BACKGROUND Although severe haemoglobinopathies can be cured with allogeneic blood or bone marrow transplantation, availability of matched donors and toxic effects can be problematic. We previously found that non-myeloablative haploidentical related bone marrow transplantation with post-transplantation cyclophosphamide expanded the donor pool while limiting graft-versus-host disease (GVHD). However, graft failure-albeit with full host haemopoietic recovery-occurred in 50% of patients. In this study, we investigated whether increasing total body irradiation from 200 cGy to 400 cGy would improve engraftment while maintaining the safety profile. METHODS This study was done at Johns Hopkins Hospital (Baltimore, MD, USA). Patients aged 2-70 years receiving their first bone marrow transplant were eligible for inclusion in the study. Patients received rabbit-derived intravenous anti-thymocyte globulin 0·5 mg/kg on day -9 and 2 mg/kg on days -8 and -7, intravenous fludarabine 30 mg/m2 on days -6 to -2, intravenous cyclophosphamide 14·5 mg/kg on days -6 and -5, and total body irradiation 400 cGy administered as a single fraction on day -1. We collected unmanipulated bone marrow and infused on day 0. GVHD prophylaxis comprised intravenous cyclophosphamide 50 mg/kg per day on days 3 and 4 after transplantation, oral mycophenolate mofetil 15 mg/kg per dose (maximum 1 g) every 8 h on days 5 to 35, and oral sirolimus to maintain a level of 5-15 ng/dL for at least 1 year starting on day 5. The original planned primary objectives of this phase 2 clinical trial were transplant-related mortality and progression-free survival. However, the coverage decision by the Centers for Medicare and Medicaid Services to only provide payment for allogeneic bone marrow transplantation for patients with sickle cell disease on a clinical trial that had a comparison arm with patients not receiving bone marrow transplantation prompted the closure of this trial to accrual in 2017. Therefore, as we were unable to perform our planned statistical analysis, the primary objective was modified to evaluate engraftment, assessed by chimerism. This trial is registered with ClinicalTrials.gov, number NCT00489281. The study is closed to new participants and this is the primary analysis. FINDINGS Between Sept 24, 2014, and Aug 1, 2017, we enrolled 17 consecutive patients: 12 (71%) with sickle cell disease and 5 (29%) with β-thalassaemia major. The median patient age was 16 years (range 6-31, IQR 7·7-27·5). One (6%) of 17 patients had primary graft failure with recovery of host haemopoiesis. 13 (76%) of 17 patients achieved full donor chimerism and three (18%) had mixed donor-host chimerism. Five (29%) of 17 patients developed grade 2-4 acute GVHD, including four (24%) with maximal grade 2 GVHD and one (6%) with grade 3 GVHD. Chronic GVHD developed in three (18%) patients. As of their last follow-up visit, GVHD had resolved in all patients and no patients were receiving systemic GVHD therapy. All patients remained alive as of Aug 4, 2019, and the median follow-up duration was 705 days (range 355-1294; IQR 398-943). Only one (6%) of the 16 engrafted patients remained transfusion dependent, and 14 (88%) discontinued immunosuppression. INTERPRETATION Increasing total body irradiation to 400 cGy substantially reduced graft failure while maintaining the safety of haploidentical bone marrow transplantation with post-transplantation cyclophosphamide. These results suggest that engraftment after haploidentical bone marrow transplantation for haemoglobinopathies is possible, and primary graft failure-the main problem previously reported-might be addressed by this strategy. Therefore, this curative approach should no longer be restricted to patients with HLA-matched donors. FUNDING Maryland Stem Cell Research Fund and US National Institutes of Health.

中文翻译：

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全身照射剂量增加对重度血红蛋白病患者HLA-单倍体移植相关的移植失败的影响：一项前瞻性临床试验。

背景技术尽管严重的血红蛋白病可以用同种异体血液或骨髓移植治愈，但是匹配的供体的可用性和毒性作用可能是有问题的。我们先前发现，非清髓性单倍体相关的骨髓移植与环磷酰胺移植后扩大了供体库，同时限制了移植物抗宿主病（GVHD）。但是，有50％的患者发生了移植失败-尽管具有完整的宿主造血功能。在这项研究中，我们调查了将全身辐射从200 cGy增加到400 cGy是否会改善植入，同时保持安全性。方法该研究在约翰霍普金斯医院（美国马里兰州巴尔的摩）进行。接受首次骨髓移植的2至70岁的患者符合纳入研究的条件。患者在第-9天接受兔源性静脉抗胸腺细胞球蛋白0·5 mg / kg，在第-8和-7天接受2 mg / kg，在第-6至-2天接受静脉氟达拉滨30 mg / m2，静脉给予环磷酰胺14 ·在第-6天和第-5天为5 mg / kg，在第-1天以单次剂量全身辐射400 cGy。我们收集未处理的骨髓并在第0天输注。预防GVHD包括在移植后第3天和第4天每天静脉注射环磷酰胺50 mg / kg，在第5天每8小时口服口服霉酚酸酯15 mg / kg每剂（最大1 g）。从第5天开始，口服西罗莫司的浓度维持在35至15纳克/分升之间，并保持至少1年5-15 ng / dL的水平。该2期临床试验的最初计划主要目标是与移植有关的死亡率和无进展生存期。然而，医疗保险和医疗补助服务中心的承保范围决定仅针对镰状细胞病患者的同种异体骨髓移植支付费用，该临床试验的比较对象是未接受骨髓移植的患者，这促使该试验应计入结帐在2017年。因此，由于我们无法执行计划的统计分析，因此对主要目标进行了修改，以评估通过嵌合体评估的植入。该试验已在ClinicalTrials.gov上注册，编号为NCT00489281。该研究对新参与者不开放，这是主要分析。结果在2014年9月24日至2017年8月1日之间，我们连续招募了17名患者：镰状细胞病12例（71％），重度β地中海贫血5例（29％）。患者平均年龄为16岁（范围6-31，IQR 7·7-27·5）。17例患者中有1例（6％）发生了原发性移植失败，并恢复了宿主造血功能。17名患者中有13名（76％）实现了完全的供体嵌合，三名（18％）出现了混合的供体-宿主嵌合体。17名患者中有5名（29％）发生2-4级急性GVHD，其中4名（24％）达到2级GVHD最大，而1名（6％）达到3级GVHD。在三名（18％）患者中发生了慢性GVHD。截至上一次随访，GVHD在所有患者中均已治愈，没有患者接受全身性GVHD治疗。截至2019年8月4日，所有患者均存活，中位随访时间为705天（范围355-1294; IQR 398-943）。16例移植患者中只有1例（6％）仍然依赖输血，而14例（88％）停止了免疫抑制。解释将全身照射增加到400 cGy可以显着减少移植失败，同时通过移植后的环磷酰胺维持单倍体骨髓移植的安全性。这些结果表明，单倍体骨髓移植后可发生血红蛋白病，并且原发性移植失败-先前报道的主要问题-可以通过该策略解决。因此，这种治疗方法不应再局限于HLA匹配供体的患者。资金马里兰干细胞研究基金和美国国立卫生研究院。这种策略可以解决原发性移植物衰竭和先前报道的主要问题。因此，这种治疗方法不应再局限于HLA匹配供体的患者。资金马里兰州干细胞研究基金和美国国立卫生研究院。这种策略可以解决原发性移植物衰竭和先前报道的主要问题。因此，这种治疗方法不应再局限于HLA匹配供体的患者。资金马里兰干细胞研究基金和美国国立卫生研究院。