High Rates of Spleen Volume Reduction and Symptom Improvement for Flonoltinib Maleate in MF

Flonoltinib maleate (FM) treatment achieved notable early spleen volume reduction and symptom improvement for most patients with myelofibrosis (MF). Benefits were observed regardless of prior Janus kinase (JAK) inhibitor exposure, and adverse events were tolerable, warranting further investigation.

MF causes splenomegaly, anemia, and bone marrow fibrosis; and patients frequently have poor prognoses. JAK inhibitors are the standard of care for MF treatment, but only 42% of patients receiving ruxolitinib achieve spleen volume reduction of more than 35% (SVR35%).¹ FM is a new-generation JAK2 inhibitor that is 600 times more selective for JAK2 than JAK1 or JAK2. FM also targets FLT3, which is frequently mutated in acute myeloid leukemia transformation, and CDK6, which is involved in bone marrow fibrosis.

Lijuan Chen, PhD, Sichuan University, Chengdu, Sichuan Province, China, presented the first-in-human, open-label, phase 1/2a trial evaluating FM tolerability and efficacy for patients with MF.² The trial included patients with intermediate- to high-risk primary MF, post-essential thrombocythemia MF, and post-polycythemia vera MF. Patients also had measurable splenomegaly and platelet counts greater than 50 × 10⁹/L. The dose-escalation arm (n=15) included six doses, and 100 mg daily was established as the dose for the dose-expansion phase (n=15).

At week 24, SVR35% was observed in 77.3% of patients, 17 of 22 in the combined escalation and expansion arms. “FM showed a rapid and long-lasting splenomegaly reduction,” Dr. Chen emphasized. Bone marrow fibrosis was seen in 26.1% of the combined patient populations. These values were marginally higher in the dose expansion phase than in the dose escalation phase. Symptom improvement rates of greater than 50% were seen in 76.7% of participants (23 of 30). Notably, the symptom improvement and SVR35% improvements were experienced by populations with and without prior JAK inhibitor exposure. “Patients with or without exposure to JAK inhibitor can benefit from the FM treatment,” said Dr. Chen. The most common adverse effects were anemia (50.0%) and thrombocytopenia (29.0%); platelet levels remained constant during the trial.

Dr. Chen concluded, “FM has an outstanding efficacy and manageable safety tolerability.” This study is being expanded in an ongoing, multicenter, open-label, positive control phase 2 trial (NCT06457425).

REFERENCES

1. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-98. doi: 10.1056/NEJMoa1110556
2. Chen L, Wang Y, Wang J, Yang L, Niu T. First-in-human phase I/IIa safety and efficacy of flonoltinib maleate, a new generation of JAK2/FLT3 inhibitor in myelofibrosis. Abstract #486. Presented at the ASH Annual Meeting; December 7-10, 2024; San Diego, California.