JAK2 inhibitors in the treatment of myeloproliferative neoplasms: rationale and clinical data

Author(s): Raoul Tibes, Ruben Mesa

The seminal discovery of the high prevalence of the JAK2-V617F mutation in essential thrombocythemia, polycythemia vera and myelofibrosis has led to a renewed interest in the science and therapy of Philadelphia chromosomenegative myeloproliferative neoplasms (MPNs). Within a short period of discovery, close to ten JAK2 inhibitor small molecules with different JAK2 kinase specificity have entered clinical trials for patients with MPNs. In myelofibrosis patients, these novel agents have been shown to decrease pathologic splenomegaly and improve disease-associated symptoms, as well as helping to improve cytopenias. Their ability to substantially impact disease progression, bone marrow histologic features and JAK2 allele burden remains to be shown. JAK2 inhibition in polycythemia vera and essential thrombocythemia appears to be promising in reducing myeloproliferation, constitutional symptoms and, possibly, thrombohemorrhagic events. Agents targeting alternative mechanisms, either used alone or in combination with JAK2 inhibitors, may further augment their clinical efficacy and broaden the therapeutic spectrum for patients with MPNs.