Malard Florent, Thepot Sylvain, Cluzeau Thomas, Carré Martin, Lebon Delphine, Bories Pierre, Legrand Ollivier, Schwarz Marianne, Loschi Michael, Meunier Mathieu, Joris Magalie, Gasc Cyrielle, Jouve Juliette, Levast Benoît, Plantamura Emilie, Prestat Emmanuel, Sabourin Antoine, Gaugler Béatrice, Dore Joel, Récher Christian, Mohty Mohamad
Department of Clinical Hematology and Cellular Therapy, Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris, Sorbonne University, INSERM Unité mixte de recherche 938, Centre de Recherche Saint-Antoine, Paris, France.
Clinical Hematology, Angers University Hospital, Angers, France.
Blood Adv. 2025 Aug 12;9(15):3739-3749. doi: 10.1182/bloodadvances.2024015571.
Intensive induction chemotherapy (IC) combined with broad-spectrum antibiotics for acute myeloid leukemia (AML) leads to gut microbiota dysbiosis, promoting pathological conditions and an increased incidence of complications, possibly limiting eligibility to allogeneic hematopoietic cell transplantation (alloHCT). The purpose of this dose-ranging phase 1 study (CIMON) was to evaluate the first-in-man use of MaaT033, a pooled, allogeneic, lyophilized, and standardized fecal microbiotherapeutic product, formulated as a delayed-release capsule for oral administration. Primary objectives of the study were to evaluate the maximum tolerable dose of MaaT033 in 21 patients with AML having undergone IC and antibiotics. Secondary objectives were to assess MaaT033 safety, its efficacy in restoring the patients' gut microbiome using shotgun sequencing to evaluate the recommended dose regimen, and patient compliance. MaaT033 was shown to be safe and effective for gut microbiota restoration in patients with AML receiving IC and antibiotics, with an excellent gut microbiota reconstruction based on diversity indices at the species level and restoration of microbial communities close to the composition of the drug product. The maximum tolerable dose of MaaT033 was not determined because the interim results suggested adequate efficacy as measured by engraftment at lower doses (3 capsules per day). Moreover, inflammatory markers (C-reactive protein, interleukin-6) decrease with treatment, whereas short-chain fatty acids increase over time. A randomized, placebo-controlled phase 2b trial, in recipients of alloHCT patients is ongoing. This trial was registered at www.clinicaltrials.gov as #NCT04150393.
强化诱导化疗（IC）联合广谱抗生素治疗急性髓系白血病（AML）会导致肠道微生物群失调，引发病理状况并增加并发症发生率，这可能会限制异基因造血细胞移植（alloHCT）的适用性。这项剂量范围的1期研究（CIMON）的目的是评估MaaT033的首次人体使用情况，MaaT033是一种经过汇集、同种异体、冻干和标准化处理的粪便微生物治疗产品，制成口服缓释胶囊。该研究的主要目标是评估21例接受过IC和抗生素治疗的AML患者中MaaT033的最大耐受剂量。次要目标是评估MaaT033的安全性、其使用鸟枪法测序恢复患者肠道微生物群的疗效以评估推荐剂量方案，以及患者的依从性。结果表明，MaaT033对接受IC和抗生素治疗的AML患者恢复肠道微生物群是安全有效的，基于物种水平的多样性指数，其肠道微生物群重建效果良好，且微生物群落恢复接近药品的组成。未确定MaaT033的最大耐受剂量，因为中期结果表明，在较低剂量（每天3粒胶囊）下通过植入情况衡量的疗效足够。此外，炎症标志物（C反应蛋白、白细胞介素-6）随治疗而降低，而短链脂肪酸随时间增加。一项针对alloHCT患者接受者的随机、安慰剂对照2b期试验正在进行中。该试验已在www.clinicaltrials.gov上注册，编号为#NCT04150393。
