Treatment‐associated decline inJAK2V617F allele burden in polycythemia vera: What does it mean?

Abstract

The discovery of JAK2V617F, 20 years ago, 1 has opened a Pandora's box of pathogenetic insights and targeted therapies in myeloproliferative neoplasms (MPNs). The specific mutation has positioned the JAK-STAT pathway at the center of activities and has led to the discovery of other JAK-STAT activating mutations in MPNs, including CALR 2,3 and MPL. 4 A number of small molecule JAK1/2 inhibitors (JAKi) have since been approved for use in JAK2 mutation-prevalent MPNs, including myelofibrosis (MF) and polycythemia vera (PV). 5 These drugs are not specific to mutant JAK2 and their mechanism of therapeutic benefit in MPN has been attributed to their nonspecific suppression of JAK-STAT-driven clonal myeloproliferation and inflammationassociated disease manifestations, including constitutional symptoms and cachexia. 6 The first JAKi to be approved for use in MPN, is ruxolitinib, which has been evaluated in patients with MF, 7 PV, 8 and essential thrombocythemia (ET). 9 In all instances, treatment-associated symptomatic improvement has been demonstrated and, in some, was accompanied by a decline in JAK2V617F variant allele frequency (VAF). The latter phenomenon has also been observed in PV patients treated with interferon-alpha (IFN-α), 10-12 busulfan, 13 or hydroxyurea (HU). 12,14,15 However, the two drugs that have so far garnered significant notoriety in treatment-associated reductions in JAK2V617F VAF are IFN-α and ruxolitinib.In a randomized study comparing HU with pegylated IFN-α (PEG),