Janus Kinase 3 Inhibitor Whi-P131/Janex-1 Prevents Graft-Versus-Host Disease But Spares The Graft-Versus-Leukemia Function Of The Bone Marrow Allografts In A Murine Bone Marrow Transplantation Model

The purpose of the present study was to evaluate the effects of graft-versus-host disease (GVHD) prophylaxis with the Janus kinase 3 (JAK3) inhibitor WIHI-P131/JANEX-1 on the graft-versus-leukemic (GVL) function of marrow allografts in mice undergoing bone marrow transplantation (BMT) after being challenged with an otherwise invariably fatal dose of BCL-1 leukemia cells. GVHD prophylaxis using WHI-P131 markedly improved the survival outcome after BMT. The probability of survival at 30 days after BMT was 11% +/- 6% for vehicle-treated recipients (median survival time, 25 days) versus 63% +/- 12% for recipients treated with WHI-P131 (median survival time, 36 days; P < .0001). Because WHI-P131 is devoid of antileukemic activity against BCL-1 leukemia cells, this marked improvement in survival outcome was due to reduced incidence of GVHD-associated fatalities combined with sustained GVL function of the allografts in the WHI-P131 group. Notably, adoptive transfer experiments demonstrated that the spleens of WHI-P131-treated allograft recipients contained less than 0.001% BCL-1 cells. Notably, GVHD prophylaxis with WHI-P131 plus methotrexate resulted In 100% survival of mice receiving allotransplants challenged with an otherwise Invariably fatal dose of BCL-1 leukemia. Taken together, our results provide strong experimental evidence that GVHD prophylaxis using WHI-P131 does not Impair the GVL function of the allografts and consequently contributes to an Improved post-BMT survival outcome of the recipient mice. (C) 2002 by The American Society of Hematology.