Momelotinib improves transfusion independence and OS in patients with myelofibrosis

Momelotinib, a potent Janus kinase 1 and 2 (JAK1/2) inhibitor (JAKi) and an inhibitor of activin A receptor type I (ACVR1; also known as ALK-2), is currently being investigated as a novel approach for treating myelofibrosis (MF). This approach is through ACVR1/ALK2 inhibition, which in turn reduces hepcidin levels to relieve iron-restricted anemia of inflammation, caused by heightened hepcidin. Anemia is an important prognostic factor that markedly reduces survival expectancy and increases the need for transfusion.

The clinical value of momelotinib for anemic patients was discussed in an interview with Abdulraheem Yacoub, which you can watch here.

Data from the phase III SIMPLIFY-1 (S1) (NCT01969838) and SIMPLIFY-2 (S2) (NCT02101268) trials, summarized on the MPN Hub, demonstrated robust overall survival (OS) with momelotinib for patients with MF who were either JAKi naïve (S1) or who had previous JAKi treatment (S2). Momelotinib also improved transfusion independence (TI), and reduced the severity of anemia, constitutional symptoms, and splenomegaly.¹

During the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting and the European Haematology Association (EHA) 2021 Virtual Congress, the MPN Hub Steering Committee members, Ruben A. Mesa and Jean-Jacques Kiladjian, presented updated results on the SIMPLIFY trials, respectively. Mesa reported on the association of TI with OS in patients receiving momelotinib, and you can watch his interview with the MPN Hub summarizing these data below.¹ Kiladjian compared expanded data on TI between momelotinib- and ruxolitinib-treated patients, who were randomized by baseline hemoglobin (HgB), platelet count, or transfusion status.² We summarise the key findings below.^1,2

Key results

TI is associated with superior OS in patients receiving momelotinib¹

• Subgroup analysis of the JAKi-naïve patients receiving momelotinib in S1 showed a statistically significant association of TI at Week 24 with improved OS (median OS, not reached; 3-year survival, 80%) compared with transfusion-dependent responders (3-year survival rate, 50%) (hazard ratio [HR], 0.3; p < 0.0001).
• For patients previously treated with JAKi (S2), TI responders showed a trend of superior OS compared with dependent patients (HR, 0.57; p = 0.0652)
• When adjusting for time to response bias, associations were maintained.
• In both studies, spleen volume and symptomatic improvement, commonly used to evaluate treatment benefit, did not demonstrate a significant association with improved OS (S1: HR, 0.59; p = 0.0904 and HR, 0.66, p = 0.1657, respectively. S2: HR, 2.06; p = 0.1004 and HR, 0.67; p = 0.2513, respectively).

Momelotinib improves TI for JAKi-naïve patients compared with ruxolitinib²

The following results were presented by Jean-Jacques Kiladjian at EHA2021 in an updated comparison of TI by baseline Hgb and platelet levels and transfusion status between momelotinib and ruxolitinib.

• In the intent to treat population, momelotinib treatment produced a greater TI rate compared with ruxolitinib.
• Notably, greater TI was observed with momelotinib when accounting for baseline HgG levels ranging from <8 g/dl to ≤14 g/dl, alongside baseline platelet count, and baseline transfusion status vs ruxolitinib (Table 1).
• Around 93% of patients from the S1 trial had baseline HgG levels ≤14 g/dl, inferring a degree of anemia.

Table 1. Transfusion independence response rates at Week 24 in momelotinib- and ruxolitinib-treated patients

*Adapted from Kiladjian et al.2
Baseline characteristic, %	Momelotinib	Ruxolitinib
Baseline hemoglobin
<8 g/dl	29	18
<10 g/dl	47	27
<12 g/dl	62	37
<14 g/dl	67	45
≥14 g/dl	64	91
Baseline platelet count
<150 ml	62	43
<300 ml	68	48
≥300 ml	63	51
Baseline transfusion status
Transfusion independent	81	62
Transfusion requiring	53	31
Transfusion dependent	30	17

Conclusion

Overall, further analysis of the SIMPLIFY trials provided two key insights. Firstly, momelotinib demonstrated a further benefit compared with ruxolitinib, producing significantly greater rates of TI for patients with MF, irrespective of the degree of baseline anemia, baseline platelet count, or transfusion status. TI appears to be a determining factor for improving OS for these patients (p < 0.0001), presenting an advantage for the use of momelotinib over the current JAKi standard in patients with MF who are anemic or at risk of myelosuppression.