The lysine-specific demethylase 1 (LSD1) inhibitor bomedemstat in myelofibrosis: results from a phase 1/2 study.

Novel therapies are needed for myelofibrosis (MF), particularly after Janus kinase (JAK) inhibitor failure. This open-label, phase 1/2 study evaluated bomedemstat, an irreversible inhibitor of lysine-specific demethylase 1, in participants with MF refractory or resistant to, inadequately controlled by, or intolerant of approved therapies. Eighty-nine participants initially received bomedemstat at doses 0.25, 0.5, or 0.6 mg/kg orally once per day, titrated to achieve a target platelet count of ≥50 × 109/L to ≤75 × 109/L. Primary end points were safety and change in spleen volume. Hematologic response and change in symptom burden, bone marrow fibrosis score, and variant allele frequency (VAF) were exploratory. Eighty-seven (97%) participants experienced ≥1 any-cause adverse event (AE), most commonly thrombocytopenia (48%) and dysgeusia (36%); 62 (69%) participants experienced ≥1 grade 3 to 5 AE. Three participants (3%) experienced AEs that led to death; none were related to treatment. Of 35 participants with spleen volume data at week 24, 23 (66%) had a reduction in spleen volume; 9 (26%) had a reduction of ≥20%. Mean platelet and white blood cell counts normalized over 24 weeks; hemoglobin levels remained stable. Participants reported improvement in most symptoms, including fatigue. Of 35 participants with baseline and week 24 data, 8 (23%) had improved bone marrow fibrosis by ≥1 grade per central review, and 21 (60%) were stable. Of 36 participants with CALR, JAK2, or MPL mutations and data at week 24, 56% had a reduction in VAF. Bomedemstat had manageable safety and clinical activity in participants with MF in need of an alternative therapy. This trial was registered at www.ClinicalTrials.gov as NCT03136185.