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Rebecca Olin, MD, MS


First-in-Class LSD1 Inhibitor Under Study in Resistant AML

By: Celeste L. Dixon
Posted: Tuesday, February 23, 2021

To evaluate the preliminary antileukemic activity in humans of iadademstat (ORY-1001), a novel oral agent that is a selective inhibitor of lysine-specific demethylase 1 (LSD1), Olga Salamero, MD, of Vall D’Hebron Institute of Oncology in Barcelona, and colleagues conducted a phase I trial in patients with relapsed or refractory acute myeloid leukemia (AML). Iadademstat showed both clinical and biologic activity and was mainly well tolerated. Hence, a phase II trial of the drug, this time in combination with azacitidine, is underway, the investigators reported in the Journal of Clinical Oncology.

The trial included dose-escalation and extension-cohort phases. The dose-escalation phase’s 27 patients received between 5 and 220 µg/m2 of iadademstat on days 1 to 5 of each week in 28-day cycles. One patient experienced a complete remission with incomplete blood cell count recovery, although efficacy was not a main study endpoint. From there, the recommended dose of this first-in-class agent was determined to be 140 µg/m2 daily.

In the extension-cohort phase, 14 patients with AML, including 5 evaluable patients with mixed-lineage leukemia (MLL) or KMT2A rearrangements, received iadademstat. “Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular [in those] patients with MLL translocations,” wrote Dr. Salamero and co-researchers. They noted that most adverse events were expected among patients with relapsed or refractory AML, including myelosuppression, infections, and asthenia.

Pharmacodynamic analyses demonstrated rapid target engagement, said the research team. However, the specific molecular subtypes of AML that may be most sensitive to combination antileukemic approaches, including inhibitors of LSD1, still need to be established.

Disclosure: The study authors’ disclosure information can be found at

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