Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia

医学 地中海贫血 临床终点 胎儿血红蛋白 内科学 输血 胃肠病学 儿科 外科 临床试验 生物 胎儿 怀孕 遗传学
作者
Franco Locatelli,Peter Lang,Selim Corbacioglu,Donna A. Wall,Roland Meisel,Amanda M. Li,Josu de la Fuente,Ami J. Shah,Ben Carpenter,Janet L. Kwiatkowski,Markus Y. Mapara,Robert I. Liem,Maria Domenica Cappellini,Mattia Algeri,Antonis Kattamis,Sujit Sheth,Stephan A. Grupp,Puja Kohli,Daoyuan Shi,Leorah Ross
出处
期刊:Blood [Elsevier BV]
卷期号:142 (Supplement 1): 1053-1053 被引量:2
标识
DOI:10.1182/blood-2023-190534
摘要

Background: Exagamglogene autotemcel (exa-cel) is a non-viral cell therapy designed to reactivate fetal hemoglobin (HbF) via ex vivo CRISPR-Cas9 gene-editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A in patients (pts) with transfusion-dependent β-thalassemia (TDT). Here we report that in a pre-specified interim analysis, the pivotal CLIMB THAL-111 trial of exa-cel met primary and key secondary endpoints. Methods: CLIMB THAL-111 is an ongoing, 24-month (mo), phase 3 trial of exa-cel in pts age 12-35y with TDT and a history of ≥100 mL/kg/y or ≥10 U/y packed red blood cell (RBC) transfusions in the 2y before screening. Primary endpoint is transfusion independence defined as proportion of pts maintaining a weighted average hemoglobin (Hb) ≥9 g/dL without RBC transfusion for ≥12 consecutive mos (TI12). Key secondary endpoint is proportion of pts maintaining a weighted average Hb ≥9 g/dL without RBC transfusion for ≥6 consecutive mos (TI6). Evaluable pts had ≥16 mos of follow-up after exa-cel infusion. Evaluation of TI12 and TI6 started 60 days after last RBC transfusion for post-transplant support or TDT management. Pts completing trial enrolled in long-term follow-up Study 131. Mean (SD) shown except where noted. Results: As of 16 Jan 2023, 52 pts (mean age 21.5[range 12-35]y; 18[34.6%] age ≥12 to <18y; 31[59.6%] with severe genotypes [β 0/β 0 or β 0/β 0-like], median annualized transfusion volume 201.0 mL/kg) received exa-cel; median follow-up 20.4 (range 2.1-48.1) mos. Following infusion, all pts engrafted neutrophils and platelets (median 29 and 44 days, respectively). Of the 35 pts evaluable for primary and key secondary endpoints, 32 (91.4%) achieved TI12 and TI6 (95% CI: 76.9%, 98.2%; P<0.0001). Pts achieving TI12 stopped transfusions 35.2 (SD, 18.5) days after exa-cel infusion and remained transfusion independent for 22.5 (range, 13.3, 45.1) mos (Fig). For 3 pts not achieving TI12, one had reductions in annualized RBC transfusion volume of 83.9%, while the others have been transfusion-free for 7.3 mos and 4.0 mos starting 60 days after the last transfusion. For all pts, total Hb was 11.4 g/dL at Month 3 (≥12g/dL Month 6 onward) and HbF was 7.7 g/dL at Month 3 (≥ 10 g/dL Month 6 onward) with pancellular distribution (≥95% RBCs expressing HbF Month 6 onward). Proportion of edited BCL11A alleles was stable over time in bone marrow CD34 + and peripheral blood nucleated cells. Pts not yet evaluable and with sufficient follow-up were also transfusion-free. Quality-of-life (QOL) measures showed clinically significant improvements. All pts had ≥1 adverse event (AE), most were Grade 1 or 2; 46 (88.5%) pts had AEs of Grade 3 or 4 severity. Most common AEs were febrile neutropenia (61.5%), headache (53.8%), and stomatitis (50.0%). Most AEs and serious AEs (SAEs) occurred within first 6 mos after infusion. Two pts had SAEs considered related to exa-cel: headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and idiopathic pneumonia syndrome (latter also considered related to busulfan) all in the context of HLH (n=1) and delayed engraftment and thrombocytopenia (both also considered related to busulfan) (n=1), which all resolved. There were no deaths, discontinuations, or malignancies. Conclusions: The CLIMB THAL-111 trial met primary and key secondary endpoints, with exa-cel treatment resulting in early and sustained increases in Hb and HbF leading to transfusion independence in >90% of pts with TDT and improved QOL. Safety profile of exa-cel was generally consistent with myeloablative busulfan conditioning and autologous transplantation. These results show exa-cel has the potential to deliver a one-time functional cure to pts with TDT.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
杨瑞东完成签到 ,获得积分10
3秒前
yyyy完成签到,获得积分10
11秒前
缥缈的平卉完成签到 ,获得积分10
12秒前
量子星尘发布了新的文献求助10
23秒前
李爱国应助大橙子采纳,获得10
24秒前
magictoo发布了新的文献求助30
30秒前
32秒前
yang完成签到,获得积分10
32秒前
Minicoper发布了新的文献求助10
33秒前
快乐丸子完成签到,获得积分10
34秒前
简单而复杂完成签到,获得积分10
34秒前
大橙子发布了新的文献求助10
38秒前
张牧之完成签到 ,获得积分10
40秒前
冷冷暴力完成签到,获得积分10
42秒前
YYY完成签到,获得积分10
42秒前
42秒前
gujian完成签到 ,获得积分10
45秒前
帅气的秘密完成签到 ,获得积分10
46秒前
自然函发布了新的文献求助10
50秒前
冰冰双双完成签到,获得积分10
50秒前
开心夏旋完成签到 ,获得积分0
52秒前
我要读博士完成签到 ,获得积分10
55秒前
活泼的大船完成签到,获得积分10
55秒前
AFF完成签到,获得积分10
56秒前
57秒前
无私小小完成签到,获得积分10
58秒前
随心所欲完成签到 ,获得积分10
59秒前
润润轩轩完成签到 ,获得积分10
1分钟前
CodeCraft应助大橙子采纳,获得10
1分钟前
ZR完成签到,获得积分10
1分钟前
magictoo完成签到,获得积分10
1分钟前
陈昊发布了新的文献求助10
1分钟前
zhangliangfu完成签到 ,获得积分10
1分钟前
金石为开完成签到,获得积分10
1分钟前
王QQ完成签到 ,获得积分10
1分钟前
唐唐完成签到 ,获得积分10
1分钟前
最棒哒完成签到 ,获得积分10
1分钟前
鸣鸣完成签到,获得积分10
1分钟前
123321完成签到 ,获得积分10
1分钟前
卓若之完成签到 ,获得积分10
1分钟前
高分求助中
【提示信息,请勿应助】关于scihub 10000
Les Mantodea de Guyane: Insecta, Polyneoptera [The Mantids of French Guiana] 3000
徐淮辽南地区新元古代叠层石及生物地层 3000
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
Handbook of Industrial Diamonds.Vol2 1100
Global Eyelash Assessment scale (GEA) 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 550
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 4038128
求助须知:如何正确求助?哪些是违规求助? 3575831
关于积分的说明 11373827
捐赠科研通 3305610
什么是DOI,文献DOI怎么找? 1819255
邀请新用户注册赠送积分活动 892655
科研通“疑难数据库(出版商)”最低求助积分说明 815022