Phase 2 study of the lysine-specific demethylase 1 (LSD1) inhibitor bomedemstat in patients with polycythemia vera (PV).
Authors: Rinaldi Ciro , Rein Lindsay , Livings Alice , Innes Andrew J. , Pettit Kristen , Yeh Paul , Larsen Stephen R. , Watson Anne-Marie , Leahy Michael F. , Curto-Garcia Natalia , Mahdi Ali , Frewin Rebecca , Qureshi Haifz , Shatzel Joseph , Vaughn Jennifer , Tashi Tsewang , Amin Harshad , Ogbu Uzor , Gumuscu Burak , Ross David M. 
Published: June 2024

TPS6595 Background: PV is a myeloproliferative neoplasm (MPN) characterized by clonal erythrocytosis that is driven by mutations in JAK2. Currently available treatments reduce thrombotic risk and symptom burden but have little impact on disease course or risk of progression to post-PV myelofibrosis (PPV-MF) or acute myeloid leukemia (AML). There remains a need for novel treatments that can alter the natural history of PV. LSD1 is an enzyme that regulates megakaryocytes and erythrocyte maturation. Bomedemstat is an irreversible inhibitor of LSD1 that has been shown to have manageable safety and clinically relevant activity in other JAK2-mutation–prevalent MPNs (essential thrombocythemia and myelofibrosis). Here, we describe the methods for an open-label phase 2 study (NCT05558696) that has been designed to evaluate the efficacy and safety of bomedemstat in patients with PV who are resistant to or intolerant of standard cytoreductive therapy. Methods: Eligible patients are ≥18 years, have a confirmed diagnosis of PV per World Health Organization 2016 diagnostic criteria, a bone marrow fibrosis score of grade 0 or 1, an ECOG performance status of 0-2, a platelet count of ≥250 × 109/L, an absolute neutrophil count of ≥1.5 × 109/L, and resistance to or intolerance of ≥1 standard cytoreductive therapy. All patients will receive bomedemstat at a starting dose of 40 mg/d by mouth for 36 weeks, with dose titration to a hematocrit target of <45% with no grade ≥1 thrombocytopenia. Treatment with bomedemstat can continue beyond week 36 in patients deriving clinical benefit. Clinic visits will occur every 2 weeks until week 12 and monthly thereafter. Adverse events will be graded per NCI CTCAE version 5.0 criteria and will be monitored for up to 30 days after treatment end. Transfusions or phlebotomy can be administered during treatment as needed. The primary end points are safety and the proportion of patients who achieve a reduction in hematocrit to <45% without phlebotomy by week 36. Secondary end points will be the durability of reduction in hematocrit <45% without phlebotomy; the incidence and durability of reduction in platelet count to ≤450 × 109/L and white blood cell count to <10 × 109/L; the incidence of new thrombotic or major hemorrhagic events; reduction in spleen volume by week 36 in patients with an enlarged spleen at baseline; progression to PPV-MF or myelodysplastic syndrome or transformation to AML; pharmacokinetics; and change in patient-reported symptom burden assessed using the MSAF v4.0 and PGIC. Exploratory end points include change in the concentration of circulating inflammatory cytokines and growth factors, change in mutant allele frequency of JAK2and other mutations, and change in bone marrow fibrosis grade. Approximately 20 patients will be enrolled. Recruitment for this study is currently underway in Australia, the United Kingdom, and the United States. Clinical trial information: NCT05558696 .