Pacritinib protects dendritic cells more efficiently than ruxolitinib.

Targeting Janus kinase (JAK) has revolutionized the treatment of myeloproliferative neoplasms. The JAK inhibitor ruxolitinib has improved the outcome and quality of life of patients dramatically at the cost of increased risk of infections. As previously reported, ruxolitinib severely impairs the differentiation of peripheral blood mononuclear cells to monocyte-derived dendritic cells and inhibits the function of dendritic cells in vitro and in vivo, which expanded its use as an immunomodulatory compound. Pacritinib is a novel JAK inhibitor that will soon be approved for the treatment of myeloproliferative neoplasms, and early results are promising. We investigated the impact of the novel JAK inhibitor pacritinib on the function of monocyte-derived dendritic cells and compared it with that of ruxolitinib. In contrast to ruxolitinib, pacritinib exhibits only mild suppressive effects on dendritic cells. The upregulation of activation markers and CCR7 after TLR4 ligation is not or is only marginally affected by pacritinib. Pacritinib, at concentrations reflecting patients' plasma levels, reduces interleukin (IL)-12 secretion, whereas IL-6 and tumor necrosis factor α levels are unchanged at this concentration. In conclusion, the immunosuppressive effect of pacritinib on dendritic cells is significantly less pronounced than the effect of ruxolitinib. Therefore, our data may help to identify those patients with myelofibrosis who may benefit from pacritinib treatment.