Sensitization of Non‐<scp>M3</scp> Acute Myeloid Leukemia Blasts to All‐<i>Trans</i> Retinoic Acid by the <scp>LSD1</scp> Inhibitor Tranylcypromine: <scp>TRANSATRA</scp> Phase I Study
The treatment of elderly, nonfit acute myeloid leukemia (AML)/MDS patients with relapsed/refractory (R/R) disease remains challenging. As histone demethylase LSD1 (KDM1A) is a rational therapeutic target in AML, we conducted a phase I trial ("rolling-six design") with the LSD1 inhibitor tranylcypromine (TCP, dose levels [DL] 20, 40, 60, 80 mg p.o. d1-28) combined with fixed-dose ATRA (45 mg/m<sup>2</sup> p.o. d10-28) and low-dose cytarabine (LDAC, 40 mg s.c. d1-10). The primary endpoint was dose-limiting toxicity (DLT) in the first 28 days of treatment. The aim was the determination of the maximum tolerated TCP dose (MTD). Twenty-three patients with AML and 2 with MDS were accrued. TCP was administered for a median of 39.5 days (range: 11-228). No DLTs were observed at any DL; MTD could not be established. No differentiation syndrome occurred. Two patients attained a PR; SD was achieved in 10 of 22 evaluable patients. Median OS was 62 days (range: 14-325). Accompanying studies included pharmacokinetics, serial determinations of fetal hemoglobin (HbF), detection of CD38 upregulation with treatment, as well as transcriptome changes in purified blood blasts over time. In conclusion, the combination of TCP with ATRA and LDAC was well feasible, even at the highest DL. Hence, studies with more potent LSD1 inhibitors appear warranted. Trial Registration: German Clinical Trials Register (DRKS): DRKS00006055. For further Information see https://drks.de/search/en/trial/DRKS00006055.
Authors
- Tobias Berg (ORCID: https://orcid.org/0000-0003-2668-0449)
- Johanna Thomas
- Eric Metzger (ORCID: https://orcid.org/0000-0002-1394-1083)
- Kevin Moschallski
- Anna Frey (ORCID: https://orcid.org/0009-0000-9706-6417)
- Caroline Pabst (ORCID: https://orcid.org/0000-0001-9716-5909)
- Andrea Kündgen
- Dietmar Pfeifer (ORCID: https://orcid.org/0000-0003-2684-5944)
- Manfred Jung (ORCID: https://orcid.org/0000-0002-6361-7716)
- Marcus M. Schittenhelm (ORCID: https://orcid.org/0000-0002-5400-5582)
- Julia Stomper (ORCID: https://orcid.org/0000-0002-3858-4385)
- Michael Kruszewski
- Tobias Ma (ORCID: https://orcid.org/0009-0009-1258-8976)
- Justus Duyster (ORCID: https://orcid.org/0009-0003-1497-3954)
- Johannes Jung (ORCID: https://orcid.org/0000-0003-0137-7929)
- Usama‐Ur Rehman
- Katharina S. S. Götze (ORCID: https://orcid.org/0000-0002-6276-8002)
- Claudia Schmoor (ORCID: https://orcid.org/0000-0001-5610-9425)
- Gesine Bug (ORCID: https://orcid.org/0000-0003-2359-131X)
- Ralph Wäsch (ORCID: https://orcid.org/0000-0002-0813-3444)
- Roland Schüle (ORCID: https://orcid.org/0000-0001-8147-634X)
- Olga Grishina
- Michael Lübbert
Institutions
- Goethe University Frankfurt (DE)
- University of Freiburg (DE)
- German Cancer Research Center (DE)
- University of St.Gallen (CH)
- Heidelberg University (DE)
- Kantonsspital St. Gallen (CH)
- University Medical Center Freiburg (DE)
- University Hospital Heidelberg (DE)
- TUM Klinikum (DE)
- Population Health Research Institute (CA)
- Düsseldorf University Hospital (DE)
- University Children's Hospital Tübingen (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Heinrich Heine University Düsseldorf (DE)
- Technical University of Munich (DE)
- Hamilton Health Sciences (CA)
- McMaster University (CA)
Publication Details
- Journal
- European Journal Of Haematology
- Published
- 2025-06-03
- DOI
- https://doi.org/10.1111/ejh.14426
- Citations
- 1
- Primary Topic
- Retinoids in leukemia and cellular processes
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Deutschen Konsortium für Translationale Krebsforschung