JAK2 inhibitors for myeloproliferative neoplasms: what is next?

Abstract

Since its approval in 2011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant or intolerant polycythemia vera (PV) is steadily increasing. Several other JAK2 inhibitors have entered clinical testing, but none have been approved and many have been discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, in which survival is short. Many such combinations are being explored, as are other novel agents, some of which could successfully be combined with JAK2 inhibitors in the future. In addition, new JAK2 inhibitors with the potential for less myelosuppression continue to be investigated. Given the proven safety and efficacy of ruxolitinib, it is likely that ruxolitinib-based combinations will be a major way forward in drug development for MF. If approved, less myelosuppressive JAK2 inhibitors such as pacritinib or NS-018 could prove to be very useful additions to the therapeutic armamentarium in MF. In PV, inhibitors of histone deacetylases and human double minute 2 have activity, but their role, if any, in the future treatment algorithm is uncertain, given the availability of ruxolitinib and renewed interest in interferons. Ruxolitinib is in late-phase clinical trials in essential thrombocythemia, in which it could fill an important void for patients with troublesome symptoms.

Inflammatory functional iron deficiency common in myelofibrosis, contributes to anaemia and impairs quality of life. From the Nordic MPN study Group

“…Interestingly, an influence on QoL from both inflammatory cytokines and lowered Tsat was shown. This is in line with the assumption that at least part of the symptomatic effect of JAK2 inhibitors is due to their anti‐inflammatory effects . It is also in line with recent studies showing that iron deficiency per se may give symptoms, especially fatigue, which is the main QoL‐reducing symptom in MF …”

“…inhibitors is due to their anti-inflammatory effects. 18 It is also in line with recent studies showing that iron deficiency per se may give symptoms, especially fatigue, which is the main QoL-reducing symptom in MF . 19,20 Patients with transfusion dependency and s-ferritin >500 µg/L had higher levels of inflammatory cytokines and hepcidin.…”

The JAK1/2 inhibitor ruxolitinib delays premature aging phenotypes

“…Ruxolitinib is currently used as an antitumor agent in the context of myeloproliferative disorders and is proposed to decreased inflammation (Bose & Verstovsek, ; Ghoreschi & Gadina, ; Lussana & Rambaldi, ), in agreement with previous observations that ruxolitinib represses pro‐inflammatory SASP production (Farr et al, ; Xu et al, , ). Although the use of ruxolitinib is relatively safe, there are reports of reduced blood cell counts and increased risk of infection and nonmelanoma skin cancer, which would be important to consider before testing in HGPS patients (Fabiano et al, ; Saeed, McLornan, & Harrison, ).…”

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

“…The discovery of GOF mutations in the pseudokinase domain of JAK2 (e.g., JAK2 V617F and other mutations) in the spectrum of disorders including polycythemia vera, essential thrombocytosis and myelofibrosis provided strong rationale for the use of jakinibs in this setting . In fact, ruxolitinib has been approved for this indication.…”

“…The discovery of GOF mutations in the pseudokinase domain of JAK2 (e.g., JAK2 V617F and other mutations) in the spectrum of disorders including polycythemia vera, essential thrombocytosis and myelofibrosis provided strong rationale for the use of jakinibs in this setting. 22,105,106 In fact, ruxolitinib has been approved for this indication. Though JAK2 inhibitors provide substantial clinical benefit, there is little evidence that they reduce the natural progression of myeloproliferative disease in a manner seen with the introduction of the Abl kinase inhibitor, imatinib, for chronic myeloid leukemia.…”