Servei d'Hematologia de l'Hospital Vall d'Hebron i Unitat d'Hematología Experimental del Vall d'Hebron Institut d'Oncología, Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
Servei d'Hematologia de l'Hospital Vall d'Hebron i Unitat d'Hematología Experimental del Vall d'Hebron Institut d'Oncología, Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
Lancet Haematol. 2024 Jul;11(7):e487-e498. doi: 10.1016/S2352-3026(24)00132-7. Epub 2024 May 30.
Iadademstat is a potent, selective, oral inhibitor of both the enzymatic and scaffolding activities of the transcriptional repressor lysine-specific demethylase 1 (LSD1; also known as KDM1A) that showed promising early activity and safety in a phase 1 trial and strong preclinical synergy with azacitidine in acute myeloid leukaemia cell lines. Therefore, we aimed to investigate the combination of iadademstat and azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukaemia.
The open-label, phase 2a, dose-finding ALICE study was conducted at six hospitals in Spain and enrolled patients aged 18 years or older with newly diagnosed acute myeloid leukaemia not eligible for intensive chemotherapy and an ECOG performance status of 0-2. In the dose escalation portion of the trial, patients received a starting dose of iadademstat at 90 μg/m per day (with de-escalation to 60 μg/m per day and escalation up to 140 μg/m per day) orally, for 5 days on, 2 days off weekly, with azacitidine 75 mg/m subcutaneously, for seven of 28 days. The primary objectives were safety (analysed in the safety analysis set; all patients who received at least one dose of study treatment) and establishing the recommended phase 2 dose; secondary objectives included response rates in the efficacy analysis set (all patients who had at least one efficacy assessment). This study is registered on EudraCT (EudraCT 2018-000482-36) and has been completed.
Between Nov 12, 2018, and Sept 30, 2021, 36 patients with newly diagnosed acute myeloid leukaemia were enrolled; the median age was 76 (IQR 74-79) years, all patients were White, 18 (50%) were male, and 18 (50%) were female, and all had intermediate-risk or adverse-risk acute myeloid leukaemia. The median follow-up was 22 (IQR 16-31) months. The most frequent (≥10%) adverse events considered to be related to treatment were decreases in platelet (25 [69%]) and neutrophil (22 [61%]) counts (all grade 3-4) and anaemia (15 [42%]; of which ten [28%] were grade 3-4). Three patients had treatment-related serious adverse events (one fatal grade 5 intracranial haemorrhage, one grade 3 differentiation syndrome, and one grade 3 febrile neutropenia). Based on safety, pharmacokinetic and pharmacodynamic data, and efficacy, the recommended phase 2 dose of iadademstat was 90 μg/m per day with azacitidine. 22 (82%; 95% CI 62-94) of 27 patients in the efficacy analysis set had an objective response. 14 (52%) of 27 patients had complete remission or complete remission with incomplete haematological recovery; of these, ten of 11 evaluable for measurable residual disease achieved negativity. In the safety analysis set, 22 (61%) of 36 patients had an objective response.
The combination of iadademstat and azacitidine has a manageable safety profile and shows promising responses in patients with newly diagnosed acute myeloid leukaemia, including those with high-risk prognostic factors.
Oryzon Genomics and Spain's Ministerio de Ciencia, Innovacion y Universidades (MICIU)-Agencia Estatal de Investigacion (AEI).
Iadademstat 是一种有效的、选择性的、转录抑制剂赖氨酸特异性去甲基酶 1（LSD1；也称为 KDM1A）的酶和支架活性的口服抑制剂，在 1 期试验中显示出有希望的早期活性和安全性，并且在急性髓系白血病细胞系中与阿扎胞苷具有很强的临床前协同作用。因此，我们旨在研究 iadademstat 与阿扎胞苷联合治疗新诊断的急性髓系白血病成人患者。
这项在西班牙六家医院进行的开放标签、2a 期、剂量确定的 ALICE 研究纳入了年龄在 18 岁及以上、不符合强化化疗条件且 ECOG 体能状态为 0-2 的新诊断为急性髓系白血病的患者。在试验的剂量递增部分，患者每天接受 90μg/m 的起始剂量的 iadademstat（每日一次，连续 5 天，停药 2 天），每周一次，同时每天皮下给予阿扎胞苷 75mg/m，共 28 天中的 7 天。主要目的是安全性（在安全性分析集中分析；所有至少接受过一次研究治疗的患者）和确定 2 期推荐剂量；次要目标包括疗效分析集中的反应率（所有至少有一次疗效评估的患者）。这项研究在 EudraCT（EudraCT 2018-000482-36）上注册，并已完成。
2018 年 11 月 12 日至 2021 年 9 月 30 日，共纳入 36 例新诊断为急性髓系白血病的患者；中位年龄为 76（IQR 74-79）岁，所有患者均为白人，18 例（50%）为男性，18 例（50%）为女性，所有患者均为中危或高危急性髓系白血病。中位随访时间为 22（IQR 16-31）个月。最常见（≥10%）认为与治疗相关的不良事件是血小板（25 [69%]）和中性粒细胞（22 [61%]）计数下降（均为 3-4 级）和贫血（15 [42%]；其中 10 例[28%]为 3-4 级）。3 例患者发生与治疗相关的严重不良事件（1 例致命性 5 级颅内出血，1 例 3 级分化综合征，1 例 3 级发热性中性粒细胞减少症）。基于安全性、药代动力学和药效学数据以及疗效，iadademstat 的 2 期推荐剂量为 90μg/m，与阿扎胞苷联合使用。27 例疗效分析集中的 22 例（82%；95%CI 62-94）患者有客观反应。27 例患者中 14 例（52%）有完全缓解或不完全血液学恢复的完全缓解；其中 11 例可评估的患者中有 10 例达到了可测量残留疾病的阴性。在安全性分析集中，36 例患者中有 22 例（61%）有客观反应。
Iadademstat 与阿扎胞苷联合具有可管理的安全性，并在新诊断的急性髓系白血病患者中显示出有希望的反应，包括具有高风险预后因素的患者。
Oryzon Genomics 和西班牙的 Ministerio de Ciencia，Innovation y Universidades（MICIU）-Agencia Estatal de Investigacion（AEI）。
