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Venetoclax enhances FLT3-ITD inhibition in AML
occurring mutations, the data presented here describes combination activity for venetoclax and FLT3 inhibition in multiple FLT3-ITD+ preclinical models.
The BM microenvironment can provide protection from cytotoxic agents and secreted factors in conditioned media from immortalized BM stromal cells increased BCL-XL (BCL2L1) mRNA expression and decreased BCL2 in pri- mary AML samples, correlating to loss of venetoclax sen- sitivity compared to samples cultured in normal media.48 This altered expression was also observed in MV4;11 cells grown in vivo versus in vitro (Online Supplementary Figure S6B). As seen in this and other studies,13,49 the Molm13 and MV4;11 cell lines are sensitive to venetoclax in vitro, how- ever, when grown in vivo sensitivity is greatly lost (Figure 1). Therefore, the contribution of anti-apoptotic proteins in promoting survival may be underestimated outside of the tumor microenvironment. In support, quizartinib monotherapy eliminated tumor cells from the periphery (<5% hCD45+ cells) but not the spleen or BM of the FLT3- ITD+ PDX model while quizartinib plus venetoclax more completely eliminated leukemic cells from the tumor microenvironment (Figure 3B). Importantly, anti-tumor activity was achieved with clinically relevant doses of both venetoclax and quizartinib.
Together, the preclinical data presented here provides strong mechanistic rationale for the combination of vene- toclax and FLT3 inhibitors in FLT3-ITD+ AML. Indeed, clinical investigation has been initiated through a phase 1b multi-center study of venetoclax and gilteritinib in R/R AML (clinicaltrials gov. Identifier: 03625505) and a phase 1b/II study of quizartinib and venetoclax in R/R FLT3- mutated AML (clinicaltrials gov. Identifier: 03735875). Perl et al. recently reported that the combination of vene- toclax and gilteritinib is well-tolerated with febrile neu- tropenia (47%), anemia (27%), thrombocytopenia and neutropenia (each 7%) being the most common treat-
ment-related adverse events. In the dose escalation por- tion of this study, the drug combination showed high response rates, with 90% of FLT3 mutant patients demon- strating blast clearance.50 The data collected from these on-going trials will be important to define the mechanistic activity and safety of venetoclax combined with FLT3- ITD inhibition in patients.
Disclosures
Venetoclax is developed in collaboration between Genentech, Inc. and AbbVie. RSM, VM, EFC, MD, DS and EAL are cur- rent or former employees of Genentech, Inc.. NPS received research funding from Bristol-Myers Squibb. MK is a consultant for AbbVie, Genentech, F. Hoffman La-Roche; served as advisory board member for F. Hoffman La-Roche and AbbVie; holds shares from Reata Pharmaceuticals; honoraria from Amgen, Abbvie, Genentech; research funding from AbbVie, Genentech, Eli Lilly, Cellectis, Calithera, Stemline, Threshold, Flexus Biosciences, Novartis, Ablynx, Agios and Amgen. All other authors declare no conflicts of interest.
Contributions
RSM, QZ, RD, EFC, MD, NPS, MK, DS and EAL designed experiments and analyzed data; RSM, EAL, QZ, RD, VMK, AC, VM and JR performed experiments; RSM, MD, DS and EAL wrote the manuscript. All authors reviewed and edited the manuscript.
Acknowledgments
The authors acknowledge Kyle Edgar for support on the Bliss analysis, and Aaron Logan and colleagues at the UCSF tissue bank for providing primary patient samples (supported by the UCSF Cancer Center Support Grant). The authors also acknowledge and thank the Genentech dosing core, cell line core group, animal resources personnel and veterinary staff for their assistance and contributions to this project.
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