research funding from AbbVie, Genentech, Pharmacyclics, TG Therapeutics, and Infinity; and is a consultant for Genentech, AbbVie, Pharmacyclics, Janssen, and Merck. MC is an advisory board member and consultant for AbbVie, Gilead, and Pharmacyclics; reports institutional research funding from AbbVie; and is on speakers bureau for Gilead, AbbVie, Pharmacyclics, and Genentech. BDC reports consultancy fees from AbbVie, Genentech, Pharmacyclics, Gilead, and Acerta, and research support to his institution from Acerta, Pharmacyclics, Gilead, Genentech, and AbbVie. RRF is a consultant for AbbVie, Pharmacyclics, Janssen, Gilead, and Genentech. NL is an advisory board member for AbbVie, Celgene, Genentech, Janssen, and Pharmacyclics, and reports institutional research funding from AbbVie, Genentech, Gilead, Infinity, and Acerta. PMB reports consultancy fees from AbbVie. SC reports research funding from AbbVie. JW reports clinical trial support from Morphosys, Acerta, and Karyopharm. JCB reports clinical trial support from Pharmacyclics and Acerta, and is an unpaid consultant for Genentech, AbbVie, Acerta, Pharmacyclics, and Leukemia and Lymphoma Society. BC, LZ, AHS, MV, RAH, and JP are employees of AbbVie and own stock.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/1
Y1 - 2018/1
N2 - Background Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy. Methods In this interim analysis of a multicentre, open-label, non-randomised, phase 2 trial, we enrolled patients aged 18 years or older with a documented diagnosis of chronic lymphocytic leukaemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance score of 2 or lower. All patients had relapsed or refractory disease after previous treatment with a BCR signalling pathway inhibitor. All patients were screened for Richter's transformation and cases confirmed by biopsy were excluded. Eligible patients received oral venetoclax, starting at 20 mg per day with stepwise dose ramp-up over 5 weeks to 400 mg per day. Patients with rapidly progressing disease received an accelerated dosing schedule (to 400 mg per day by week 3). The primary endpoint was overall response, defined as the proportion of patients with an overall response per investigator's assessment according to IWCLL criteria. All patients who received at least one dose of venetoclax were included in the activity and safety analyses. This study is ongoing; data for this interim analysis were collected per regulatory agencies' request as of June 30, 2017. This trial is registered with ClinicalTrials.gov, number NCT02141282. Findings Between September, 2014, and November, 2016, 127 previously treated patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled from 15 sites across the USA. 91 patients had received ibrutinib as the last BCR inhibitor therapy before enrolment, 43 of whom were enrolled in the main cohort and 48 in the expansion cohort recruited later after a protocol amendment. At the time of analysis, the median follow-up was 14 months (IQR 8–18) for all 91 patients, 19 months (9–27) for the main cohort, and 12 months (8–15) for the expansion cohort. 59 (65%, 95% CI 53–74) of 91 patients had an overall response, including 30 (70%, 54–83) of 43 patients in the main cohort and 29 (60%, 43–72) of 48 patients in the expansion cohort. The most common treatment-emergent grade 3 or 4 adverse events were neutropenia (46 [51%] of 91 patients), thrombocytopenia (26 [29%]), anaemia (26 [29%]), decreased white blood cell count (17 [19%]), and decreased lymphocyte count (14 [15%]). 17 (19%) of 91 patients died, including seven because of disease progression. No treatment-related deaths occurred. Interpretation The results of this interim analysis show that venetoclax has durable clinical activity and favourable tolerability in patients with relapsed or refractory chronic lymphocytic leukaemia whose disease progressed during or after discontinutation of ibrutinib therapy. The durability of response to venetoclax will be assessed in the final analysis in 2019. Funding AbbVie, Genentech.
AB - Background Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy. Methods In this interim analysis of a multicentre, open-label, non-randomised, phase 2 trial, we enrolled patients aged 18 years or older with a documented diagnosis of chronic lymphocytic leukaemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance score of 2 or lower. All patients had relapsed or refractory disease after previous treatment with a BCR signalling pathway inhibitor. All patients were screened for Richter's transformation and cases confirmed by biopsy were excluded. Eligible patients received oral venetoclax, starting at 20 mg per day with stepwise dose ramp-up over 5 weeks to 400 mg per day. Patients with rapidly progressing disease received an accelerated dosing schedule (to 400 mg per day by week 3). The primary endpoint was overall response, defined as the proportion of patients with an overall response per investigator's assessment according to IWCLL criteria. All patients who received at least one dose of venetoclax were included in the activity and safety analyses. This study is ongoing; data for this interim analysis were collected per regulatory agencies' request as of June 30, 2017. This trial is registered with ClinicalTrials.gov, number NCT02141282. Findings Between September, 2014, and November, 2016, 127 previously treated patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled from 15 sites across the USA. 91 patients had received ibrutinib as the last BCR inhibitor therapy before enrolment, 43 of whom were enrolled in the main cohort and 48 in the expansion cohort recruited later after a protocol amendment. At the time of analysis, the median follow-up was 14 months (IQR 8–18) for all 91 patients, 19 months (9–27) for the main cohort, and 12 months (8–15) for the expansion cohort. 59 (65%, 95% CI 53–74) of 91 patients had an overall response, including 30 (70%, 54–83) of 43 patients in the main cohort and 29 (60%, 43–72) of 48 patients in the expansion cohort. The most common treatment-emergent grade 3 or 4 adverse events were neutropenia (46 [51%] of 91 patients), thrombocytopenia (26 [29%]), anaemia (26 [29%]), decreased white blood cell count (17 [19%]), and decreased lymphocyte count (14 [15%]). 17 (19%) of 91 patients died, including seven because of disease progression. No treatment-related deaths occurred. Interpretation The results of this interim analysis show that venetoclax has durable clinical activity and favourable tolerability in patients with relapsed or refractory chronic lymphocytic leukaemia whose disease progressed during or after discontinutation of ibrutinib therapy. The durability of response to venetoclax will be assessed in the final analysis in 2019. Funding AbbVie, Genentech.
UR - http://www.scopus.com/inward/record.url?scp=85039078201&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85039078201&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(17)30909-9
DO - 10.1016/S1470-2045(17)30909-9
M3 - Article
C2 - 29246803
AN - SCOPUS:85039078201
SN - 1470-2045
VL - 19
SP - 65
EP - 75
JO - The lancet oncology
JF - The lancet oncology
IS - 1
ER -