TY - JOUR
T1 - Combined ibrutinib and venetoclax treatment vs single agents in the TCL1 mouse model of chronic lymphocytic leukemia
AU - Kater, Arnon P.
AU - Slinger, Erik
AU - Cretenet, Gaspard
AU - Martens, Anne W.
AU - Balasubramanian, Sriram
AU - Leverson, Joel D.
AU - Eldering, Eric
N1 - Funding Information: This work was supported by a research grant from AbbVie and Jans-sen. A.P.K. is funded by a Dutch Research Council grant (VIDI-91715337) and a European Research Council grant (2020 BOOT-CAMP). Whole-exome sequencing and RNA-sequencing were performed at the University of Heidelberg by Martina Seiffert and Mark Zapatka, funded by the ERA-NET on Translational Cancer Research Publisher Copyright: © 2021 by The American Society of Hematology.
PY - 2021/12/14
Y1 - 2021/12/14
N2 - The covalent inhibitor of Bruton’s tyrosine kinase ibrutinib and the specific Bcl-2 inhibitor venetoclax are both highly efficacious single-agent drugs in the treatment of chronic lymphocytic leukemia (CLL). Based on their complementary modes of action, ibrutinib and venetoclax are hypothesized to act in a synergistic fashion. Currently, it is unclear whether combined treatment is indeed superior to continuous single-agent treatment and what mechanisms underlie the resistance to combination treatment. In addition, the effects of such treatment on the skewed T-cell compartment characteristic of CLL are as yet unknown. In the murine Em-TCL1 adoptive transfer model resembling aggressive CLL, we found that combined treatment resulted in the deepest responses, with the longest duration related to a combination of decreased proliferation and increased induction of apoptosis. In addition, alterations in T-cell subsets were most prominent after combination treatment, with increased naive cells and reduced effector memory cells. Remarkably, effects of single agents but also combination treatment were eventually interrupted by relapse, and we found downregulation of BIM expression as a plausible cause of acquired drug resistance. Nevertheless, in this murine model, the combination of venetoclax and ibrutinib has increased efficacy over single agents, accompanied by a restoration of the T-cell compartment.
AB - The covalent inhibitor of Bruton’s tyrosine kinase ibrutinib and the specific Bcl-2 inhibitor venetoclax are both highly efficacious single-agent drugs in the treatment of chronic lymphocytic leukemia (CLL). Based on their complementary modes of action, ibrutinib and venetoclax are hypothesized to act in a synergistic fashion. Currently, it is unclear whether combined treatment is indeed superior to continuous single-agent treatment and what mechanisms underlie the resistance to combination treatment. In addition, the effects of such treatment on the skewed T-cell compartment characteristic of CLL are as yet unknown. In the murine Em-TCL1 adoptive transfer model resembling aggressive CLL, we found that combined treatment resulted in the deepest responses, with the longest duration related to a combination of decreased proliferation and increased induction of apoptosis. In addition, alterations in T-cell subsets were most prominent after combination treatment, with increased naive cells and reduced effector memory cells. Remarkably, effects of single agents but also combination treatment were eventually interrupted by relapse, and we found downregulation of BIM expression as a plausible cause of acquired drug resistance. Nevertheless, in this murine model, the combination of venetoclax and ibrutinib has increased efficacy over single agents, accompanied by a restoration of the T-cell compartment.
UR - http://www.scopus.com/inward/record.url?scp=85122151097&partnerID=8YFLogxK
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UR - https://www.ncbi.nlm.nih.gov/pubmed/34555843
U2 - https://doi.org/10.1182/bloodadvances.2021004861
DO - https://doi.org/10.1182/bloodadvances.2021004861
M3 - Article
C2 - 34555843
SN - 2473-9529
VL - 5
SP - 5410
EP - 5414
JO - Blood advances
JF - Blood advances
IS - 23
ER -