TY - JOUR
T1 - Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia
AU - Khaw, Seong Lin
AU - Suryani, Santi
AU - Evans, Kathryn
AU - Richmond, Jennifer
AU - Robbins, Alissa
AU - Kurmasheva, Raushan T.
AU - Billups, Catherine A.
AU - Erickson, Stephen W.
AU - Guo, Yuelong
AU - Houghton, Peter J.
AU - Smith, Malcolm A.
AU - Carol, Hernan
AU - Roberts, Andrew W.
AU - Huang, David C.S.
AU - Lock, Richard B.
N1 - Funding Information:
This research was funded by grants from the National Institutes of Health, National Cancer Institute (NOI-CM-42216 and NOI-CM- 91001-03), the Leukemia and Lymphoma Society (SCOR 7417-07 and 7001-13), and the National Health and Medical Research Council (NHMRC) of Australia (1016647 and 1016701). S.S. was supported by Postdoctoral Fellowships from the Leukaemia Foundation of Australia and the Cure Cancer Australia Foundation, and an Early Career Fellowship from the Cancer Institute New South Wales. R.B.L., A.W.R., and D.C.S.H. are supported by Fellowships from theNHMRC(1059804, 1079560, 1043149). The authors thank AbbVie for providing navitoclax, venetoclax, A-1113567, and A-1155463. The Walter and Eliza Hall Institute of Medical Research is supported by an Independent Research Institutes Infrastructure Support Scheme grant 9000220 (NHMRC) and Victorian State Government Operational Infrastructure Support grant.
PY - 2016/9/8
Y1 - 2016/9/8
N2 - The clinical success of the BCL-2-selective BH3-mimetic venetoclax in patients with poor prognosis chronic lymphocytic leukemia (CLL) highlights the potential of targeting the BCL-2-regulated apoptotic pathway in previously untreatable lymphoid malignancies. By selectively inhibiting BCL-2, venetoclax circumvents the dose-limiting, BCL-XL-mediated thrombocytopenia of its less selective predecessor navitoclax, while enhancing efficacy in CLL. We have previously reported the potent sensitivity of many high-risk childhood acute lymphoblastic leukemia (ALL) xenografts to navitoclax. Given the superior tolerability of venetoclax, here we have investigated its efficacy in childhood ALL. We demonstrate that in contrast to the clear dependence of CLL on BCL-2 alone, effective antileukemic activity in the majority of ALL xenografts requires concurrent inhibition of both BCL-2 and BCL-XL. We identify BCL-XL expression as a key predictor of poor response to venetoclax and demonstrate that concurrent inhibition of both BCL-2 and BCL-XL results in synergistic killing in the majority ofALLxenografts.Anotable exception is mixed lineage leukemia-rearranged infant ALL, where venetoclax largely recapitulates the activity of navitoclax, identifying this subgroup of patients as potential candidates for clinical trials of venetoclax in childhood ALL. Conversely, our findings provide a clear basis for progressing navitoclax into trials ahead of venetoclax in other subgroups. (Blood. 2016;128(10):1382-1395).
AB - The clinical success of the BCL-2-selective BH3-mimetic venetoclax in patients with poor prognosis chronic lymphocytic leukemia (CLL) highlights the potential of targeting the BCL-2-regulated apoptotic pathway in previously untreatable lymphoid malignancies. By selectively inhibiting BCL-2, venetoclax circumvents the dose-limiting, BCL-XL-mediated thrombocytopenia of its less selective predecessor navitoclax, while enhancing efficacy in CLL. We have previously reported the potent sensitivity of many high-risk childhood acute lymphoblastic leukemia (ALL) xenografts to navitoclax. Given the superior tolerability of venetoclax, here we have investigated its efficacy in childhood ALL. We demonstrate that in contrast to the clear dependence of CLL on BCL-2 alone, effective antileukemic activity in the majority of ALL xenografts requires concurrent inhibition of both BCL-2 and BCL-XL. We identify BCL-XL expression as a key predictor of poor response to venetoclax and demonstrate that concurrent inhibition of both BCL-2 and BCL-XL results in synergistic killing in the majority ofALLxenografts.Anotable exception is mixed lineage leukemia-rearranged infant ALL, where venetoclax largely recapitulates the activity of navitoclax, identifying this subgroup of patients as potential candidates for clinical trials of venetoclax in childhood ALL. Conversely, our findings provide a clear basis for progressing navitoclax into trials ahead of venetoclax in other subgroups. (Blood. 2016;128(10):1382-1395).
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U2 - 10.1182/blood-2016-03-707414
DO - 10.1182/blood-2016-03-707414
M3 - Article
C2 - 27343252
AN - SCOPUS:84987792531
SN - 0006-4971
VL - 128
SP - 1382
EP - 1395
JO - Blood
JF - Blood
IS - 10
ER -