Ross David M, Heidel Florian H, Perkins Andrew Charles, Reiter Andreas, Crodel Carl, Riley Caroline, Gómez-Casares María Teresa, Takacs Istvan, Becker Heiko, Lehmann Thomas, Vinogradova Olga, Burbury Kate, Vannucchi Alessandro M, Gupta Vikas, Wondergem Marielle, Kiladjian Jean-Jacques, Cleary Grace, Zhang Angela, Kota Jagannath, Prahallad Anirudh, Wroclawska Monika, Lu Min, Harrison Claire N
Department of Haematology, Royal Adelaide Hospital and SA Pathology, Adelaide, Australia.
Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Blood Adv. 2025 Aug 26;9(16):4195-4205. doi: 10.1182/bloodadvances.2025015860.
Ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for symptomatic patients with myelofibrosis (MF). However, ∼70% of patients discontinue ruxolitinib after ∼5 years, a third of whom report suboptimal splenic response. ADORE was a phase 1b/2 study with an innovative open platform design that assessed the safety, efficacy, and pharmacokinetics of novel compounds in combination with ruxolitinib in patients with MF who had a suboptimal response to ruxolitinib alone. A total of 44 patients were enrolled in part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Most patients were allocated to receive ruxolitinib plus siremadlin (N = 23). The most frequent adverse events with siremadlin were gastrointestinal (nausea and diarrhea) and hematological (thrombocytopenia, anemia, and neutropenia). Siremadlin 30 mg orally once daily on days 1 to 5 of a 28-day cycle was selected as the recommended phase 2 dose. The most robust spleen volume reduction (SVR) at 24 weeks was observed with ruxolitinib plus siremadlin 30 mg. Reductions in percent JAK2V617F allele burden at week 24 were observed, notably in several patients with SVR. An increase in growth differentiation factor 15 protein levels in patients receiving siremadlin demonstrated the on-target modulation of downstream p53 targets. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone. This trial was registered at www.clinicaltrials.gov as #NCT04097821.
芦可替尼是一种Janus激酶（JAK）1/JAK2抑制剂，是有症状的骨髓纤维化（MF）患者的标准治疗药物。然而，约70%的患者在使用芦可替尼约5年后停药，其中三分之一的患者报告脾脏反应未达最佳。ADORE是一项1b/2期研究，采用创新的开放平台设计，评估新型化合物与芦可替尼联合应用于对单独使用芦可替尼反应欠佳的MF患者的安全性、疗效和药代动力学。共有44例患者入组了芦可替尼与西瑞马德林、利奈特基布、沙巴托利单抗、克唑单抗或NIS793联合应用的研究的第1部分。大多数患者被分配接受芦可替尼加西瑞马德林（N = 23）。西瑞马德林最常见的不良事件是胃肠道（恶心和腹泻）和血液学（血小板减少、贫血和中性粒细胞减少）。在28天周期的第1至5天，每日口服一次30 mg西瑞马德林被选为推荐的2期剂量。在24周时，观察到芦可替尼加30 mg西瑞马德林时脾脏体积缩小最为显著。在第24周时观察到JAK2V617F等位基因负担百分比降低，特别是在一些有脾脏体积缩小的患者中。接受西瑞马德林的患者生长分化因子15蛋白水平升高，证明了下游p53靶点的靶向调节。总体而言，ADORE的现有数据表明，在对单独使用芦可替尼反应欠佳的患者中，将新型药物与芦可替尼联合应用是可行且有益的。该试验在www.clinicaltrials.gov上注册，编号为#NCT04097821。
