Janus kinase inhibitors as an evolving treatment for lymphomas and immune-mediated complications

Abstract

The Janus kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) signaling pathway orchestrates the cellular response to multiple cytokine families, including interleukins, hematopoietic growth factors, and interferons. JAK inhibitors were initially approved for the treatment of primary inflammatory disorders. The more recent identification of mutations that constitutively activate the JAK/STAT pathway in both myeloproliferative disorders as well as lymphoid malignancies has led to clinical exploration of JAK inhibitors for the treatment of hematopoietic cancers as well as immune-mediated complications of either hematopoietic cancers or treatment-associated, immune-mediated complications, such graft-versus-host disease (GVHD). In this review, we summarize the current understanding of the JAK/STAT pathway in the pathogenesis of both lymphoid malignancies and lymphoma-associated immune complications and discuss both the clinical efficacy and mechanisms of action of JAK inhibitors in lymphoid malignancies as well as their inflammatory complications, for which JAK inhibition has revolutionized the therapeutic landscape. In contrast, the variable clinical efficacy of JAK inhibitors across B- and T-cell malignancies highlights the need for biomarker-driven patient selection and rational combination approaches to maximize the efficacy across malignant disease contexts.