Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China.
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
BMC Med. 2022 Apr 27;20(1):140. doi: 10.1186/s12916-022-02338-9.
Poor graft function (PGF) or prolonged isolated thrombocytopenia (PT), which are characterized by pancytopenia or thrombocytopenia, have become serious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our previous single-arm trial suggests that N-acetyl-L-cysteine (NAC) prophylaxis reduced PGF or PT after allo-HSCT. Therefore, an open-label, randomized, phase 3 trial was performed to investigate the efficacy and tolerability of NAC prophylaxis to reduce PGF or PT after allo-HSCT.
A phase 3, open-label randomized trial was performed. Based on the percentage of CD34VEGFR2 (CD309) endothelial cells (ECs) in bone marrow (BM) detected by flow cytometry at 14 days before conditioning, patients aged 15 to 60 years with acute leukemia undergoing haploidentical HSCT were categorized as low-risk (EC ≥ 0.1%) or high-risk (EC < 0.1%); patients at high risk were randomly assigned (2:1) to receive NAC prophylaxis or nonprophylaxis. The primary endpoint was PGF and PT incidence at +60 days post-HSCT.
Between April 18, 2019, and June 24, 2021, 120 patients with BM EC <0.1% were randomly assigned for NAC (group A, N = 80) or nonprophylaxis (group B, N = 40), and 105 patients with EC≥0.1% (group C) were also analyzed. The +60 days incidence of PGF and PT was 7.5% (95% CI, 1.7 to 13.3%) and 22.5% (95% CI, 9.1 to 35.9%) in group A and group B (hazard ratio, 0.317; 95% CI, 0.113 to 0.890; P = 0.021) and 11.4% (95% CI, 5.2 to 17.6%) in group C (hazard ratio, 0.643; 95% CI, 0.242 to 1.715; P = 0.373). Consistently, NAC prophylaxis gradually improved BM ECs and CD34 cells in group A, whereas reduced their reactive oxygen species (ROS) levels post-HSCT. Within 60 days post-HSCT, the most common grade 3 to 5 adverse events for the NAC and control groups were infections (19/80 [24%] vs. 10/40 [25%]) and gastrointestinal adverse events (16/80 [20%] vs. 7/40 [18%]). There were no treatment-related deaths.
N-Acetyl-L-cysteine prophylaxis can prevent the occurrence of poor hematopoietic function and is well tolerated in haploidentical HSCT. It may offer a potential pathogenesis-oriented therapeutic approach for patients with poor hematopoietic function.
This trial was registered at ClinicalTrials.gov as #NCT03967665.
异基因造血干细胞移植（allo-HSCT）后出现骨髓增生不良（PGF）或孤立性血小板减少症（PT），表现为全血细胞减少或血小板减少，已成为严重并发症。我们之前的单臂试验表明，N-乙酰-L-半胱氨酸（NAC）预防可降低 allo-HSCT 后的 PGF 或 PT。因此，进行了一项开放性、随机、3 期试验，以研究 NAC 预防对降低 allo-HSCT 后 PGF 或 PT 的疗效和耐受性。
一项 3 期、开放性随机试验。根据流式细胞术在预处理前 14 天检测到的骨髓（BM）中 CD34VEGFR2（CD309）内皮细胞（EC）的百分比，年龄在 15 至 60 岁之间患有急性白血病接受单倍体 HSCT 的患者分为低危（EC≥0.1%）或高危（EC<0.1%）；高危患者随机（2:1）接受 NAC 预防或非预防。主要终点是 HSCT 后+60 天 PGF 和 PT 的发生率。
2019 年 4 月 18 日至 2021 年 6 月 24 日，120 例 BM EC<0.1%的患者被随机分配接受 NAC（A 组，n=80）或非预防（B 组，n=40），105 例 EC≥0.1%的患者（C 组）也进行了分析。A 组和 B 组+60 天 PGF 和 PT 的发生率分别为 7.5%（95%CI，1.7 至 13.3%）和 22.5%（95%CI，9.1 至 35.9%）（危险比，0.317；95%CI，0.113 至 0.890；P=0.021），C 组为 11.4%（95%CI，5.2 至 17.6%）（危险比，0.643；95%CI，0.242 至 1.715；P=0.373）。同样，NAC 预防逐渐改善了 A 组的 BM EC 和 CD34 细胞，而降低了其 HSCT 后的活性氧（ROS）水平。HSCT 后 60 天内，NAC 和对照组最常见的 3 级至 5 级不良事件是感染（19/80 [24%] vs. 10/40 [25%]）和胃肠道不良事件（16/80 [20%] vs. 7/40 [18%]）。没有治疗相关死亡。
N-乙酰-L-半胱氨酸预防可预防造血功能不良的发生，在单倍体 HSCT 中耐受性良好。它可能为造血功能不良的患者提供一种潜在的以发病机制为导向的治疗方法。
本试验在 ClinicalTrials.gov 注册为 #NCT03967665。
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