Systematic Review Evaluates LSD1 Inhibitors Across Early Blood Cancer Trials

A systematic review examining 13 early-phase clinical trials that enrolled a total of 456 participants has found that pharmacologic inhibition of lysine-specific demethylase 1 (LSD1/KDM1A) exhibits biological activity and encouraging disease-specific signals in hematologic malignancies, particularly when administered within rational combination approaches. The comprehensive review, published in Annals of Hematology, evaluated the emerging therapeutic landscape by screening eligible full-text reports as well as conference abstracts identified through systematic searches of PubMed/MEDLINE, Scopus, and Web of Science from database inception through May 31, 2026. The researchers extracted detailed study parameters, treatment regimens, clinical efficacy outcomes, overall survival data, adverse event profiles, and biomarker data across trials investigating five pharmacologic inhibitors: iadademstat, bomedemstat, tranylcypromine, GSK2879552, and seclidemstat. Owing to substantial clinical and methodological heterogeneity among the included studies, the authors synthesized all extracted findings narratively.

When assessing therapeutic efficacy in relapsed or refractory acute myeloid leukemia (R/R AML), the authors observed that monotherapy regimens and combinations utilizing an all-trans retinoic acid (ATRA) backbone generally produced modest clinical responses. Conversely, higher response rates were reported in clinical cohorts consisting of newly diagnosed patients or molecularly selected patient subsets who received treatment combinations centered on iadademstat. Crucially, the review cautioned that clear differences in baseline patient populations, clinical settings, and active background treatment backbones make it impossible to attribute these cross-study differences in therapeutic response directly to LSD1 inhibition itself. In parallel evaluations focusing on myeloproliferative neoplasms, the specific inhibitor bomedemstat demonstrated tangible biologic activity, achieving blood count control alongside variable degrees of improvement in spleen volume, disease-related symptoms, bone marrow fibrosis, and driver mutation burden.

Safety and tolerability analyses revealed significant toxicities across the early-phase clinical trials, although treatment-related mortality remained rare. Among the analyzed studies that reported explicit denominators, study-level rates of any-grade treatment-related adverse events were high, ranging from 72% to 95%. Grade 3 or higher treatment-related adverse events were documented at study-level frequencies ranging from 10% to 86%, while serious treatment-related adverse events were observed at rates between 7% and 17%. Across the various patient cohorts and drug regimens, hematologic toxicity was identified as the predominant adverse effect, presenting most commonly as thrombocytopenia and neutropenia. Despite the frequent occurrence of these hematologic adverse events and high overall toxicity rates in several trials, treatment-related death was uncommon.

The underlying biological rationale for targeting lysine-specific demethylase 1 rests on its role in regulating hematopoietic differentiation and leukemic stem cell programs, which makes its pharmacologic inhibition a potential therapeutic strategy for patients with blood cancers. However, the authors concluded that the existing evidence base remains constrained by the small sample sizes, nonrandomized trial methodologies, and substantial heterogeneity characteristic of these early-phase investigations. To transition beyond these preliminary, disease-specific signals and determine true therapeutic efficacy, the investigators emphasized that randomized controlled trials must be conducted. Such future randomized trials will require standardized clinical outcome measures, mature survival follow-up, and prospectively validated predictive biomarkers before definitive clinical benefit can be established across diverse hematologic disease settings worldwide.

Subject of Research: Clinical efficacy and safety of LSD1 inhibitors in hematologic malignancies

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

Article References: Falahatdoust, A., Mohammadpour, M., Ramezani, F., & Namjoo, S. (2026). Clinical efficacy and safety of lysine-specific demethylase 1 inhibitors in hematologic malignancies: a systematic review of clinical trials. Annals of Hematology. https://doi.org/10.1007/s00277-026-07344-y

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DOI: 10.1007/s00277-026-07344-y

Keywords: LSD1 inhibitors, hematologic malignancies, systematic review, acute myeloid leukemia, myeloproliferative neoplasms, iadademstat, bomedemstat, clinical trials, Clinical, efficacy, safety, lysine-specific