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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.
In this video, Srdan Verstovsek, MD, PhD, The University of Texas MD Anderson Cancer Center, Houston, TX, shares some insights into the promise of momelotinib for the treatment of MF, and further comments on the potential approval of this agent in the near future.
Dr Verstovsek concludes, “in the therapeutic spectrum of medications for myelofibrosis, we may have an anemia drug. Because remember, ruxolitinib, fedratinib, and pacritinib, the approved JAK inhibitors, are mainly for controlling spleen and symptoms, and some of them actually cause anemia. So momelotinib is completely different, and we expect it to be such a valuable asset for us to use in the second-line setting.”
Another JAK inhibitor being extensively investigated for the treatment of MF is fedratinib, which was approved by the FDA in 2019 for adults with intermediate-2 or high-risk primary or secondary MF, following the results of the JAKARTA trial (NCT01437787).5 Fedratinib has demonstrated clinical benefits in patients, including a reduction in spleen volume and an improvement in symptoms.2 In this video, Claire Harrison, MD, DM, FRCP, FRCPath, Guy’s and St Thomas’ NHS Foundation Trust, London, UK, discusses the promising role of fedratinib in the treatment of MF and where this agent may fit in the MPN treatment armamentarium.
Prof. Harrison states, “there’s now some real-world analysis… as patients outside of clinical trials are having access to this medication, one, showing that outcome in terms of spleen and symptom responses as measured in the real-world setting appears to be good. And two, there is some data from several hundreds of patients suggesting that survival is not impacted and may actually be improved with fedratinib.”
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.
Along with pelabresib, other agents being evaluated in combination with ruxolitinib are the BCLxL inhibitor navitoclax, and the PI3Kδ inhibitor parsaclisib. Several clinical trials evaluating these combinations are underway and will provide insight into optimal treatment strategies for JAK inhibitor-naïve patients. In this video, Prithviraj Bose, MBBS, The University of Texas MD Anderson Cancer Center, Houston, TX, gives a detailed overview of various combination approaches being explored in MPNs.
Dr Bose states, “these are mechanistic combos, combos that are intended to lead to synergism, but then you also have combos which are just logical, because you want to improve blood counts with the other drug, which ruxolitinib doesn’t really do.”
The treatment and management of patients with MF who fail JAK inhibitor therapy represents a major unmet need in the field, and combination strategies are a valuable approach to improving therapeutic options available to this patient population.
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.
In this video, Ruben Mesa, MD, UT Health San Antonio MD Anderson Cancer Center, San Antonio, TX, gives an overview of novel agents being explored in PV and ET, and clinical trials investigating these agents.
Dr Mesa states, “we fortunately have a robust pipeline of therapies in both PV and in ET. In ET, we have both ongoing studies with ropeginterferon alfa-2b… In PV, we one, have the recent approval of ropeginterferon alfa-2b, so that’s an important new option… and two, we have a whole portfolio of hepcidin mimetics, rusfertide, the most developed of those… a robust pipeline for both groups of diseases and we’re excited to see it.”
The ongoing research and clinical trials in the MPN field will hopefully transform the treatment landscape of these diseases, offering patients with ET, PV, and MF valuable therapeutic options in the future.
The MPN Channel on VJHemOnc is supported by Constellation Pharmaceuticals, Kartos Therapeutics, Inc. and Sierra Oncology.
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