Bomedemstat improved symptoms in most patients with myelofibrosis, with no dose-limiting toxicities or progressions to acute myeloid leukemia, according to results from the first clinical study of a lysine-specific demethylase (LSD1) inhibitor in patients with myeloproliferative neoplasms. In her presentation at the 2019 ASH Annual Meeting, lead investigator Kristen Pettit, MD, from the Rogel Cancer Center at the University of Michigan, noted that a subset of patients also experienced reductions in splenomegaly.
Bomedemstat has a distinct mechanism of action from ruxolitinib and fedratinib, the two U.S. Food and Drug Administration (FDA)−approved therapies for myelofibrosis. LSD1 is an epigenetic enzyme critical for self-renewal of malignant myeloid cells and differentiation of myeloid progenitors, Dr. Pettit explained. When it is bound to GFI1b, LSD1 permits progenitors to mature to megakaryocytes, enabling their normal function.
Based on preclinical research, the investigators evaluated bomedemstat in this ongoing, open-label, dose-finding phase IIb study, which enrolled adults with intermediate-2 or high-risk myelofibrosis that was intolerant of or resistant to ruxolitinib. Eligible patients had a platelet count of ≥100×109/L.
Per study protocol, participants were treated with bomedemstat for 12 weeks, followed by a washout period of up to 28 days. After the washout period, patients receiving clinical benefits could resume treatment for additional 12 weeks. Bone marrow biopsies and imaging studies were conducted at baseline and during washout (after day 84).
Using platelet count as a biomarker for effective thrombopoiesis, dosing was individually tailored to patients, with all patients starting at a presumed subtherapeutic dose of 0.25 mg/kg per day. Dose was up-titrated weekly until the platelet count reached between 50 and 100×109/L.
Dr. Pettit reported results from a preliminary analysis of 20 patients enrolled in the trial: 18 in the phase I/IIa portion and two in the phase IIb portion. Their median age was 65 years (range = 48-89).
Half of patients had primary myelofibrosis, 35% had post-essential thrombocythemia myelofibrosis, and 15% had post-polycythemia vera myelofibrosis. Sixty percent had high-risk disease, and the rest had intermediate risk-2.
At data cutoff, the median duration of treatment was 166 days (range = 14-539). Sixteen patients completed the first 12 weeks of bomedemstat, while four withdrew for the following reasons:
- fatigue (n=1, day 33)
- disease progression (n=1, day 39)
- physician decision (n=1, day 76)
- cellulitis (n=1, day 83)
Following up-titration, study participants received an average daily dose of 0.89 mg/kg, which was identified as the dose needed to achieve the target platelet count range. The 17 patients who achieved the target platelet range did so within an average of 45 days.
Of the 14 patients who were evaluable for response after cycle 1 in phase I/IIa study, half had a reduction in spleen volume from baseline, with a median change of -14% (range = –2% to –30%). In addition, 79% (n=11) had a reduction in total symptom score, with a mean change of –28% (range = –13% to –69%); for 21% of patients (n=3), the reduction was greater than 50%. In addition, two patients showed improved bone marrow fibrosis scores during the first 12 weeks of treatment.
Dr. Pettit also highlighted that, of the 12 patients (56%) who were transfusion-dependent at baseline, two experienced reductions in transfusion requirements.
Nearly all patients experienced at least one adverse event (AE; n=19, 95%). Of a total of 358 reported AEs, 22 were considered severe. The investigators considered two of the higher-grade, severe AEs – heart failure and painful splenomegaly – to be related to treatment.
“Despite under-dosing and slow dose escalation,” Dr. Pettit said, “bomedemstat improved symptom burdens in most patients and modestly reduced spleen volumes in a subset of patients.” However, the implications of this analysis are limited by the small patient population and lack of a comparator arm. The study also was conducted before the FDA’s approval of fedratinib in August 2019, so the results might not apply to patients who received treatment with this newer agent.
Study authors report relationships with Imago BioSciences, the manufacturer of bomedemstat.
Pettit K, Gerds AT, Yacoub A, et al. A phase 2a study of the LSD1 inhibitor Img-7289 (bomedemstat) for the treatment of myelofibrosis. Abstract #556. Presented at the 2019 ASH Annual Meeting, December 9, 2019; Orlando, FL.