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Ferrata Storti Foundation
Haematologica 2021 Volume 106(4):1022-1033
Acute Myeloid Leukemia
A novel combination regimen of BET and FLT3 inhibition for FLT3-ITD acute myeloid leukemia
Lauren Y. Lee,1 Yoshiyuki Hizukuri,2 Paul Severson,3 Benjamin Powell,3 Chao Zhang,3 Yan Ma,3 Maiko Narahara,2 Hiroyuki Sumi,2
Daniela Hernandez,1 Trivikram Rajkhowa,1 Gideon Bollag3 and Mark Levis1
1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA; 2Daiichi Sankyo Co. Ltd., Tokyo, Japan and 3Plexxikon Inc., Berkeley, CA, USA
ABSTRACT
Acute myeloid leukemia (AML) patients with FLT3-ITD mutations have a high risk of relapse and death. FLT3 tyrosine kinase inhibitors improve overall survival, but their efficacy is limited and most patients who relapse will ultimately die of the disease. Even with potent FLT3 inhibition, the disease persists within the bone mar- row (BM) microenvironment, mainly due to BM stroma activating paral- lel signaling pathways that maintain pro-survival factors. BET inhibitors suppress pro-survival factors such as MYC and BCL2, but these drugs thus far have shown only limited single-agent clinical potential. We demonstrate here, using pre-clinical and clinical correlative studies, that the novel 4-azaindole derivative, PLX51107, has BET-inhibitory activity in vitro and in vivo. The combination of BET and FLT3 inhibition induces a synergistic anti-leukemic effect in a murine xenograft model of FLT3- ITD AML, and against primary FLT3-ITD AML cells co-cultured with BM stroma. Using suppression of MYC as a surrogate for BET inhibition, we demonstrate BET inhibition in human patients. The short plasma half-life of PLX51107 results in intermittent target inhibition to promote tolerability while overcoming the protective effect of the microenviron- ment. Mechanistically, the synergistic cytotoxicity is associated with suppression of key survival genes such as MYC. These data provide the scientific rationale for a clinical trial of a BET plus FLT3 inhibitor for the treatment of relapsed/refractory FLT3-ITD AML. A clinical trial of PLX51107 as monotherapy in patients with different malignancies is underway and will be reported separately.
Introduction
Internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 are associated with a poor prognosis in acute myeloid leukemia (AML), both at diagnosis and in the relapsed/refractory setting.1-3 Several FLT3 tyrosine kinase inhibitors (TKI) have recently been approved for use in this disease subtype at var- ious stages of the disease, and outcomes for patients with FLT3-mutated AML are now improving.4 Unfortunately, relapses still occur, and the presence of a FLT3- ITD mutation is one of the worst prognostic factors at relapse, with few patients achieving cure.5,6 FLT3 inhibitors such as gilteritinib and quizartinib only prolong survival and very few relapsed patients are cured.7,8 In relapsed FLT3-ITD AML patients treated with these drugs, circulating peripheral blasts are eliminated, but marrow blasts persist,9,10 and resistance-conferring FLT3 point mutations or RAS- pathway mutations soon emerge.11-13 Combinations with chemotherapy and hypomethylating agents are under investigation, but a combination with a more targeted agent might represent a better option.
We and others have previously reported that marrow blasts are protected from the FLT3 inhibition via signaling through stromal-derived cytokines.9,10,14,15 Rather than target individual cytokines, we looked further downstream at the convergence of their signaling pathways, which drive transcription of pro-survival genes such as MYC. This led us to explore the inhibition of bromodomain and extra-terminal domain (BET) proteins, which are master transcription regulators.16 This family of proteins includes BRD2, BRD3, BRD4 and BRDT. They associate with acetylated
Correspondence:
MARK LEVIS
levisma@jhmi.edu
Received: January 16, 2020. Accepted: November 9, 2020. Pre-published: January 28, 2021.
https://doi.org/10.3324/haematol.2020.247346
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