意大利罗马大学Franco Locatelli团队研究了Betibeglogene Autotemcel基因治疗非β0/β0基因型β-地中海贫血的疗效和安全性。这一研究成果发表在2021年12月11日出版的《新英格兰医学杂志》上。

用于输血依赖性β-地中海贫血的betibeglogene autotemcel（beti-cel）基因疗法，包含用编码β-珠蛋白（βA-T87Q）基因的BB305慢病毒载体转导的自体CD34+造血干祖细胞。

在这项开放性的临床3期研究中，研究组评估了beti-cel疗法在成人和儿童输血依赖性β-地中海贫血和非β0/β0基因型患者中的疗效和安全性。患者接受白消安（根据药代动力学分析调整剂量）进行骨髓消融，并接受静脉注射beti-cel。主要终点为输血独立性（即加权平均血红蛋白水平为≥9 g/dL，≥12个月无需输注红细胞）。

共有23名患者入组并接受治疗，平均随访29.5个月。22例患者中有20例（91%）可接受评估，其中6例（86%）年龄小于12岁。输血独立期间的平均血红蛋白水平为11.7 g/dL。在beti-cel输注12个月后，输血独立患者中带有T87Q氨基酸替代物（HbAT87Q）的基因治疗衍生成人血红蛋白（HbA）的平均水平为8.7 g/dL。

beti-cel的安全性与基于白消安的骨髓消融一致。4名患者至少有1例不良事件，研究者认为这些不良事件与beti-cel有关或可能有关；除血小板减少症（1例）外，所有事件均不严重。没有观察到癌症病例。

研究结果表明，对于大多数非β0/β0基因型患者（包括年龄小于12岁的患者），使用beti-cel治疗后，HbAT87Q水平和总血红蛋白水平持续升高，足以实现输血独立。

附：英文原文

Title: Betibeglogene Autotemcel Gene Therapy for Non–β0/β0 Genotype β-Thalassemia | NEJM

Author: Franco Locatelli, M.D., Ph.D.,, Alexis A. Thompson, M.D., M.P.H.,, Janet L. Kwiatkowski, M.D.,, John B. Porter, M.D.,, Adrian J. Thrasher, M.D., Ph.D.,, Suradej Hongeng, M.D.,, Martin G. Sauer, M.D.,, Isabelle Thuret, M.D.,, Ashutosh Lal, M.D.,, Mattia Algeri, M.D.,, Jennifer Schneiderman, M.D.,, Timothy S. Olson, M.D., Ph.D.,, Ben Carpenter, M.D.,, Persis J. Amrolia, M.D., Ph.D.,, Usanarat Anurathapan, M.D.,, Axel Schambach, M.D., Ph.D.,, Christian Chabannon, M.D., Ph.D.,, Manfred Schmidt, Ph.D.,, Ivan Labik, M.Sc.,, Heidi Elliot,, Ruiting Guo, M.S.,, Mohammed Asmal, M.D., Ph.D.,, Richard A. Colvin, M.D., Ph.D.,, and Mark C. Walters, M.D.

Issue&Volume: 2021-12-11

Abstract:

Background

Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the β-globin (βA-T87Q) gene.

Methods

In this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent β-thalassemia and a non–β0/β0 genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of ≥9 g per deciliter without red-cell transfusions for ≥12 months).

Results

A total of 23 patients were enrolled and received treatment, with a median follow-up of 29.5 months (range, 13.0 to 48.2). Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter (range, 9.5 to 12.8). Twelve months after beti-cel infusion, the median level of gene therapy–derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q) was 8.7 g per deciliter (range, 5.2 to 10.6) in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed.

Conclusions

Treatment with beti-cel resulted in a sustained HbAT87Q level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non–β0/β0 genotype, including those younger than 12 years of age.

DOI: 10.1056/NEJMoa2113206

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2113206