Bomedemstat Improved Clinical Profile of Patients with Advanced Myelofibrosis

Because many patients lose response or become intolerant to ruxolitinib (RUX), there is an unmet need for safe and clinically effective alternative therapeutic options in patients with myelofibrosis (MF). Bomedemstat, an orally active lysine-specific demethylase-1 (LSD1) inhibitor, has recently emerged as a potential candidate to fill this treatment gap in MF. In mouse models of myeloproliferative neoplasms, bomedemstat reduced peripheral cell counts, splenomegaly, inflammatory cytokines, bone marrow fibrosis, mutant cell burden, and survival. Overexpression of LSD1 is associated with cancer progression by promoting tumor cell growth and survival. LSD1 also stimulates maturation of megakaryocytes, one cell type critical to the pathogenesis of MF. Inhibition of LSD1 may provide clinical benefit to patients with advanced MF.

The data presented here are part of an ongoing, open-label phase 1/2 study evaluating once-daily bomedemstat in 89 patients with MF (46% primary MF, 34% post-essential thrombocythemia-MF, 20% post-polycythemia vera-MF). Dosing for each patient is determined and adjusted as needed by individual platelet count, which is used as a biomarker of bomedemstat 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 ≤3 different treatments. Mutations observed at screening included JAK2 (64%), CALR (22%), and MPL (7%). A total of 64% of patients had ≥2 mutations of which 66% had high-risk mutations in ASXL1, IDH1/2 , EZH2 , and/or SRSF2.

Primary end points, safety, reduction of spleen volume (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 an SVR from baseline, with 35% having ≥20% SVR and 8% having >35% decrease. In evaluable patients (n = 23) at 24 weeks for TSS with baseline value ≥20, 74% recorded a reduction in TSS with 26% reporting reductions at ≥50. Serial bone marrow biopsies and germline and somatic mutant allele frequencies (MAFs) were also evaluated during bomedemstat treatment. Although bone marrow fibrosis scoring post-baseline is still in progress, preliminary data show 17% of patients improved by 1 grade and 66% were stable. Overall, MAFs were stable in 45% of patients (n = 127). MAFs in ≥1 alleles decreased in 36% of patients (JAK2= 41%, CALR = 43%, MPL = 1 of 3), increased in 19% (MPL = 2 of 3), and 4 patients achieved complete molecular remission. The high-risk allele, ASXL1, 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 and no new mutations or progression to acute myeloid leukemia were noted with bomedemstat treatment. Compared with baseline, 89% of patients who were transfusion-independent (n = 36) and 59% of transfusion-dependent patients (n = 17) had stable or improved hemoglobin by week 12, with 1 patient becoming transfusion-independent.

Bomedemstat appears to reduce spleen volume, improve symptoms, and reduce MAFs without inducing therapy-related toxicities and deaths. Further investigation is needed to determine whether bomedemstat is an effective option for patients with advanced MF, including in combination with RUX and the mechanism by which bomedemstat reduces frequency of the high-risk allele ASXL1.

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.