Peterlin Pierre, Garnier Alice, Le Bourgeois Amandine, Guillaume Thierry, Le Bris Yannick, Theisen Olivier, Béné Marie C, Eveillard Marion, Rimbert Marie, Jullien Maxime, Planche Lucie, Gaschet Joelle, Chevallier Patrice
Clinical Hematology, Nantes University Hospital, Nantes, France.
Nantes Université, Inserm, CNRS, Université d'Angers, CRCI2NA, Nantes, France.
EClinicalMedicine. 2023 Sep 28;64:102254. doi: 10.1016/j.eclinm.2023.102254. eCollection 2023 Oct.
In acute myeloid leukaemia (AML), interleukin-6 (IL-6) promotes chemo-resistance and its levels correlate with poor prognosis. IL-6 blockade may represent a promising therapeutic strategy. We aimed to test, tocilizumab, an anti-IL-6 receptor (R) monoclonal antibody in combination with standard intensive AML induction chemotherapy.
This investigator-initiated single-centre phase 1 trial was conducted at Nantes University Hospital in France. According to a continual reassessment method, three escalating doses were tested of intravenous (IV) tocilizumab (4, 6, and 8 mg/kg) administered at day (d) 8 of a standard AML induction chemotherapy (IV idarubicine 8 mg/m d1 to d5 + IV cytarabine 100 mg/m d1 to d7). All adults (aged ≥ 18 years) with an Eastern Cooperative Oncology Group performance status of 0-2 and with a newly diagnosed (excluding patients with a favourable risk according to ELN-2017 classification if <60 year-old) or a relapsed/refractory AML were eligible. The primary objective was to determine the maximum tolerated dose of tocilizumab to administrate with a standard intensive AML induction. Safety outcomes were continuously monitored for at each participant contact. This trial is registered with ClinicalTrials.gov, NCT04547062.
Between Dec 29, 2020 and Dec 1, 2022, 12 patients were enrolled, of whom 75% had an ELN-2017 high-risk profile, and were treated with tocilizumab- two patients at 4 mg/kg, two at 6 mg/kg and eight at 8 mg/kg of tocilizumab. No dose-limiting toxicity related to tocilizumab was documented. There were nine serious adverse events, none of which were related to tocilizumab, and there was no treatment-related deaths. MTD was thus not reached. Two deaths occurred during induction. In the remaining ten evaluable patients, nine responded to treatment.
The combination of tocilizumab with standard AML intensive induction appears to be safe and resulting responses are encouraging. A dose of 8 mg/kg of tocilizumab given at day 8 of induction could be used for further phase 2/3 studies.
The Leucémie Espoir Atlantique Famille (LEAF)-"Tous avec Fabien" association.
在急性髓系白血病（AML）中，白细胞介素-6（IL-6）可促进化疗耐药，其水平与预后不良相关。阻断IL-6可能是一种有前景的治疗策略。我们旨在测试托珠单抗，一种抗IL-6受体（R）单克隆抗体与标准强化AML诱导化疗联合使用的效果。
这项由研究者发起的单中心1期试验在法国南特大学医院进行。根据连续重新评估法，测试了在标准AML诱导化疗（静脉注射伊达比星8mg/m²第1至5天 + 静脉注射阿糖胞苷100mg/m²第1至7天）的第8天静脉注射（IV）托珠单抗的三个递增剂量（4、6和8mg/kg）。所有年龄≥18岁、东部肿瘤协作组体能状态为0至2且新诊断（根据ELN-2017分类，<60岁且非低危患者）或复发/难治性AML的成年人符合条件。主要目标是确定与标准强化AML诱导联合使用时托珠单抗的最大耐受剂量。在每次与参与者接触时持续监测安全结果。该试验已在ClinicalTrials.gov注册，注册号为NCT04547062。
在2020年12月29日至2022年12月1日期间，招募了12名患者，其中75%具有ELN-2017高危特征，接受了托珠单抗治疗——2名患者接受4mg/kg托珠单抗治疗，2名接受6mg/kg治疗，8名接受8mg/kg治疗。未记录到与托珠单抗相关的剂量限制性毒性。发生了9起严重不良事件，均与托珠单抗无关，且无治疗相关死亡。因此未达到最大耐受剂量。诱导期间发生了2例死亡。在其余10名可评估患者中，9名对治疗有反应。
托珠单抗与标准AML强化诱导联合使用似乎是安全的，且产生的反应令人鼓舞。诱导第8天给予8mg/kg托珠单抗的剂量可用于进一步的2/3期研究。
大西洋希望白血病家庭（LEAF）-“与法比安在一起”协会。
