New Applications of JAK/STAT Inhibitors in Pediatrics: Current Use of Ruxolitinib

Abstract

Janus kinases (JAK) are a family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) that transduce cytokine-mediated signals through the JAK-STAT metabolic pathway. These kinases act by regulating the transcription of specific genes capable of inducing biological responses in several immune cell subsets. Inhibition of Janus kinases interferes with the JAK-STAT signaling pathway. Besides being used in the treatment of cancer and inflammatory diseases, in recent years, they have also been used to treat inflammatory conditions, such as graft-versus-host disease (GVHD) and cytokine release syndrome as complications of allogeneic hematopoietic stem cell transplantation and cell therapy. Recently, the FDA approved the use of ruxolitinib, a JAK1/2 inhibitor, in the treatment of acute steroid-refractory GVHD (SR-aGVHD), highlighting the role of JAK inhibition in this immune deregulation. Ruxolitinib was initially used to treat myelofibrosis and true polycythemia in a high-dose treatment and caused hematological toxicity. Since a lower dosage often could not be effective, the use of ruxolitinib was suspended. Subsequently, ruxolitinib was evaluated in adult patients with SR-aGVHD and was found to achieve a rapid and effective response. In addition, its early low-dose use in pediatric patients affected by GVHD has proved effective, safe, and reasonably preventive. The review aims to describe the potential properties of ruxolitinib to identify new therapeutic strategies.

Keywords: GVHD; Janus kinase; cytokines; inflammation; pediatrics; ruxolitinib.

Figure 1

Schematic representation of JAK/STAT signal transduction pathway by cytokines. A cytokine binding to the receptor induces JAK activation and, consequently, STAT phosphorylation. Activated STATs form hetero- or homodimers that translocate to the nucleus and regulate the transcription of genes that cause hyperinflammation and cytokine storm. Created with BioRender.com (accessed on 16 March 2022).

Figure 2

Schematic representation of ruxolitinib’s effect on inflammation induced by the JAK–STAT signal transduction pathway. Ruxolitinib, administered during inflammation, blocks the receptors and triggers the reduction of STAT phosphorylation and, consequently, decreases hyperinflammation and cytokine storm. Created with BioRender.com (accessed on 16 March 2022).

Figure 3

Schematic representation of the preventive anti-inflammatory action of ruxolitinib. (A) Ruxolitinib, administered at low dosage and in the absence of cytokine induction, can partially block JAK receptors. (B) Partial inhibition of JAK receptors by ruxolitinib reduces STAT activation and prevents hyperinflammation. Created with BioRender.com (accessed on 16 March 2022).