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Effects of XPO1 and FLT3 inhibition on AML
The selinexor and sorafenib combination has marked anti-leukemia efficacy in a mouse xenograft model of human FLT3-ITD-mutated acute myeloid leukemia
We next assessed in vivo efficacy of the selinexor and sorafenib combination in a murine leukemia model. NOG mice bearing xenografts of MOLM13-Luc-GFP cells were treated with either selinexor or sorafenib alone or the drug combination. The vehicle served as a control. The mice received 39 days of treatment starting from day 4 after injection of leukemia cells. The median survival in the vehicle, sorafenib, selinexor, and combination treatment groups was 16, 23, 31, and 51 days, respectively (P<0.001) (Figure 5A). In addition, the combination significantly reduced leukemia burden compared with that in the con- trol mice after 10 days of treatment (day 14). The mean luminescence was ~1x107 photons/s in the vehicle-treated group versus ~2x105 photons/s in the group treated with the combination (Figure 5B,C). The mice tolerated the individual drugs and the combination well, without signs of anorexia, weight loss, or other signs/symptoms of dis- tress. One week after treatment cessation (i.e., day 49), the mice in the combination group developed increased leukemia burden and succumbed to AML (Figure 5D).
Further analysis revealed that the infiltration of leukemic cells was significantly reduced in peripheral blood after receiving 14 days of either single-agent treat- ment or combination treatment (Figure 6A). However, the
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bone marrow environment protected against sorafenib treatment-mediated leukemia cell killing, while selinexor alone had anti-leukemia efficacy. Impressively, the combi- nation treatment almost eliminated leukemic cells from the bone marrow (i.e., approximately 100-fold lower lev- els than following treatment with the vehicle, P<0.001) (Figure 6B), which suggests potent killing of leukemia cells by this combinatorial regimen in the bone marrow envi- ronment. Immunohistochemical analysis further con- firmed the profound reduction of leukemia cells in the bone marrow and other organs (Figure 6C).
The selinexor and sorafenib combination exerted anti-leukemia effects in patients with FLT3-mutated acute myeloid leukemia in a phase IB clinical trial
The preclinical synergy of selinexor and sorafenib led to the initiation of a phase IB/II study of the combination in relapsed/refractory patients harboring FLT3 mutations. Fourteen patients enrolled in this clinical trial were eligible for analysis. Remarkably, four of the 14 patients (29%) achieved a sustained CRp/CRi and two others (14%) had >50% blast reduction (Table 2). Six of the 11 (55%) patients treated previously with FLT3 inhibitors achieved responses. These patients comprised: (i) two FLT3-ITD mutated patients, previously treated with sorafenib, who achieved CRp with molecular CR with selinexor plus sorafenib; (ii) one FLT3-ITD and FLT3-D835 dual mutated
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Figure 5. Combination treatment significantly improves mice survival and reduces leukemia burden in a MOLM13-engrafted murine leukemia model. (A) The medi- an survival were assessed for each group by the Kaplan–Meier method, and log-rank statistics applied to test for differences in survival. (B) Serial bioluminescence images of representative mice at day 4 and day 14 after injection of leukemic cells in the groups treated with selinexor or sorafenib alone or the combination. (C) Quantitative analysis of the leukemia burden. (D) Serial bioluminescence images of representative mice at 26, 33, 40 and 49 days after leukemia cell injection.
haematologica | 2018; 103(10)
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