Abstract
BCR-ABL1-negative myeloproliferative neoplasms are burdened by a reduced life expectancy mostly due to an increased risk of thrombo-hemorrhagic events, fibrotic progression/leukemic evolution, and infectious complications. In these clonal myeloid malignancies, JAK2V617F is the main driver mutation, leading to an aberrant activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Therefore, its inhibition represents an attractive therapeutic strategy for these disorders. Several JAK inhibitors have entered clinical trials, including ruxolitinib, the first JAK1/2 inhibitor to become commercially available for the treatment of myelofibrosis and polycythemia vera. Due to interference with the JAK-STAT pathway, JAK inhibitors affect several components of the innate and adaptive immune systems such as dendritic cells, natural killer cells, T helper cells, and regulatory T cells. Therefore, even though the clinical use of these drugs in MPN patients has led to a dramatic improvement of symptoms control, organ involvement, and quality of life, JAK inhibitors–related loss of function in JAK-STAT signaling pathway can be a cause of different adverse events, including those related to a condition of immune suppression or deficiency. This review article will provide a comprehensive overview of the current knowledge on JAK inhibitors’ effects on immune cells as well as their clinical consequences, particularly with regards to infectious complications.
Highlights
The BCR-ABL1-negative myeloproliferative neoplasms (MPNs) are a heterogenous group of clonal disorders of the hematopoietic stem cell, mainly characterized by hyperproliferative bone marrow with varying degrees of reticulin/collagen fibrosis, extramedullary hematopoiesis, abnormal peripheral blood counts, and constitutional symptoms
JAK2 is activated by several cytokines and growth factors including erythropoietin, thrombopoietin, IL-3, IL-6, G-CSF, and IFN-g [18, 19], while JAK3 is associated with the Υc chain family of cytokines [20] and Tyk2 is triggered by cytokines such as type I IFNs, IL-6, IL-10, and the IL-12 and IL-23 families [21]
In a similar retrospective study based on the French Pharmacovigilance database, between August 2012 and August 2017, in 24 MPN subjects and two GRAFT-VERSUS-HOST DISEASE (GVHD) cases all treated with ruxolitinib, 30 cases of infections were reported: nine were bacterial, five mycobacterial, ten viral, four fungal, one protozoan, and one non-specified opportunistic infection, being Herpes zoster the most frequently identified pathogen [49]
Summary
The BCR-ABL1-negative myeloproliferative neoplasms (MPNs) are a heterogenous group of clonal disorders of the hematopoietic stem cell, mainly characterized by hyperproliferative bone marrow with varying degrees of reticulin/collagen fibrosis, extramedullary hematopoiesis, abnormal peripheral blood counts, and constitutional symptoms. They include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). The latter may present as a primary disorder (PMF) or evolve from another pre-existing BCR-ABL1-negative MPN, such as PV or ET, globally identified as secondary MF (SMF) [1]. This review article will provide a comprehensive overview of the current knowledge on JAK inhibitors’ effects on immune cells, as well as their clinical consequences with regards to infectious complications
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