JOURNAL ARTICLE

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

Maxi Wass, Stefanie Göllner, Birgit Besenbeck, Richard F Schlenk, Petra Mundmann, Joachim R Göthert, Richard Noppeney, Christoph Schliemann, Jan-Henrik Mikesch, Georg Lenz, Martin Dugas, Martin Wermke, Christoph Röllig, Martin Bornhäuser, Hubert Serve, Uwe Platzbecker, Kathrin I Foerster, Jürgen Burhenne, Walter E Haefeli, Lutz P Müller, Mascha Binder, Caroline Pabst, Carsten Müller-Tidow
Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K 2020 June 19
32561840
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.

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