While ruxolitinib (RUX) and other JAK inhibitors improve clinical outcomes in patients with myelofibrosis (MF), most patients are forced to terminate their treatment due to emergence of refractoriness. Bomedemstat (IMG-7289), an orally active lysine-specific demethylase-1 (LSD1) inhibitor, has recently emerged as a potentially safe and clinically effective alternative therapeutic option for this patient population. In mouse models of myeloproliferative neoplasms, bomedemstat demonstrated meaningful activity, including reductions in peripheral cell counts, splenomegaly, inflammatory cytokines, bone marrow fibrosis, mutant cell burden, and survival. Overexpression of LSD1 promotes tumor cell growth and survival and regulates development of megakaryocytes, which are key to the pathophysiology of MF.
In this currently ongoing, open-label, phase 1/2 study, 89 patients with MF (49% primary MF, 30% post-essential thrombocythemia-MF, 21% post-polycythemia vera-MF) were enrolled to assess the effects of once-daily bomedemstat. Patient-specific dosing was determined by platelet count, a biomarker of the drug’s activity on megakaryocyte function. The median duration of treatment is 17 weeks (range, 2-102 weeks). All patients met International Prognostic Scoring System─defined criteria for intermediate-1 (6%), intermediate-2 (40%), or high risk (54%) and were refractory or resistant to, inadequately controlled by, intolerant of, or ineligible for available approved therapy. Previous treatment with RUX was reported in 81% of patients (n = 72) and 43% (n = 38) had also received up to 3 different treatments. Mutations were observed at screening in the JAK2 (70%), CALR (22%), and MPL (7%) genes. Two or more mutations were found in 64% of patients, of which 66% were high-risk mutations (ASXL1, IDH1/2, EZH2, and/or SRSF2).
Safety and reduction in spleen volume response (SVR) and total symptom scores (TSS) were assessed only in evaluable patients for each parameter. Early terminations (<24 weeks of treatment) due to adverse events occurred in 13 (15%) patients, 5 of which were related to bomedemstat. The most commonly observed adverse event was thrombocytopenia (47%). Nonhematologic adverse events reported were diarrhea and dysgeusia, each at 28% (25/89). For SVR at 24 weeks (N = 27), 75% of patients (N = 40) had a reduction in spleen volume from baseline (mean SVR, ─4%; –41% to 107%) with 37% having ≥20% SVR. In 23 evaluable patients at 24 weeks for TSS with baseline value ≥20, 74% recorded a reduction in TSS (mean change –36%; –81% to 21%) with 26% reporting reductions at ≥50%. Serial bone marrow biopsies and germline and somatic mutant allele frequencies (MAFs) were also evaluated during bomedemstat treatment. Regarding bone marrow fibrosis scoring, 17% of patients improved by 1 grade and 66% were stable when compared with baseline. MAFs were stable in 45% of patients, while MAFs decreased for ≥1 alleles in 36% of patients; 4 patients achieved complete molecular remission. ASXL1 MAF was stable in 56% of patients and decreased in 31%. Interestingly, patients with reductions in MAFs were observed to also have improved SVR and TSS.
The evidence presented here indicates that bomedemstat decreases spleen volume, improves symptoms, and decreases MAFs. Notably, treatment with bomedemstat was not associated with therapy-related toxicities and deaths. Taken together, bomedemstat may be a safe option for patients with advanced MF.
Source: Gill H, Yacoub A, Pettit KM, et al. A phase 2 study of the LSD1 inhibitor Img-7289 (bomedemstat) for the treatment of advanced myelofibrosis. American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 139.