Dual SVR/TI response to momelotinib with OS benefit in patients with myelofibrosis with anemia and low platelet count

Subgroup analysis data showed that after achieving bilateral splenic volume (SVR) and transfusion-independent (TI) response at 24 weeks, molotinib/momelotinib had a better prognosis than ruxolitinib (Ruxolitinib)-Jakafi, supports molotinib as the initial JAK inhibitor of choice for treatment-naive patients with myelofibrosis (MF) who have anemia and low platelet counts.

Results from the Phase 3 SIMPLIFY-1 trial (NCT01969838) support 2023 U.S. Food and Drug Administration approval of molotinib for the treatment of adult patients with moderate or high-risk myelofibrosis and anemia. 1 In this trial, JAK inhibitor-naïve patients were randomly assigned to receive molotinib (n = 86) or ruxolitinib (n = 95). 2 The SVR rate between the two groups was at least 35% (SVR35), non-inferiority, 31.4% (95% CI, 21.8%-42.3%) for molotinib and 32.6% (95% CII, 23.4%-43.0%) for ruxolitinib.

Based on these data, researchers evaluated different clinical outcomes in patients with lower baseline platelet counts and the clinical relevance of achieving dual SVR35 and TI responses with molotinib at week 24. 3 Study results presented at the 2025 EHA Congress showed that among patients with baseline hemoglobin levels below 10 g/dL and baseline platelet levels below 200x10*9/L at week 24, the SVR35 rate and TI rate were 33% (n=49) in the molotinib group and 2% (n=47) in the ruxolitinib group. Additionally, patients who achieved SVR35+TI (HR, 0.40; 95% CI: 0.18-0.89) or TI alone at week 24 had better overall survival (OS) outcomes compared with patients who achieved SVR35 alone (HR, 0.78; 95% CI, 0.18-3.34).

The SIMPLIFY-1 trial was a prospective, randomized trial including patients with myelofibrosis who had splenomegaly and symptoms. The patients were randomized to receive 200 mg of molotinib once daily or 20 mg of ruxolitinib twice daily in the frontline setting. 2 After 24 weeks, [patients in the ruxolitinib group] may be transferred to [the molotinib group]. Double response rates were significantly higher with molotinib in [most] patient subgroups. The SIMPLIFY-1 results were the impetus for this subgroup analysis, the key results of the analysis, and how these findings may impact future clinical practice.

This trial is the first and only comparison in the first-line setting in myelofibrosisTrial of 2 JAK2 inhibitors and demonstrated non-inferiority of mometinib in achieving splenic response. Ruxolitinib is more effective in symptom control. However, SIMPLIFY-1 is important because the ability of mometinib to improve hemoglobin levels, thereby curing anemia in myelofibrosis, was demonstrated for the first time.

In this subgroup analysis, only patients who initiated molotinib treatment with hemoglobin[levels] below 10 g/dL were focused on, as this is an actual population that will be treated in a real-world setting. 3We wanted to understand the extent of dual response, meaning response to molotinib or ruxolitinib in the spleen and TI. Dual responses were significantly higher in patients treated with molotinib compared with patients [receiving] ruxolitinib. This is especially true when the patient's platelet count is below 200 x 109/L, but it also persists when the platelet count is above 200 x 109g/L.

In a sense, even if higher splenic response rates can be achieved with ruxolitinib, if the platelet count is above 200x 109/L, the splenic response will come at the expense of increased hematologic toxicity and transfusion requirements. The study also performed a Kaplan-Meier analysis of OS and divided patients into subgroups based on the response observed at 24 weeks. For patients with TI response with or without splenic response, the prognosis was much better, with prolonged OS. This may be the first time that TI status at week 24 is more prognostically important compared with splenic controls. Treatment goals are shifting from pure spleen/symptom control to resolution of anemia.

Reference materials:https://en.wikipedia.org/wiki/Momelotinib