Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with a higher incidence in older people. Most elderly AML patients are unfit for intensive chemotherapy and their treatment remains a challenge. Remission and survival rates decrease with age, and there is rather limited treatment success with standard (chemo)therapy, leading to 5-year survival rates of 20% or lower. Recent combinations of hypomethylating agents with pro-apoptotic agents such as venetoclax, a Bcl-2 inhibitor, have shown improved therapeutic prospects in early phase clinical trials, which still need to be supported by data from ongoing phase III confirmatory trials.

Lysine-specific demethylase 1 (LSD1) participates in malignant transformation in AML. Iadademstat is a differentiating drug that selectively inhibits LSD1 and has shown efficacy in preclinical models, both alone and in combination with other compounds including azacitidine and Bcl-2 inhibitors. A First-in-Man phase I study in refractory-relapsed acute leukemia patients treated with iadademstat in monotherapy showed a good safety profile, strong differentiating activity and preliminary signs of anti-leukemic activity. In the last year, we have reported interim results of the ongoing ALICE clinical trial with progressively more patients treated with iadademstat combined with azacitidine. Now, we report additional positive results in this hard-to-treat population. The efficacy of this combination may offer an alternative therapeutic option for previously untreated elderly AML population.

Methods: ALICE is an open-label, single arm, phase IIa clinical trial to assess the safety, tolerability and dose finding of iadademstat in combination with azacitidine for the treatment of elderly AML patients. Secondary end points of the study are to describe the anti-leukemic activity of the combination (overall response rate, time to response and duration of response), to assess the hematological improvement along with PK/PD measures. ALICE includes patients older than 60 yrs, diagnosed with AML according to the WHO classification, who have not received prior treatment for AML other than hydroxyurea and are considered by the investigator as ineligible for intensive chemotherapy or refuse this treatment option.

Results: At ASH2020 we will report compiled results of the ALICE study based on a November cut-off, when we expect to have recruited around 24 subjects. At the time this abstract is written, among the 18 currently recruited patients, 13 have had at least 1 bone marrow evaluation and achieved a 77% objective response rate (ORR): 4 Complete Remissions, 2 Complete Remissions with incomplete hematological recovery and 4 Partial Remissions. The current mean duration in the study is 20 weeks, with a mean Time to Response of only 37 days. The Progression Free Survival in the patients under remission is, so far, 250 days and the longest response in CR is above 550 days (still under treatment and in CR). Moreover, those patients with longer treatment periods have also improved or overcome their dependency on blood transfusions.

Main safety events include neutropenia and thrombocytopenia in most of the patients, whereas only 3 non-hematological AEs (asthenia, dysgeusia and weight reduction) have been observed. Among the 38 serious AEs reported so far, only 2 were considered as related to iadademstat, corresponding to a differentiation syndrome (Grade 3) and a fatal intracranial hemorrhage on C1D15. Besides the expected hematological impact, the combination appears to be safe and well tolerated.

Conclusions: Data to-date support iadademstat as an effective oral agent with a good safety profile compared with other anti-leukemic agents and hence as a meaningful candidate for selective combinations with other agents. Toxicity appears to be predictable, manageable and restricted only to the hematologic compartment. Under azacitidine alone, the historical response rates were 27% in this elderly AML population; the current results are supportive of a significant synergistic effect for iadademstat. The ORR of this combo is, so far, in line with the one shown by venetoclax combinations in similar early phase clinical trials. A confirmatory phase IIb trial is planned. With its oral administration, safety profile and novel MoA, iadademstat combo therapy may increase the therapeutic options for this AML population.


Salamero:Daichii Sankyo: Honoraria; Pfizer: Consultancy; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Somervaille:Novartis: Consultancy, Honoraria; Imago Bioscience: Research Funding. Gutierrez:Oryzon Genomics: Current Employment. Bullock:Oryzon Genomics: Current Employment. Buesa:Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bosch:Roche: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Astra Zeneca: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Jansen: Honoraria. Montesinos:Pfizer, Abbvie, Daiichi Sankyo: Research Funding; Astellas, Novartis, Janssen: Speakers Bureau; Celgene, Pfizer, Abbvie: Consultancy.

Author notes


Asterisk with author names denotes non-ASH members.

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