Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review
INTRODUCTION The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway mediates signaling by cytokine, chemokine and growth factor receptors on cell surface to the nucleus. JAK/STAT pathway is aberrantly activated in a variety of lymphomas, with a dual role of promoting cell survival/proliferation and immune evasion. AREAS COVERED This review describes the preclinical rationale behind the development of JAK inhibitors in lymphoma, some of which are being evaluated in Phase I/II studies, and summarizes the characteristics and clinical results of different JAK inhibitors in clinical development. Available preclinical and clinical data about JAK inhibition in lymphoid malignancies were reviewed using a PubMed access. To date, pacritinib (SB1518), a selective JAK2/FLT3 inhibitor is the first and only JAK inhibitor that has been evaluated in patients with relapsed lymphoma. EXPERT OPINION The preclinical rationale behind the development of pacritinib in lymphoproliferative neoplasms is strong, as the deregulation of the JAK/STAT pathway is involved in the pathogenesis of multiple lymphoma subtypes, although with different mechanisms. Pacritinib demonstrated safety and early clinical efficacy in a variety of lymphoma histologic types, providing the first proof of principle of the potential clinical value of targeting JAK/STAT pathway in lymphoma.