Pacritinib protects dendritic cells more efficiently than ruxolitinib.

Area of Science:

• Immunology
• Hematology
• Pharmacology

Background:

• Janus kinase (JAK) inhibitors like ruxolitinib have transformed myeloproliferative neoplasm (MPN) treatment.
• Ruxolitinib improves patient outcomes but increases infection risk due to impaired dendritic cell (DC) function.
• Pacritinib is a new JAK inhibitor for MPNs with promising early results.

Purpose of the Study:

• To investigate the effect of pacritinib on monocyte-derived dendritic cell (moDC) function.
• To compare pacritinib's immunomodulatory effects with those of ruxolitinib.

Main Methods:

• Assessing moDC differentiation and function in vitro.
• Evaluating the impact of pacritinib and ruxolitinib on DC activation markers and cytokine secretion (IL-12, IL-6, TNF-α) after TLR4 ligation.
• Comparing drug effects at concentrations reflecting patient plasma levels.

Main Results:

• Pacritinib demonstrated only mild suppressive effects on moDC differentiation and function compared to ruxolitinib.
• Pacritinib minimally affected the upregulation of DC activation markers and CCR7 post-TLR4 ligation.
• While pacritinib reduced IL-12 secretion at therapeutic concentrations, IL-6 and TNF-α levels remained largely unchanged.

Conclusions:

• Pacritinib exhibits significantly less immunosuppressive activity on dendritic cells than ruxolitinib.
• The reduced impact on DC function suggests pacritinib may have a more favorable safety profile concerning infection risk.
• These findings could aid in selecting MPN patients, particularly those with myelofibrosis, who may benefit from pacritinib treatment.