Background

Relapsed severe aplastic anaemia is a marrow failure disorder with high morbidity and mortality. It is often treated with bone marrow transplantation at relapse post-immunosuppressive therapy, but under-represented minorities often cannot find a suitably matched donor. This study aimed to understand the 1-year overall survival in patients with relapsed or refractory severe aplastic anaemia after haploidentical bone marrow transplantation.

Methods

We report the outcomes of BMT CTN 1502, a single-arm, phase 2 clinical trial done at academic bone marrow transplantation centres in the USA. Included patients were children and adults (75 years or younger) with severe aplastic anaemia that was refractory (fulfilment of severe aplastic anaemia disease criteria at least 3 months after initial immunosuppressive therapy) or relapsed (initial improvement of cytopenias after first-line immunosuppressive therapy but then a later return to fulfilment of severe aplastic anaemia disease criteria), adequate performance status (Eastern Cooperative Oncology Group score 0 or 1, Karnofsky or Lansky score ≥60%), and the presence of an eligible related haploidentical donor. The regimen used reduced-intensity conditioning (rabbit anti-thymocyte globulin 4·5 mg/kg in total, cyclophosphamide 14·5 mg/kg daily for 2 days, fludarabine 30 mg/m² daily for 5 days, total body irradiation 200 cGy in a single fraction), related HLA-haploidentical donors, and post-transplantation cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis. Additionally, for GVHD prophylaxis, mycophenolate mofetil was given orally at a dose of 15 mg/kg three times a day up to 1 g three times a day (maximum dose 3000 mg per day) from day 5 to day 35, and tacrolimus was given orally or intravenously from day 5 to day 180 as per institutional standards to maintain a serum concentration of 10–15 ng/mL. The primary endpoint was overall survival 1 year after bone marrow transplantation. All patients treated per protocol were analysed. This study is complete and is registered with ClinicalTrials.gov, NCT02918292.

Findings

Between May 1, 2017, and Aug 30, 2020, 32 patients with relapsed or refractory severe aplastic anaemia were enrolled from 14 centres, and 31 underwent bone marrow transplantation. The median age was 24·9 years (IQR 10·4–51·3), and median follow-up was 24·3 months (IQR 12·1–29·2). Of the 31 patients who received a transplant, 19 (61%) were male and 12 (39%) female. 13 (42%) patients were site-reported as non-White, and 19 (61%) were from under-represented racial and ethnic groups; there were four (13%) patients who were Asian, seven (23%) Black, one (3%) Hawaiian/Pacific Islander, and one (3%) more than one race, with seven (23%) patients reporting Hispanic ethnicity. 24 (77%) of 31 patients were alive with engraftment at 1 year, and one (3%) patient alive with autologous recovery. The 1-year overall survival was 81% (95% CI 62–91). The most common grade 3–5 adverse events (seen in seven or more patients) included seven (23%) patients with abnormal liver tests, 15 (48%) patients with cardiovascular changes (including sinus tachycardia, heart failure, pericarditis), ten (32%) patients with gastrointestinal issues, seven (23%) patients with nutritional disorders, and eight (26%) patients with respiratory disorders. Six (19%) deaths, due to disease and unsuccessful bone marrow transplantation, were reported after transplantation.

Interpretation

Haploidentical bone marrow transplantation using this approach results in excellent overall survival with minimal GVHD in patients who have not responded to immunosuppressive therapy, and can expand access to bone marrow transplantation across all populations. In clinical practice, this could now be considered a standard approach for salvage treatment of severe aplastic anaemia. Attention to obtaining high cell doses (>2·5 × 10⁸ nucleated marrow cells per kg of recipient ideal bodyweight) from bone marrow harvests is crucial to the success of this approach.

Funding

US National Heart, Lung, and Blood Institute and US National Cancer Institute.

中文翻译：

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美国复发性或难治性严重再生障碍性贫血患者的单倍相合骨髓移植（BMT CTN 1502）：一项多中心、单臂、2 期试验

背景

复发性严重再生障碍性贫血是一种骨髓衰竭性疾病，发病率和死亡率很高。通常在免疫抑制治疗后复发时采用骨髓移植进行治疗，但代表性不足的少数群体往往无法找到合适的匹配供体。本研究旨在了解半相合骨髓移植后复发或难治性严重再生障碍性贫血患者的 1 年总生存率。

方法

我们报告 BMT CTN 1502 的结果，这是一项在美国学术骨髓移植中心进行的单臂 2 期临床试验。纳入的患者是患有严重再生障碍性贫血的儿童和成人（75 岁或以下），这些贫血是难治性的（在初始免疫抑制治疗后至少 3 个月满足严重再生障碍性贫血疾病标准）或复发性贫血（一线免疫抑制治疗后血细胞减少初步改善，但然后稍后恢复满足严重再生障碍性贫血疾病标准）、足够的表现状态（东部肿瘤合作组评分 0 或 1，卡诺夫斯基或兰斯基评分≥60%），以及存在合格的相关单倍体捐献者。方案采用减强度预处理（兔抗胸腺细胞球蛋白总计4·5 mg/kg，环磷酰胺14·5 mg/kg，每日1次，持续2天，氟达拉滨30 mg/m 2 每日，持续5天，全身照射²⁰⁰ cGy单一部分）、相关 HLA 单倍体供体以及移植后基于环磷酰胺的移植物抗宿主病 (GVHD) 预防。此外，为了预防 GVHD，从第 5 天到第 35 天，口服吗替麦考酚酯，剂量为 15 mg/kg，每天 3 次，直至 1 g，每天 3 次（最大剂量为每天 3000 mg），并给予他克莫司根据机构标准，从第 5 天到第 180 天口服或静脉注射，以维持血清浓度为 10–15 ng/mL。主要终点是骨髓移植后 1 年的总体生存率。对按照方案治疗的所有患者进行了分析。该研究已完成并已在 ClinicalTrials.gov 注册，NCT02918292。

发现

2017年5月1日至2020年8月30日期间，来自14个中心的32名复发或难治性严重再生障碍性贫血患者入组，其中31人接受了骨髓移植。中位年龄为 24·9 岁（IQR 10·4–51·3），中位随访时间为 24·3 个月（IQR 12·1–29·2）。在接受移植的 31 名患者中，19 名（61%）为男性，12 名（39%）为女性。现场报告的 13 名患者（42%）为非白人，19 名患者（61%）来自代表性不足的种族和族裔群体；其中四名 (13%) 患者为亚洲人，七名 (23%) 黑人，一名 (3%) 夏威夷/太平洋岛民，以及一名 (3%) 多于一种种族的患者，其中七名 (23%) 患者报告为西班牙裔。31 名患者中有 24 名 (77%) 在移植后 1 年存活，1 名 (3%) 患者在自体移植后存活。1 年总生存率为 81% (95% CI 62-91)。最常见的 3-5 级不良事件（7 名或更多患者中出现）包括 7 名（23%）肝功能检查异常的患者、15 名（48%）心血管变化（包括窦性心动过速、心力衰竭、心包炎）的患者、10 名(32%) 患有胃肠道问题的患者，七名 (23%) 患有营养障碍的患者，以及八名 (26%) 患有呼吸系统疾病的患者。据报道，移植后有六人 (19%) 因疾病和骨髓移植不成功而死亡。

解释

使用这种方法的单倍相合骨髓移植可以使对免疫抑制治疗无反应的患者获得优异的总生存率和最小的 GVHD，并且可以扩大所有人群接受骨髓移植的机会。在临床实践中，这现在可以被认为是严重再生障碍性贫血抢救治疗的标准方法。注意从骨髓收获中获得高细胞剂量（>2·5 × 10 ^{8每公斤受体理想体重有核骨髓细胞）对于该方法的成功至关重要。}

资金

美国国家心肺血液研究所和美国国家癌症研究所。