Kruszewski Michael, Schmoor Claudia, Berg Tobias, Rehman Usama-Ur, Schittenhelm Marcus, Götze Katharina, Kündgen Andrea, Pabst Caroline, Ma Tobias, Frey Anna, Stomper Julia, Pfeifer Dietmar, Metzger Eric, Jung Johannes, Moschallski Kevin, Thomas Johanna, Bug Gesine, Duyster Justus, Jung Manfred, Schüle Roland, Wäsch Ralph, Grishina Olga, Lübbert Michael
Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Freiburg, Germany.
Clinical Trials Unit, Medical Center-University of Freiburg, Freiburg, Germany.
Eur J Haematol. 2025 Sep;115(3):266-277. doi: 10.1111/ejh.14426. Epub 2025 Jun 3.
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 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.
治疗复发/难治性（R/R）疾病的老年、身体状况不佳的急性髓系白血病（AML）/骨髓增生异常综合征（MDS）患者仍然具有挑战性。由于组蛋白去甲基化酶LSD1（KDM1A）是AML的合理治疗靶点，我们开展了一项I期试验（“滚动六设计”），使用LSD1抑制剂反苯环丙胺（TCP，剂量水平[DL]20、40、60、80mg口服，第1 - 28天）联合固定剂量全反式维甲酸（ATRA，45mg/m²口服，第10 - 28天）和小剂量阿糖胞苷（LDAC，40mg皮下注射，第1 - 10天）。主要终点是治疗前28天的剂量限制性毒性（DLT）。目的是确定最大耐受TCP剂量（MTD）。共纳入23例AML患者和2例MDS患者。TCP的中位给药时间为39.5天（范围：11 - 228天）。在任何剂量水平均未观察到DLT；无法确定MTD。未发生分化综合征。2例患者达到部分缓解（PR）；22例可评估患者中有10例达到疾病稳定（SD）。中位总生存期（OS）为62天（范围：14 - 325天）。伴随研究包括药代动力学、胎儿血红蛋白（HbF）的系列测定、治疗时CD38上调的检测以及纯化血母细胞随时间的转录组变化。总之，即使在最高剂量水平，TCP与ATRA和LDAC联合使用也具有良好的可行性。因此，开展使用更有效的LSD1抑制剂的研究似乎是必要的。试验注册：德国临床试验注册中心（DRKS）：DRKS00006055。如需更多信息，请访问https://drks.de/search/en/trial/DRKS00006055。
