Figure 2.
In vivo combinatorial treatment with menin and FLT3 inhibitors. (A) Flow cytometric quantification of hCD45+ cells in PB of mice during treatment with vehicle, MI-3454 (100 mg/kg orally twice daily), AC220 (10 mg/kg orally once daily), or a combination of the 2 agents (doses same as for single agents) in the MOLM13 xenotransplantation model. Mean ± standard error of the mean (SEM; n = 8). (B) Kaplan-Meier survival curves in the MOLM13 xenotransplantation model. Doses as in panel A. P values were calculated using log-rank (Mantel-Cox) test. (C) Left: flow cytometric quantification of hCD45+ cells in PB, spleen, and bone marrow (BM) samples harvested from the vehicle-treated mice (at the terminal stage of leukemia: day 16 posttransplantation) and mice treated with the combination of MI-3454 and AC220 (samples collected at day 292 posttransplantation) in the MOLM13 model. Mean ± standard deviation (SD; n = 3-6 [vehicle: n = 6 for PB, n = 3 for BM and spleen; MI-3454 + AC220 group: n = 6). Right: images of spleens collected from the vehicle and combination cohorts of mice. (D) Wright-Giemsa–stained cytospins for BM samples isolated from the vehicle and MI-3454 + AC220 cohorts of MOLM13 mice at the same time points as in panel C. (E) Flow cytometric quantification of hCD45+ cells in PB of MLL-6315 patient-derived xenograft (PDX) mice during treatment with vehicle, MI-3454 (80 mg/kg orally twice daily), gilteritinib (Gilt; 35 mg/kg orally once daily), or the combination of MI-3454 and Gilt (doses same as for single agents). Mean ± SEM (n = 8). (F) Flow cytometric quantification of hCD45+ cells in PB from MLL-6315 PDX mice 27 days after treatment was stopped (day 82 posttransplantation). Doses as in panel E. Mean ± SD. (G) Flow cytometric quantification of hCD45+ cells in PB of MLL-6315 PDX mice treated with the combination of MI-3454 and Gilt. Mean ± SEM (n = 8). (H) Kaplan-Meier survival curves for MLL-6315 PDX mice (n = 8). Treatment doses as in panel E. Treatment time is indicated by the arrow. P values were calculated using the log-rank (Mantel-Cox) test. (I) Flow cytometric quantification of hCD45+ cells in PB of NPM1-5577 PDX mice during 60 days of treatment with vehicle, Gilt (35 mg/kg orally once daily), MI-3454 (80 mg/kg twice daily for the first 28 days, followed by 80 mg/kg orally once daily for an additional 32 days; treatment with MI-3454 was reduced to once-daily administration because of limited tolerance of prolonged treatment in the combination group), or combination of MI-3454 and Gilt (doses same as for single agents). Mean ± SD (n = 7). (J) Flow cytometric quantification of hCD45+ cells in PB of NPM1-5577 PDX mice at the last day of treatment. Mean ± SD. *P < .05, **P < .01, ****P < .0001 by 2-tailed Student t test (C) or 2- (E,I) or 1-way (F,J) analysis of variance with Tukey multiple comparison test. ns, not significant.

In vivo combinatorial treatment with menin and FLT3 inhibitors. (A) Flow cytometric quantification of hCD45+ cells in PB of mice during treatment with vehicle, MI-3454 (100 mg/kg orally twice daily), AC220 (10 mg/kg orally once daily), or a combination of the 2 agents (doses same as for single agents) in the MOLM13 xenotransplantation model. Mean ± standard error of the mean (SEM; n = 8). (B) Kaplan-Meier survival curves in the MOLM13 xenotransplantation model. Doses as in panel A. P values were calculated using log-rank (Mantel-Cox) test. (C) Left: flow cytometric quantification of hCD45+ cells in PB, spleen, and bone marrow (BM) samples harvested from the vehicle-treated mice (at the terminal stage of leukemia: day 16 posttransplantation) and mice treated with the combination of MI-3454 and AC220 (samples collected at day 292 posttransplantation) in the MOLM13 model. Mean ± standard deviation (SD; n = 3-6 [vehicle: n = 6 for PB, n = 3 for BM and spleen; MI-3454 + AC220 group: n = 6). Right: images of spleens collected from the vehicle and combination cohorts of mice. (D) Wright-Giemsa–stained cytospins for BM samples isolated from the vehicle and MI-3454 + AC220 cohorts of MOLM13 mice at the same time points as in panel C. (E) Flow cytometric quantification of hCD45+ cells in PB of MLL-6315 patient-derived xenograft (PDX) mice during treatment with vehicle, MI-3454 (80 mg/kg orally twice daily), gilteritinib (Gilt; 35 mg/kg orally once daily), or the combination of MI-3454 and Gilt (doses same as for single agents). Mean ± SEM (n = 8). (F) Flow cytometric quantification of hCD45+ cells in PB from MLL-6315 PDX mice 27 days after treatment was stopped (day 82 posttransplantation). Doses as in panel E. Mean ± SD. (G) Flow cytometric quantification of hCD45+ cells in PB of MLL-6315 PDX mice treated with the combination of MI-3454 and Gilt. Mean ± SEM (n = 8). (H) Kaplan-Meier survival curves for MLL-6315 PDX mice (n = 8). Treatment doses as in panel E. Treatment time is indicated by the arrow. P values were calculated using the log-rank (Mantel-Cox) test. (I) Flow cytometric quantification of hCD45+ cells in PB of NPM1-5577 PDX mice during 60 days of treatment with vehicle, Gilt (35 mg/kg orally once daily), MI-3454 (80 mg/kg twice daily for the first 28 days, followed by 80 mg/kg orally once daily for an additional 32 days; treatment with MI-3454 was reduced to once-daily administration because of limited tolerance of prolonged treatment in the combination group), or combination of MI-3454 and Gilt (doses same as for single agents). Mean ± SD (n = 7). (J) Flow cytometric quantification of hCD45+ cells in PB of NPM1-5577 PDX mice at the last day of treatment. Mean ± SD. *P < .05, **P < .01, ****P < .0001 by 2-tailed Student t test (C) or 2- (E,I) or 1-way (F,J) analysis of variance with Tukey multiple comparison test. ns, not significant.

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