Effects of the JAK3 inhibitor WHI-P131 in combination with methotrexate on the post-BMT survival outcome in a murine model of acute GVHD.

In 2 independent experiments, irradiated (7.5 Gy) C57BL6 (H-2^b) recipients were given BM and splenocytes (25 × 10⁶ of each) from BALB/c (H-2^d) mice. Some recipients were transplanted with syngeneic BM/S grafts (Syngeneic). WHI-P131 was administered intraperitoneally at a dose level of 60 mg/kg per day in 3 divided doses from day 0 to day 85. MTX was used at a dose level of 10 mg/m² per day once daily and administered intraperitoneally on days 1, 3, 6, and 11 after BMT. *P < .0001 (vehicle controls vs WHI-P131, MTX, or WHI-P131 + MTX treatment groups, log-rank test). (A) Survival curves. See Table 2 for details of the life-table analysis. *MST of the control group B was 40 days in the first experiment involving 15 control mice and 33 days in the second experiment involving 23 control mice. The cumulative proportion of control mice surviving at 60 days was 13% ± 9% in the first experiment and 9% ± 6% in the second experiment. No control mouse was alive at 85 days in either of these 2 experiments. (B) Weight curves were obtained in the first, but not the second, experiment to minimize the handling of mice and the associated stress.