Venetoclax responses of pediatric ALL xenografts reveal MLLr ALL sensitivity, but overall requirement to target both BCL2 and BCLXL

Khaw, SL; Suryani, S; Evans, K; Richmond, J; Robbins, A; Kurmasheva, RT; Billups, CA; Erickson, SW; Guo, Y; Houghton, PJ; Smith, MA; Carol, H; Roberts, AW; Huang, DC; Lock, RB

Author(s): Khaw, SL; Suryani, S; Evans, K; Richmond, J; Robbins, A; Kurmasheva, RT; Billups, CA; Erickson, SW; Guo, Y; Houghton, PJ; Smith, MA; Carol, H; Roberts, AW; Huang, DC; Lock, RB;
Details: Publication Year 2016-06-24,Volume 28,Issue #10,Page 1382-1395
Journal Title: Blood
Publication Type: Journal Article
Abstract: 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 anti-leukemic 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 of ALL xenografts. A notable exception is MLL-rearranged infant ALL (MLLr-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.
Publisher: ASH
Research Division(s): Cancer And Haematology
PubMed ID: 27343252
Publisher's Version: https://doi.org/10.1182/blood-2016-03-707414
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2016-08-09 12:01:42

Last Modified: 2018-07-11 09:36:08