The S63845/MEK inhibitor combination decreases leukemic infiltration in CMML PDX models. (A) Experimental plan of PDX models obtained by IV (i.v.) injection of 0.4 × 10⁶ CD34⁺ sorted cells (B-C) or 3.5 × 10⁶ bone marrow mononucleated cells (E) at 7 weeks before starting treatment with S63845 (20 mg/kg IV once per week for 3 weeks) and gavage with either selumetinib 10 mg/kg (B-C) or trametinib 1 mg/kg (E) 5 days per week for 3 weeks. (B) Photographs of spleen size in 4 mice treated with vehicle (Veh) or the S63845/selumetinib combo. (C) Impact of the S63845/selumetinib combo on spleen weight, the absolute number of human CD45⁺ and CD45⁺CD14⁺ cells detected in the spleen, and the number of human cells per μL of peripheral blood. Results of 2 independent PDX models are mixed (vehicle, n = 13; combo, n = 15). (D) Plasma level of indicated human cytokine measured in the peripheral blood plasma of mice treated as in panel C. (E) Impact of S63845, trametinib, and their combination (n = 8 per group) on spleen weight, the absolute number of human cells detected in the spleen or the bone marrow, and the number of human cells per μL of peripheral blood. Error bars are mean ± SEM. Mann-Whitney U test: *P < .05; **P < .01; ***P < .001. p.o., by mouth.