Myelofibrosis is a chronic, progressive myeloproliferative neoplasm that might present de novo (ie, primary) or develop from essential thrombocythaemia or polycythaemia vera (ie, secondary).1 Dysregulated Janus kinase (JAK)-mediated signalling, leading to uncontrolled myeloproliferation and elevated inflammatory cytokine production, is characteristic of myelofibrosis and typically manifests as bone marrow fibrosis, anaemia, splenomegaly, and debilitating symptoms (ie, fatigue, cachexia, fever, night sweats).2 Patients with mild myelofibrosis-associated anaemia (defined as haemoglobin ≥10 g/dL but below sex-adjusted lower limit of normal) have a median survival of 4·9 years, those with moderate myelofibrosis-associated anaemia (haemoglobin between 8 g/dL and <10 g/dL) have a median survival of 3·4 years, and patients with severe myelofibrosis-associated anaemia (haemoglobin <8 g/dL or transfusion dependent) have a median survival of 2·1 years.3 Approved JAK inhibitors provide spleen and symptom improvements but do not address—and might induce or worsen—anaemia.4, 5, 6, 7, 8, 9 Disease-associated or treatment-exacerbated cytopenias might necessitate attenuated JAK inhibitor dosing or discontinuation, which limit treatment efficacy and are associated with poor survival.10, 11, 12
Research in context
Evidence before this study
Dysregulated Janus kinase (JAK)-mediated signalling leading to uncontrolled clonal proliferation and elevated inflammatory cytokine production is characteristic of myelofibrosis and typically manifests as bone marrow fibrosis, anaemia, splenomegaly, and debilitating symptoms. JAK inhibitors approved for the treatment of myelofibrosis provide spleen and symptom improvements but fail to address—and might induce or worsen—anaemia. The investigational agent momelotinib has a unique mechanism of action in that it inhibits not only disease drivers JAK1 and JAK2, but also activin A receptor type 1 (ACVR1), a key regulator of iron metabolism. In the phase 3 SIMPLIFY-1 trial in patients who are naive to JAK inhibitors, momelotinib was non-inferior to ruxolitinib in reducing spleen volume by 35% at week 24 from baseline, and patients who received momelotinib had improvements in transfusion independence rates, haemoglobin concentrations, and roughly half the transfusion burden compared with patients who received ruxolitinib. Preclinical and translational data showed a significant impact on anaemia benefits. Momelotinib did not show non-inferiority to ruxolitinib in reducing total symptom score by at least 50% at week 24 compared with baseline in SIMPLIFY-1, although patients treated with momelotinib reported a 28% symptom response rate. In the phase 3 SIMPLIFY-2 trial in patients previously treated with ruxolitinib, additional symptom responses were observed with momelotinib treatment compared with best available therapy, which was ruxolitinib in 89% of patients. However, superiority of momelotinib in providing additional spleen volume reductions of at least 35% immediately following ruxolitinib treatment without washout was not achieved in SIMPLIFY-2, necessitating a third, redesigned phase 3 study to fully understand the clinical profile of momelotinib in myelofibrosis.
Added value of this study
MOMENTUM is the first randomised, phase 3 study to assess an inhibitor of JAK1, JAK2, and ACVR1 in patients with myelofibrosis and anaemia. The study demonstrated clinically significant benefits in myelofibrosis-associated symptoms, anaemia measures, and spleen responses in symptomatic patients with myelofibrosis and anaemia and previous JAK inhibitor exposure. Furthermore, momelotinib was safe and well tolerated in this advanced patient population, with the overall safety profile of momelotinib consistent with that in previous reports.
Implications of all the available evidence
Anaemia is common in patients with myelofibrosis and is associated with poor survival. Currently approved JAK inhibitors do not meaningfully improve anaemia and can exacerbate anaemia, often requiring attenuated dosing or treatment discontinuation. The clinical benefit seen with momelotinib in patients with myelofibrosis and anaemia, including the reduction of transfusion burden for patients, underscores the potential for momelotinib as a treatment option for this population with high medical need. Given also the favourable safety profile of momelotinib, future research will explore momelotinib in combination with other agents for the treatment of patients with myelofibrosis.
Approaches to managing myelofibrosis-associated anaemia include red blood cell transfusions, erythropoiesis stimulating agents, corticosteroids, androgens such as danazol, immunomodulatory drugs, and splenectomy.10, 13, 14, 15, 16, 17 These strategies have shown modest and transient clinical benefit, and none directly target chronic inflammation and iron restriction within erythroid progenitors, which are key mechanistic contributors to myelofibrosis-associated anaemia.18, 19
Momelotinib is a first-in-class oral inhibitor of activin A receptor type 1 (ACVR1), also known as activin receptor-like kinase 2, as well as an inhibitor of JAK1 and JAK2 that has been previously studied in phase 1–3 clinical trials in myelofibrosis.20, 21, 22, 23 In the head-to-head comparison of momelotinib with ruxolitinib in JAK inhibitor-naive patients in SIMPLIFY-1, the primary endpoint of non-inferiority in reducing spleen volume by 35% at week 24 from baseline was met.20 Further, patients who received momelotinib had a higher week 24 transfusion independence rate, increased haemoglobin concentrations, and roughly half the transfusion burden compared with patients who received ruxolitinib.20, 22 Preclinical and translational studies showed that momelotinib's observed anaemia and transfusion benefits are linked to its suppression of ACVR1-mediated hepcidin production, which leads to increased serum iron availability and stimulation of erythropoiesis.24, 25 Notably, elevated hepcidin concentration is significantly associated with shortened overall survival in patients with myelofibrosis.26 Nonetheless, momelotinib did not show non-inferiority to ruxolitinib in reducing total symptom score (TSS) by at least 50% at week 24 compared with baseline in SIMPLIFY-1, although patients treated with momelotinib had a 28% symptom response rate.20 In patients previously treated with ruxolitinib in SIMPLIFY-2, additional symptom responses were observed with momelotinib treatment despite an absence of a ruxolitinib washout period.21 However, superiority of momelotinib in providing additional spleen volume reductions of at least 35% immediately following ruxolitinib treatment without washout was not achieved in SIMPLIFY-2,21 necessitating a third, redesigned phase 3 study to fully understand the clinical profile of momelotinib in myelofibrosis.
We report in this Article results from the MOMENTUM trial of momelotinib versus danazol in symptomatic patients with anaemia and primary, post-essential thrombocythaemia, or post-polycythaemia vera myelofibrosis who previously received JAK inhibitor therapy.