The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
Division of Hematologic Malignancies, Medical College of Wisconsin, Milwaukee, WI, USA.
Lancet Haematol. 2022 Sep;9(9):e660-e669. doi: 10.1016/S2352-3026(22)00206-X. Epub 2022 Jul 27.
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.
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/m 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.
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.
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 × 10 nucleated marrow cells per kg of recipient ideal bodyweight) from bone marrow harvests is crucial to the success of this approach.
US National Heart, Lung, and Blood Institute and US National Cancer Institute.
复发性严重再生障碍性贫血是一种骨髓衰竭疾病，发病率和死亡率均较高。复发后通常采用骨髓移植进行治疗，在免疫抑制治疗后，但代表性不足的少数群体往往无法找到合适的匹配供体。本研究旨在了解复发或难治性严重再生障碍性贫血患者在接受半相合骨髓移植后的 1 年总生存率。
我们报告了在美国学术骨髓移植中心进行的 BMT CTN 1502 单臂、2 期临床试验的结果。纳入的患者为儿童和成人（75 岁或以下），患有严重再生障碍性贫血，对初始免疫抑制治疗有反应（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（一线免疫抑制治疗后最初改善血细胞减少症，但随后再次满足严重再生障碍性贫血疾病标准）、有足够的表现状态（东部合作肿瘤学组评分 0 或 1，卡诺夫斯基或兰斯基评分≥60%），并且有合适的相关半相合供体。该方案采用了减低强度的预处理（兔抗胸腺细胞球蛋白 4.5mg/kg 总量，环磷酰胺 14.5mg/kg 每日 2 天，氟达拉滨 30mg/m 每日 5 天，单次全身照射 200cGy）、相关 HLA 半相合供体和移植后环磷酰胺为基础的移植物抗宿主病（GVHD）预防。此外，为了预防 GVHD，从第 5 天到第 35 天，每天给予吗替麦考酚酯 15mg/kg，每天 3 次，最高剂量为每天 3000mg（最大剂量 3000mg），从第 5 天到第 180 天，根据机构标准给予他克莫司口服或静脉注射，以维持 10-15ng/mL 的血清浓度。主要终点是骨髓移植后 1 年的总生存率。所有按方案治疗的患者均进行了分析。本研究已完成，在美国临床试验数据库注册，编号为 NCT02918292。
2017 年 5 月 1 日至 2020 年 8 月 30 日，从 14 个中心招募了 32 名复发性或难治性严重再生障碍性贫血患者，其中 31 名接受了骨髓移植。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。13 名（42%）患者被报告为非白人，19 名（61%）来自代表性不足的种族和族裔群体；4 名（13%）患者为亚洲人，7 名（23%）为黑人，1 名（3%）为夏威夷/太平洋岛民，1 名（3%）为多种族，7 名（23%）患者报告为西班牙裔。31 名患者中有 24 名（77%）在 1 年内存活并植入，1 名（3%）患者存活并自体恢复。1 年总生存率为 81%（95%CI 62-91）。最常见的 3-5 级不良事件（7 名或以上患者发生）包括 7 名（23%）患者肝功能异常，15 名（48%）患者心血管改变（包括窦性心动过速、心力衰竭、心包炎），10 名（32%）患者胃肠道问题，7 名（23%）患者营养障碍，8 名（26%）患者呼吸系统疾病。移植后报告了 6 例（19%）死亡，均为疾病和骨髓移植失败所致。
采用这种方法进行半相合骨髓移植，在未对免疫抑制治疗有反应的患者中，总体生存率高，GVHD 发生率低，可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治疗严重再生障碍性贫血的标准方法。从骨髓采集物中获得高细胞剂量（每位受体理想体重的>2.5×10 个有核骨髓细胞）是这种方法成功的关键。
美国国家心肺血液研究所和美国国家癌症研究所。
