Myeloproliferative neoplasms (MPNs) represent a heterogeneous group of diseases driven by several cytogenetic aberrations, including mutations in the genes encoding janus kinase 2 (JAK2), calreticulin (CALR), and the thrombopoietin receptor (TPOR, MPL).¹ Several advances have been made in the treatment of MPNs over the years, with JAK inhibitors marking a paradigm shift in the field.

Ruxolitinib was approved by the FDA in 2011 for the treatment of myelofibrosis (MF) and has demonstrated good safety and efficacy in patients, as well as an improvement in overall survival (OS).² Despite the clinical benefits observed with the use of this agent, many patients eventually fail ruxolitinib treatment, and may further develop dose-limiting cytopenias, anemia, and other toxicities.^{3, 4}

One novel agent of interest being explored for the treatment of MF is momelotinib, which is a small-molecule JAK inhibitor that has shown in clinical trials to improve anemia in patients, potentially offering an advantage over other JAK inhibitors.² The randomized Phase III MOMENTUM trial (NCT04173494), which is comparing the use of momelotinib versus danazol in anemic and symptomatic patients with MF previously treated with a JAK inhibitor, will provide valuable information on the efficacy of this agent.

While JAK inhibitors have greatly transformed the MF treatment landscape and have demonstrated clinical benefit in patients, these agents do not modify the underlying disease, and have several dose-limiting side effects.⁶ Therefore, there has been a recent interest in exploring novel pathways and combination approaches for the treatment of JAK inhibitor-naïve patients, several of which are ruxolitinib-based.

The ongoing Phase III MANIFEST-2 study (NCT04603495) is comparing the use of the BET inhibitor pelabresib plus ruxolitinib versus placebo plus ruxolitinib in JAK inhibitor-naïve patients. In this video, Andrew Kuykendall, MD, H. Lee Moffitt Cancer Center, Tampa, FL, shares some insights into the promise of pelabresib for the treatment of MF and highlights the excitement surrounding the ongoing MANIFEST-2 study.

Polycythemia vera (PV) is a myeloproliferative disorder characterized by an overproduction of erythrocytes, which results in a range of symptoms, including thrombosis, itching, and headache.⁷ At present, there is no cure for PV, and current treatment approaches aim to alleviate symptoms and reduce the risk of bleeding events.⁷ Common therapeutic strategies include phlebotomy, low-dose aspirin, and cytoreductive therapies, such as hydroxyurea.⁸

In 2021, the FDA approved the use of ropeginterferon alfa-2b for the treatment of adult PV patients following the results of the PEGINVERA (NCT01193699) and PROUD-PV (NCT01949805) trials.⁹ Ropeginterferon afa-2b is a novel, long-acting mono-pegylated interferon, which has shown high tolerability and long-term responses in patients,^{10, 11} and is a valuable addition to the PV treatment armamentarium.

Another agent of interest being explored in PV is rusfertide, a hepcidin mimetic, which has shown to reduce the patient’s need for phlebotomy and reverse iron deficiency. The safety and efficacy of this agent is currently being evaluated in the VERIFY trial (NCT05210790) and will provide further information on where rusfertide may fit in the treatment of PV.

Along with PV, novel treatment approaches for essential thrombocythemia (ET) are being increasingly explored, as patients with high-risk disease have limited options.¹² The ongoing Phase III SURPASS-ET trial (NCT04285086) is comparing the safety, efficacy, and tolerability of ropeginterferon alfa-2b versus anagrelide in patients with high-risk ET. Furthermore, the oral LSD1 inhibitor bomedemstat is being evaluated in an ongoing Phase IIb trial, with preliminary data suggesting that this agent is well-tolerated and efficacious in terms of reducing platelet count.