In a phase I trial, iadademstat induced blast differentiation and reduced bone marrow blast burden.

  • Major Finding: In a phase I trial, iadademstat induced blast differentiation and reduced bone marrow blast burden.

  • Concept: One patient in the dose-escalation cohort had complete remission with incomplete count recovery.

  • Impact: This study is the first to provide evidence that iadademstat has antileukemic activity in humans.

Acute myeloid leukemia (AML) is characterized by defective differentiation of cells in the myeloid lineage. Epigenetic dysregulation is a major factor, with the histone lysine demethylase LSD1 being critical for maintenance of the differentiation block observed in many cases of AML, particularly those driven by MLL translocation. In preclinical studies, the first-in-class LSD1A inhibitor iadademstat has been shown to reduce leukemic stem cell burden and promote differentiation, prompting Salamero and colleagues to initiate a first-in-human, phase I clinical trial of iadademstat in 41 patients with relapsed or refractory AML, with 27 patients in a dose-escalation cohort and 14 patients in an extension cohort. One patient in the dose-escalation cohort experienced complete remission with incomplete count recovery, and hematologic improvements were observed in several additional patients. Specifically, evidence of induction of blast differentiation and reduction of bone marrow blast burden were observed, particularly in patients with MLL translocations, as would be expected given the proposed mechanism of iadademstat. Pharmacodynamic analyses revealed that biomarkers of differentiation increased in a time- and exposure level–dependent fashion. Treatment-emergent adverse events were experienced by all patients and were most frequently hematologic, and the most common nonhematologic adverse events were infections, asthenia, mucositis, and gastrointestinal disturbances. Three grade 5 adverse events deemed to be possibly related to iadademstat treatment occurred, including pneumonia, episodic cellulitis, and differentiation syndrome. In summary, the results of this trial suggest that iadademstat has antileukemic activity in humans and provide important safety and toxicity information that can be used to guide further studies.

Salamero O, Montesinos P, Willekens C, Pérez-Simón JA, Pigneux A, Récher C, et al. First-in-human phase I study of iadademstat (ORY-1001): A first-in-class lysine-specific histone demethylase 1A inhibitor, in relapsed or refractory acute myeloid leukemia. J Clin Oncol 2020 Oct 14 [Epub ahead of print].

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