Kontro Mika, Stein Anthony Selwyn, Pyörälä Marja, Rimpiläinen Johanna, Siitonen Timo, Ylitalo Arno, Fjällskog Marie-Louise, Jalkanen Juho, Aakko Sofia, Pawlitzky Inka, Hollmén Maija, Daver Naval
Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Finnish Cancer Institute, Helsinki, Finland.
Department of Hematology, City of Hope Cancer Center, Duarte, CA, USA.
Lancet Haematol. 2025 May 28. doi: 10.1016/S2352-3026(25)00103-6.
Bexmarilimab blocks Clever-1 on macrophages to enhance antigen presentation and T cell activation. Because Clever-1 is expressed by myeloid leukaemia cells, bexmarilimab may combat leukaemia and influence the tumour microenvironment to augment the effectiveness of standard-of-care therapy in patients with myelodysplastic syndrome and acute myeloid leukaemia. The aim of this study was to determine the safety of bexmarilimab in combination with standard-of-care treatment in myelodysplastic syndrome and acute myeloid leukaemia and to identify the recommended dose for expansion of bexmarilimab in combination with standard of care.
The phase 1 dose-escalation part of this multicentre, single-arm, phase 1/2 study was done at six centres in Finland and the USA. Patients aged 18 years or older (Eastern Cooperative Oncology Group performance status of 2 or less) with myelodysplastic syndrome (2016 WHO) with a Revised International Prognostic Scoring System (IPPS-R) score of 3·5 or more for USA (3·0 for the European Union), chronic myelomonocytic leukaemia (2016 WHO) with 10-19% marrow blasts, myelodysplastic syndrome or chronic myelomonocytic leukaemia with no response to or disease progression during hypomethylating agent treatment, or relapsed or refractory acute myeloid leukaemia were treated with escalating doses of bexmarilimab (1·0 mg/kg, 3·0 mg/kg, and 6·0 mg/kg, intravenous, once weekly, 28-day cycle) in combination with azacitidine, administered as per label. Here we report the phase 1 part of the study, for which the primary outcome was safety (the incidence and frequency of dose limiting toxicities and the frequency and severity of adverse events) as well as the determination of the maximum tolerated dose and recommended expansion dose for the phase 2 part using a Bayesian optimal interval design. All patients receiving at least one dose of bexmarilimab were included in safety analyses, and those with a post-baseline activity assessment were included in activity analyses. This trial is registered with ClinicalTrials.gov (NCT05428969) and EudraCT (2021-002104-12) databases. Phase 2 of the study is ongoing in patients with myelodysplastic syndrome with no response to hypomethylating agent.
Between June 2, 2022, and Dec 7, 2023, 33 patients (14 with myelodysplastic syndrome, 19 with relapsed or refractory acute myeloid leukaemia) were enrolled in phase 1; no patients with chronic myelomonocytic leukaemia were identified. 19 (58%) patients were male and 14 (42%) were female, and 24 (73%) patients were non-Hispanic ethnicity, and eight (24%) were White. Median follow-up time for all patients was 6·2 months (IQR 3·5-10·7). The maximum tolerated dose was not reached, and the recommended expansion dose for phase 2 was established as 6·0 mg/kg in patients with myelodysplastic syndrome with no response to hypomethylating agents. There were no dose-limiting toxicities. The most common grade 3-4 treatment-emergent adverse events were febrile neutropenia (n=8 [24%]), anemia (n=7 [21%]), and thrombocytopenia (n=5 [15%]). Treatment-emergent deaths occurred as a result of sepsis (n=1 [3%]), neutropenic infection (n=1 [3%]), and haemophagocytic lymphohistiocytosis (n=1 [3%]). Four patients presented treatment-related serious adverse events, one patient in the 1·0 mg/kg group, two in the 3·0 mg/kg group and one in the 6·0 mg/kg group. These included rash (grade 3), capillary leak syndrome (grade 3), cryptogenic organising pneumonia (grade 3) and haemophagocytic lymphohistiocytosis (grade 5) which led to one death. The objective response rate was 45% (15 of 33; 95% CI 28-62) across all doses.
Bexmarilimab in combination with azacitidine has a manageable safety profile, consistent with azacitidine, and shows promising clinical activity in patients with high-risk myelodysplastic syndrome.
Faron Pharmaceuticals.
贝克斯马利单抗可阻断巨噬细胞上的Clever-1，以增强抗原呈递和T细胞活化。由于Clever-1在髓系白血病细胞中表达，贝克斯马利单抗可能对抗白血病，并影响肿瘤微环境，从而增强骨髓增生异常综合征和急性髓系白血病患者标准治疗的疗效。本研究的目的是确定贝克斯马利单抗联合标准治疗在骨髓增生异常综合征和急性髓系白血病中的安全性，并确定贝克斯马利单抗联合标准治疗扩大使用的推荐剂量。
本多中心、单臂、1/2期研究的1期剂量递增部分在芬兰和美国的六个中心进行。年龄在18岁及以上（东部肿瘤协作组体能状态评分为2或更低）、患有骨髓增生异常综合征（2016年世界卫生组织标准）且修订国际预后评分系统（IPPS-R）美国评分3.5或更高（欧盟为3.0）、慢性粒单核细胞白血病（2016年世界卫生组织标准）且骨髓原始细胞比例为10%-19%、在低甲基化药物治疗期间对骨髓增生异常综合征或慢性粒单核细胞白血病无反应或疾病进展或复发或难治性急性髓系白血病的患者，接受递增剂量的贝克斯马利单抗（1.0mg/kg、3.0mg/kg和6.0mg/kg，静脉注射，每周一次，28天为一个周期）联合阿扎胞苷治疗，阿扎胞苷按标签给药。我们在此报告该研究的1期部分，其主要结局为安全性（剂量限制毒性的发生率和频率以及不良事件的频率和严重程度），以及使用贝叶斯最优区间设计确定2期部分的最大耐受剂量和推荐扩大剂量。所有接受至少一剂贝克斯马利单抗的患者纳入安全性分析，有基线后活性评估的患者纳入活性分析。该试验已在ClinicalTrials.gov（NCT05428969）和EudraCT（2021-002104-12）数据库注册。该研究的2期部分正在对低甲基化药物治疗无反应的骨髓增生异常综合征患者中进行。
在2022年6月2日至2023年12月7日期间，33例患者（14例骨髓增生异常综合征、19例复发或难治性急性髓系白血病）入组1期研究；未识别出慢性粒单核细胞白血病患者。19例（58%）患者为男性，14例（42%）为女性，24例（73%）患者为非西班牙裔，8例（24%）为白人。所有患者的中位随访时间为6.2个月（IQR 3.5-10.7）。未达到最大耐受剂量，对于低甲基化药物治疗无反应的骨髓增生异常综合征患者，2期推荐扩大剂量确定为6.0mg/kg。无剂量限制毒性。最常见的3-4级治疗中出现的不良事件为发热性中性粒细胞减少（n=8 [24%]）、贫血（n=7 [21%]）和血小板减少（n=5 [15%]）。治疗中出现的死亡分别由败血症（n=1 [3%]）、中性粒细胞减少性感染（n=1 [3%]）和噬血细胞性淋巴组织细胞增生症（n=一个 [3%]）导致。4例患者出现与治疗相关的严重不良事件，1.0mg/kg组1例，3.0mg/kg组2例，6.0mg/kg组1例。这些包括皮疹（3级）、毛细血管渗漏综合征（3级）、隐源性机化性肺炎（3级）和噬血细胞性淋巴组织细胞增生症（5级）并导致1例死亡。所有剂量组的客观缓解率为45%（共33例中的15例；95%CI 28-62）。
贝克斯马利单抗联合阿扎胞苷具有可控的安全性，与阿扎胞苷一致，并且在高危骨髓增生异常综合征患者中显示出有前景的临床活性。
法龙制药公司。
