A proof of concept phase I/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory/relapsed AML patients not eligible for intensive therapy

• Published in: Leukemia Vol. 35; no. 3; pp. 701 - 711
• Main Authors: Wass, Maxi, Göllner, Stefanie, Besenbeck, Birgit, Schlenk, Richard F., Mundmann, Petra, Göthert, Joachim R., Noppeney, Richard, Schliemann, Christoph, Mikesch, Jan-Henrik, Lenz, Georg, Dugas, Martin, Wermke, Martin, Röllig, Christoph, Bornhäuser, Martin, Serve, Hubert, Platzbecker, Uwe, Foerster, Kathrin I., Burhenne, Jürgen, Haefeli, Walter E., Müller, Lutz P., Binder, Mascha, Pabst, Caroline, Müller-Tidow, Carsten
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2021; Nature Publishing Group
• Subjects: 692/308/2779/109/1940; 692/699/1541/1990/283/1897; Acute myeloid leukemia; Acute promyeloid leukemia; Adult; Adverse events; Aged; Antidepressive Agents - therapeutic use; Antineoplastic Agents - therapeutic use; Arabidopsis Proteins; Cancer Research; Cell differentiation; Critical Care Medicine; Differentiation; DNA-Binding Proteins; Drug Resistance, Neoplasm - drug effects; Drug Therapy, Combination; Enzymes; Female; Follow-Up Studies; Health aspects; Health services; Hematology; Humans; Hypotension; Intensive; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Leukocytes; Lysine; Male; Medicine; Medicine & Public Health; Middle Aged; Myeloid leukemia; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - pathology; Oncology; Patients; Plasma levels; Prognosis; Promyeloid leukemia; Proof of Concept Study; Prospective Studies; Regulation; Remission; Retinoic acid; Salvage Therapy; Survival Rate; Toxicity; Transcription Factors; Tranylcypromine; Tranylcypromine - therapeutic use; Tretinoin; Tretinoin - therapeutic use; Vertigo; Young Adult; Germany
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-020-0892-z

All-trans-retinoic acid (ATRA) is highly active in acute promyelocytic leukemia but not in other types of acute myeloid leukemia (AML). Previously, we showed that ATRA in combination with Lysine-specific demethylase 1 (LSD1) inhibition by tranylcypromine (TCP) can induce myeloid differentiation in AML blasts. This phase I/II clinical trial investigated the safety and efficacy of TCP/ATRA treatment as salvage therapy for relapsed/refractory (r/r) AML. The combination was evaluated in 18 patients, ineligible for intensive treatment. The overall response rate was 20%, including two complete remissions without hematological recovery and one partial response. We also observed myeloid differentiation upon TCP/ATRA treatment in patients who did not reach clinical remission. Median overall survival (OS) was 3.3 months, and one-year OS 22%. One patient developed an ATRA-induced differentiation syndrome. The most frequently reported adverse events were vertigo and hypotension. TCP plasma levels correlated with intracellular TCP concentration. Increased H3K4me1 and H3k4me2 levels were observed in AML blasts and white blood cells from some TCP/ATRA treated patients. Combined TCP/ATRA treatment can induce differentiation of AML blasts and lead to clinical response in heavily pretreated patients with r/r AML with acceptable toxicity. These findings emphasize the potential of LSD1 inhibition combined with ATRA for AML treatment.