According to results from an ongoing phase 2 study of bomedemstat and ruxolitinib for frontline treatment of patients with myelofibrosis (MF) or patients with advanced myelofibrosis with a suboptimal response to ruxolitinib, the addition of bomedemstat to a ruxolitinib regimen was well-tolerated, improved splenomegaly and symptom scores, and stabilized hemoglobin both in the frontline and second-line setting.

These results will be presented by Harinder Gill, MBBS, MD, FRCP, The University of Hong Kong, Hong Kong, at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California.

“Approximately 50% of patients with myelofibrosis discontinue ruxolitinib after 3 years, mostly due to disease progression, suboptimal response or cytopenia. Outcome after ruxolitinib discontinuation is poor with a median overall survival (OS) of approximately 14 months,” explained Gill and coauthors.

To address this unmet need, investigators sought to explore bomedemstat, an oral LSD1 inhibitor which has shown clinical activity for patients with myeloproliferative neoplasms (MPN) and for patients with MF. In this open-label, phase 2 study, investigators attempted to evaluate the safety and tolerability of the combination, the best dosing of bomedemstat, and to assess the efficacy of the combination as assessed by spleen size reduction and symptom reduction using the Myelofibrosis Symptom Assessment Form (MFSAF).

The study was split into 2 cohorts. Cohort A included 30 patients with a suboptimal response to an adequate trial of ruxolitinib defined as splenomegaly not reduced by >35% from baseline or symptoms scores that have not improved by >50%. The cohort A patients must have been on a stable dose of ruxolitinib for ≥ 8 weeks. Cohort B was comprised of 13 treatment-naïve patients with MF who require treatment per guidelines. The patients in cohort A remain on the entry dose of ruxolitinib while cohort B patients received a starting ruxolitinib dose of 10 mg twice per day throughout the study. All patients received concomitantly, a starting dose of bomedemstat of 0.4mg/kg/d, and dose adjustments up were allowed every 4 weeks to achieve a target platelet count of 50 x 10⁹/L.

Between December 2022 to December 2023, 24 men and 19 women with a median age of 64 (range: 47-81) years were enrolled. The case distribution was 26 with primary myelofibrosis (PMF), 10 with PPV-MF, and 7 with PET-MF. The mutational profile of driver genes was JAK2^V617F, N=33 (76.7%); JAK2 exon 12, N=1 (2.3%); and CALR mutations, N=8 (18.6%). Of all patients, 6 (14%) harbored high-molecular risk (HMR) mutations (ASXL, N=4; EZH2, N=2). At enrollment, the mean white blood cell count (WBC), hemoglobin (Hb), platelet count, and lactate dehydrogenase were 12.83 x 10⁹/L (1.61), 9.7 g/dL (0.3), 317 x 10⁹/L (36) and 607 IU/L (63), respectively. As for risk, 10 patients, 23 patients, and 10 patients, belonged to the Dynamic International Prognostic Scoring System (DIPSS) high, intermediate-2 and intermediate-1 risk categories, respectively.

As of a data cut-off of June 30 2024, the median duration of ruxolitinib plus bomedemstat was 61.7 (range: 27.4 to 80.4) weeks. In 40 evaluable patients at week 24, 11 patients (27.5%) had ≥ 50% reduction in MF-SAF Total Symptom Score (TSS) (cohort A: 7/27, 25.9%; cohort B: 4/13, 30.7%) and 7 patients (17.5%) had ≥ 35% spleen volume reduction (cohort A: 2/27, 7.4%; cohort B: 5/13, 38.5%). At week 24, 20 patients (50%) displayed stable (≤ 1g/dL absolute change in Hb) or improved Hb (cohort A: 14/27, 51.9%; cohort B: 6/13, 46.3%).

The most common non-hematologic adverse events were diarrhea, edema, malaise, and dysgeusia. Investigators observed no safety signals or treatment-related mortalities.

“These results suggest that the addition of bomedemstat to a ruxolitinib regimen is well-tolerated, improves splenomegaly and symptom scores, and stabilizes hemoglobin both in the frontline and second-line setting,” concluded Gill and colleagues.

Source:

Gill H, Au L, Tsai D, et al. 1796 Bomedemstat (MK3543) in Combination with Ruxolitinib in Patients with Advanced Myelofibrosis. Dec 7-10, 2024; San Diego, CA. Abstract: 1796