Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA, USA.
Hematology Department, AP-HP, Hôpital Saint-Antoine, Sorbonne Université and INSERM UMRs 938, Paris, France.
Nat Med. 2024 Aug;30(8):2277-2287. doi: 10.1038/s41591-024-03016-4. Epub 2024 Jun 6.
Acute graft-versus-host disease (aGVHD) of the lower gastrointestinal (GI) tract is a major cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vedolizumab is a gut-selective anti-αβ integrin monoclonal antibody that reduces gut inflammation by inhibiting migration of GI-homing T lymphocytes. The efficacy and safety of vedolizumab added to standard GVHD prophylaxis (calcineurin inhibitor plus methotrexate/mycophenolate mofetil) was evaluated for prevention of lower-GI aGVHD after unrelated donor allo-HSCT in a randomized, double-blind, placebo-controlled phase 3 trial. Enrollment closed early during the COVID-19 pandemic with 343 patients randomized (n = 174 vedolizumab, n = 169 placebo), and 333 received ≥1 intravenous dose of 300 mg vedolizumab (n = 168) or placebo (n = 165) and underwent allo-HSCT. The primary end point was met; Kaplan-Meier (95% confidence interval) estimated rates of lower-GI aGVHD-free survival by day +180 after allo-HSCT were 85.5% (79.2-90.1) with vedolizumab versus 70.9% (63.2-77.2) with placebo (hazard ratio, 0.45; 95% confidence interval, 0.27-0.73; P < 0.001). For the 5 key secondary efficacy end points analyzed by day +180 after allo-HSCT, rates of lower-GI aGVHD-free and relapse-free survival and grade C-D aGVHD-free survival were significantly higher with vedolizumab versus placebo. No significant treatment differences were found for the other key secondary end points of non-relapse mortality, overall survival and grade B-D aGVHD-free survival, respectively. Incidence of treatment-related serious adverse events analyzed in patients receiving ≥1 dose of study treatment (n = 334) was 6.5% (n = 11 of 169) vedolizumab versus 8.5% (n = 14 of 165) placebo. When added to standard calcineurin inhibitor-based GVHD prevention, lower-GI aGVHD-free survival was significantly higher with vedolizumab versus placebo. ClinicalTrials.gov identifier: NCT03657160 .
急性移植物抗宿主病（aGVHD）是接受异基因造血干细胞移植（allo-HSCT）患者发病和死亡的主要原因。Vedolizumab 是一种肠道选择性抗-αβ 整联蛋白单克隆抗体，通过抑制肠道归巢 T 淋巴细胞的迁移来减少肠道炎症。在一项随机、双盲、安慰剂对照的 3 期临床试验中，评估了在无关供体 allo-HSCT 后添加 vedolizumab 标准 GVHD 预防方案（钙调神经磷酸酶抑制剂加甲氨蝶呤/吗替麦考酚酯）对预防下胃肠道 aGVHD 的疗效和安全性。由于 COVID-19 大流行，该试验提前关闭，共有 343 名患者入组（n=174 例 vedolizumab，n=169 例安慰剂），333 名患者接受了至少 1 次静脉注射 300mg vedolizumab（n=168）或安慰剂（n=165），并进行 allo-HSCT。主要终点达到；移植后第 180 天 Kaplan-Meier（95%置信区间）估计下胃肠道 aGVHD 无生存的发生率为 85.5%（79.2-90.1）vedolizumab 组与 70.9%（63.2-77.2）安慰剂组（风险比，0.45；95%置信区间，0.27-0.73；P<0.001）。在移植后第 180 天分析的 5 个关键次要疗效终点中，vedolizumab 组下胃肠道 aGVHD 无复发和无生存、C-D 级 aGVHD 无生存的发生率显著高于安慰剂组。在其他关键次要终点，非复发死亡率、总生存率和 B-D 级 aGVHD 无生存方面，未发现治疗有显著差异。在接受≥1 次研究治疗剂量的患者中分析治疗相关严重不良事件的发生率（n=334）为 6.5%（n=11 of 169）vedolizumab 组与 8.5%（n=14 of 165）安慰剂组。当添加到标准钙调神经磷酸酶抑制剂为基础的 GVHD 预防时，vedolizumab 组与安慰剂组相比，下胃肠道 aGVHD 无生存的发生率显著提高。临床试验.gov 标识符：NCT03657160。
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