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Effects of XPO1 and FLT3 inhibition on AML
could achieve synergistic efficacy by overcoming the resist- ance to FLT3-targeted therapy. Our data demonstrate a syn- ergistic anti-leukemia efficacy of the drug combination in vivo. In addition, the combination regimen produced a pro- found reduction of CXCR4 and HIF1α levels in hypoxia in vitro (Figure 3C), and also marked elimination of leukemic cells in a bone marrow in vivo murine AML model (Figure 6B), suggesting a potential benefit for overcoming resist-
A
ance provided by the microenvironment. Remarkably, the combination regimen has achieved complete remissions, including ongoing complete molecular remissions, in 30% (3 of the first 10) relapsed/refractory AML patients in our on-going phase IB/II clinical trial of combinatorial therapy of selinexor and sorafenib. Of note, the three patients with CRp/CRi, who were previously clinically refractory to quizartinib/sorafenib monotherapy or to combinations
B
C
Figure 6. Combination treatment significantly eliminates leukemia cell engraftment in bone marrow and other organs. Leukemia cell infil- tration was evaluated in (A) blood circulation and (B) bone marrow (BM) at day 18 by flow cytometry after gating GFP-positive cells, and in (C) other soft organs using immunostaining with anti-luciferase antibody in paraffin sec- tions. The bar represents 100 mm.
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