Efficacy and Safety of Momelotinib in Myelofibrosis: A Systematic Review and Meta-Analysis with a Focus on Anemia Outcomes

Introduction: Myelofibrosis (MF) can be primary myelofibrosis (PMF) or secondary myelofibrosis (SMF). PMF is one of the chronic myeloproliferative disorders with unknown cause. However, consecutive activation of the JAK/STAT pathway, in association with mutations in janus kinase 2 (JAK2), thrombopoietin receptor (MPL), or calreticulin gene (CALR), plays a role. On the other hand, SMF evolves from either polycythemia vera (PCV) or essential thrombocythemia (ET). Anemia, with hemoglobin less than 10 g/dL, occurs in about 50% of PMF patients. While JAK inhibitors like ruxolitinib, fedratinib, and pacritinib have benefits, they may also worsen anemia. Momelotinib, an oral inhibitor of activin receptor type 1 (ACVR1), JAK1, and JAK2, shows promise in treating anemia, symptoms, and splenomegaly in PMF and SMF, possibly due to ACVR1 inhibition and hepcidin regulation. This review evaluates momelotinib's efficacy and safety in MF, focusing on anemia impact.

Methods: PubMed, Scopus, Cochrane Library, and Clinical Trials.gov were searched for relevant articles. Momelotinib clinical trials involving patients diagnosed with PMF or SMF were included. Cohort studies, case reports, case series, and abstracts were excluded. For efficacy assessment, data on the following outcomes was collected: Transfusion Independence Rate (TI-R) and Splenic Response Rate (SSR). For safety assessment, data on the incidence of the following outcomes was collected: development of Grade 3 or 4 Adverse Events (AE), as well as any-grade anemia, thrombocytopenia and peripheral neuropathy. A fixed-effects model was primarily used, but a random-effects model was employed when significant heterogeneity was detected. Sensitivity analyses were conducted to identify the source of heterogeneity.

Results: Seven articles met the inclusion criteria for the review, including four single-arm trials and three randomized controlled trials (RCTs). We included the three RCTs in this meta-analysis. For the TI-R pooled meta-analysis, 783 patients were included (449 and 334 for the momelotinib group and the control group, respectively). Momelotinib showed a significant advantage over the control group (OR: 2.09; 95% CI: 1.53, 2.85). No heterogeneity was detected regarding TI-R (Tau²= 0; Chi²= 0.92, with a p-value of 0.63; I2= 0%). As for the SSR outcome, involving 739 patients (418 in the Momelotinib group and 321 in the control group), there was no statistically significant difference between the two groups (OR: 1.96; 95% CI: 0.53 to 7.25), with high heterogeneity (Tau² = 1.0033; Chi² = 7.94, p = 0.02; I² = 75%). Heterogeneity was resolved in the sensitivity analysis when excluding momentum study (NCT04173494). Regarding the safety outcomes, the incidence of any adverse events was not statistically significant between the two groups (OR: 1.13; 95% CI: 0.39, 3.30) . There were no significant differences in the incidence of Grade 3 or 4 AE (OR: 0.74; 95% CI: 0.54, 1.00), any-grade anemia (OR: 0.52; 95% CI: 0.16, 1.74) , thrombocytopenia (OR: 1.04; 95% CI: 0.46 to 2.32), or peripheral neuropathy (OR: 1.33; 95% CI: 0.10, 18.56).

Conclusions: MF patients treated with momelotinib demonstrated good response and improved quality of life, particularly in anemia-related outcomes, without increase in adverse events. However, the use of different drugs in control groups introduced heterogeneity among the studies, limiting the ability to compare efficacy between groups. Further studies with larger populations are needed to further assess the effectiveness and safety of momelotinib.

No relevant conflicts of interest to declare.