Ruxolitinib and dexamethasone each prolong remission in dasatinib-treated mice. All mice were infused intravenously with 2 × 105 LICs. Mice that were left untreated or received drugs 10 days later were followed until they became moribund. (A) Mice treated for 5 days per week once per day by oral gavage with ruxolitinib alone (60 mg/kg body weight) exhibited no survival advantage compared with untreated or vehicle-treated mice, whereas mice receiving ruxolitinib plus dasatinib (10 mg/kg body weight) on the same dosing schedule showed a significant survival advantage over animals receiving dasatinib monotherapy (P < .001). (B) Mice were treated continuously for 13 days with the indicated drug combinations, after which therapy was discontinued. Dasatinib (10 mg/kg) was administered twice per day (unlike the once per day regimen in panel A) and ruxolitinib (60 mg/kg) administered once per day, each by oral gavage. Dexamethasone was added, as indicated, to the drinking water. The time to treatment failure (abscissa) reflects the level of MRD at the end of day 22. TaqMan PCR performed at necropsy on 4 animals that relapsed after combined treatment with dasatinib and ruxolitinib showed significant leukemic infiltration in their BM (11%, 31%, 31%, and 41%) and spleen (24%, 42%, 66%, and 79%), respectively. (C) Spleen weights were determined for mice euthanized after relapse in the trial shown in panel B. Despite the presence of normal spleen weights in mice that received the 3-drug combination, animals nonetheless died of leukemia after the limited 13-day drug exposure. (D) Mice were treated continuously twice daily with dasatinib alone (10 mg/kg) or together with ruxolitinib (60 mg/kg) with or without dexamethasone as indicated. Therapy in the group receiving the 3-drug combination was terminated after 6 months; surviving animals were observed for signs of disease and subjected to intermittent bioluminescence imaging for an additional 200 days. Significance for pairwise comparisons (not including 2 surviving mice) is dasatinib alone vs dasatinib plus ruxolitinib (P = .029); dasatinib plus ruxolitinib vs dasatinib plus ruxolitinib plus dexamethasone (P < .0002); dasatinib alone vs dasatinib plus ruxolitinib plus dexamethasone (P < .0001).
