Clinical efficacy and safety of lysine-specific demethylase 1 inhibitors in hematologic malignancies: a systematic review of clinical trials

Abstract Lysine-specific demethylase 1 (LSD1/KDM1A) regulates hematopoietic differentiation and leukemic stem cell programs, making its inhibition a potential therapeutic strategy for hematologic malignancies. We systematically reviewed the clinical efficacy, safety, combination approaches, and biomarkers of LSD1 inhibitors in hematologic malignancies. PubMed/MEDLINE, Scopus, and Web of Science were searched from inception through 31 May 2026 for clinical trials evaluating pharmacologic LSD1 inhibition in hematologic malignancies. Eligible full-text reports and conference abstracts were screened, and study, treatment, efficacy, survival, safety, and biomarker data were extracted. Owing to substantial clinical and methodological heterogeneity, findings were synthesized narratively. Thirteen early-phase trials involving 456 enrolled participants evaluated five inhibitors: iadademstat, bomedemstat, tranylcypromine, GSK2879552, and seclidemstat. In R/R AML, monotherapy and ATRA-based combinations generally produced modest responses, whereas newly diagnosed or molecularly selected cohorts receiving iadademstat-based combinations reported higher response rates. However, differences in patient populations and active treatment backbones preclude attributing these cross-study differences to LSD1 inhibition itself. In myeloproliferative neoplasms, bomedemstat demonstrated blood count control and variable improvements in spleen volume, symptoms, marrow fibrosis, and driver mutation burden. Among studies with explicit denominators, study-level rates of any-grade treatment-related adverse events ranged from 72% to 95%, grade 3 or higher events from 10% to 86%, and serious treatment-related events from 7% to 17%. Hematologic toxicity, mainly thrombocytopenia and neutropenia, was the most common adverse effect; treatment-related death was rare. LSD1 inhibition shows biologic activity and encouraging disease-specific signals, especially in rational combinations, but evidence remains limited by small, heterogeneous, nonrandomized studies. Randomized controlled trials with standardized outcomes, mature survival follow-up, and prospectively validated biomarkers are required before definitive clinical benefit can be established across diverse hematologic disease settings worldwide.