Momelotinib in MF and thrombocytopenia: MOMENTUM, SIMPLIFY-1 and SIMPLIFY-2 subgroup analysis

Momelotinib, an oral inhibitor of Janus kinase 1, Janus kinase 2, and activin A type 1 receptor (ACVR1), is a U.S. Food and Drug Administration (FDA) approved therapy for the treatment of patients with anemic myelofibrosis (MF). Patients with MF often also present with thrombocytopenia, which is associated with poorer clinical outcomes.

The efficacy of momelotinib was evaluated by Kiladjian et al.¹ in a post-hoc subgroup analysis of data from MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2, previously reported by the MPN Hub.

Study design

Patients from the three included studies with thrombocytopenia, characterized by a platelet count <100 × 10⁹ /L, were included. The design of this multi-trial analysis is presented in Figure 1.

Figure 1.  Post hoc analysis design*

BAT, best available therapy; JAKi, Janus kinase inhibitor.
*Adapted from Kiladjian, et al.¹

 To assess momelotinib efficacy in the <100 × 10⁹/L patient subgroups, data was collected at Week 24 in the following measures:

• spleen volume reduction ≥35%
• transfusion independence
• Total Symptom Score reduction ≥50%
• overall survival (OS)

Results

Response rates stratified by baseline platelet count for each trial are presented in Figure 2.

Figure 2. Response rates for SV35, transfusion independence, and TSS* 

BAT, best available therapy; SVR35, spleen volume reduction ≥35%; TSS, Total Symptom Score.
*Adapted from Kiladjian, et al.¹

 OS data was collected at various time points and compared with the overall populations of each trial; this data is presented in Table 1.

Table 1. OS data for SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM*

• Treatment with momelotinib consistently improved outcome measures compared with each trial comparator.
• Mean platelet counts remained consistently stable or improved following treatment with momelotinib.
• Overall, OS rates remained consistent compared with the intent to treat populations.

Safety

Grade ≥3 thrombocytopenia and hemorrhage were used as key safety indicators, alongside thrombocytopenia resulting in discontinuation or dose reduction (Table 2).

Table 2. Safety outcomes*

• Thrombocytopenia was the most common Grade ≥3 adverse event observed
• Discontinuation or dose reduction due to thrombocytopenia was observed in <20% of the momelotinib cohorts in MOMENTUM and SIMPLIFY-1
• Across all studies, 6% discontinued treatment due to thrombocytopenia
• There were no deaths due to thrombocytopenia

• The safety profile of the momelotinib cohorts was not significantly different from the overall safety populations
• Major adverse cardiovascular events were infrequent, and the rate of hemorrhage did not differ significantly from the overall population

Conclusion

Overall, momelotinib demonstrated a clinical benefit in patients with MF and thrombocytopenia compared with ruxolitinib, danazol, and best available therapy. The safety profile was comparable to the overall population. Notably, this post hoc analysis used trials not initially designed for platelet count subgroup analysis; however, it highlighted the potential of momelotinib as a treatment option for further investigation in patients with MF and thrombocytopenia.