Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial
Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial
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DOI：
10.1016/s2352-3026(19)30031-6
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发表时间：
2019-04-01
影响因子：
24.7
通讯作者：
Brodsky, Robert A.
中科院分区：
文献类型：
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作者：
Bolanos-Meade, Javier;Cooke, Kenneth R.;Brodsky, Robert A.
虽然严重的血红蛋白病可以通过同种异体血液或骨髓移植治愈，但匹配供体的可用性和毒性作用可能是个问题。我们以前发现，非清髓性单倍体相合相关骨髓移植与移植后环磷酰胺扩大供体库，同时限制移植物抗宿主病（GVHD）。然而，50%的患者发生移植物衰竭，尽管宿主造血功能完全恢复。在这项研究中，我们调查是否增加全身照射从200 cGy到400 cGy将提高植入，同时保持safety profile.Methods这项研究是在约翰霍普金斯医院（巴尔的摩，MD，美国）。接受首次骨髓移植的2-70岁患者有资格入选本研究。患者在第-9天接受静脉注射兔源性抗胸腺细胞球蛋白0.5 mg/kg，在第-8天和第-7天接受2 mg/kg，在第-6天至第-2天接受静脉注射氟达拉滨30 mg/m2，在第-6天和第-5天接受静脉注射环磷酰胺14.5 mg/kg，在第-1天接受全身照射400 cGy，作为单次照射。我们收集未经处理的骨髓并在第0天输注。GVHD预防包括在移植后第3天和第4天静脉内给予环磷酰胺50 mg/kg/天，在第5天至第35天每8小时口服霉酚酸酯15 mg/kg/剂（最大1 g），并从第5天开始口服西罗莫司以维持5-15 ng/dL的水平至少1年。这项2期临床试验最初计划的主要目的是移植相关死亡率和无进展生存率。然而，医疗保险和医疗补助服务中心的覆盖范围决定仅为镰状细胞病患者的同种异体骨髓移植提供付款，该临床试验与未接受骨髓移植的患者进行了比较，促使该试验于2017年关闭。因此，由于我们无法进行计划的统计分析，因此将主要目的修改为通过嵌合体评估植入。本试验在ClinicalTrials.gov注册，编号NCT 00489281。结果2014年9月24日至2017年8月1日期间，我们连续招募了17名患者：12名（71%）镰状细胞病患者和5名（29%）重型β地中海贫血患者。中位患者年龄为16岁（范围6-31岁，IQR 7。7-27 . 5）。17例患者中有1例（6%）发生原发性移植物衰竭，宿主造血恢复。17例患者中有13例（76%）达到完全供者嵌合体，3例（18%）达到混合供者-宿主嵌合体。17例患者中有5例（29%）发生了2-4级急性GVHD，其中4例（24%）发生了最严重的2级GVHD，1例（6%）发生了3级GVHD。慢性GVHD发生在3例（18%）患者中。截至末次随访访视，所有患者的GVHD均已消退，无患者接受全身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）。只有一个（6%）的16个移植患者仍然输血依赖，和14（88%）停止immunosuppress.Interpretation增加全身照射到400 cGy大大减少移植失败，同时保持安全的单倍体相合骨髓移植与移植后环磷酰胺。这些结果表明，血红蛋白病的单倍体相合骨髓移植后的植入是可能的，和原发性移植失败的主要问题，以前排除，可能会解决这一战略。因此，这种治疗方法不应再局限于HLA匹配供体的患者。
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/m(2) 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 beta-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.