Background

Acute graft-versus-host-disease (GVHD) after non-myeloablative human leucocyte antigen (HLA)-matched, unrelated donor, allogeneic haemopoietic stem cell transplantation (HSCT) is associated with considerable morbidity and mortality. This trial aimed to evaluate the efficacy of adding sirolimus to the standard cyclosporine and mycophenolate mofetil prophylaxis therapy for preventing acute GVHD in this setting.

Methods

This multicentre, randomised, phase 3 trial took place at nine HSCT centres based in the USA, Denmark, and Germany. Eligible patients were diagnosed with advanced haematological malignancies treatable by allogeneic HSCT, had a Karnofsky score greater than or equal to 60, were aged older than 50 years, or if they were aged 50 years or younger, were considered at high risk of regimen-related toxicity associated with a high-dose pre-transplantation conditioning regimen. Patients were randomly allocated by an adaptive randomisation scheme stratified by transplantation centre to receive either the standard GVHD prophylaxis regimen (cyclosporine and mycophenolate mofetil) or the triple-drug combination regimen (cyclosporine, mycophenolate mofetil, and sirolimus). Patients and physicians were not masked to treatment. All patients were prepared for HSCT with fludarabine (30 mg/m² per day) 4, 3, and 2 days before receiving 2 or 3 Gy total body irradiation on the day of HSCT (day 0). In both study groups, 5·0 mg/kg of cyclosporine was administered orally twice daily starting 3 days before HSCT, and (in the absence of GVHD) tapered from day 96 through to day 150. In the standard GVHD prophylaxis group, 15 mg/kg of mycophenolate mofetil was given orally three times daily from day 0 until day 30, then twice daily until day 150, and (in the absence of GVHD) tapered off by day 180. In the triple-drug group, mycophenolate mofetil doses were the same as in the standard group, but the drug was discontinued on day 40. Sirolimus was started 3 days before HSCT, taken orally at 2 mg once daily and adjusted to maintain trough concentrations between 3–12 ng/mL through to day 150, and (in the absence of GVHD) tapered off by day 180. The primary endpoint was the cumulative incidence of grade 2–4 acute GVHD at day 100 post-transplantation. Secondary endpoints were non-relapse mortality, overall survival, progression-free survival, cumulative incidence of grade 3–4 acute GVHD, and cumulative incidence of chronic GVHD. Efficacy and safety analyses were per protocol, including all patients who received conditioning treatment and underwent transplantation. Toxic effects were measured according to the Common Terminology Criteria for Adverse Events (CTCAE). The current study was closed prematurely by recommendation of the Data and Safety Monitoring Board on July 27, 2016, after 168 patients received the allocated intervention, based on the results of a prespecified interim analysis for futility. This study is registered with ClinicalTrials.gov, number NCT01231412.

Findings

Participants were recruited between Nov 1, 2010, and July 27, 2016. Of 180 patients enrolled in the study, 167 received the complete study intervention and were included in safety and efficacy analyses: 77 patients in the standard GVHD prophylaxis group and 90 in the triple-drug group. At the time of analysis, median follow-up was 48 months (IQR 31–60). The cumulative incidence of grade 2–4 acute GVHD at day 100 was lower in the triple-drug group compared with the standard GVHD prophylaxis group (26% [95% CI 17–35] in the triple-drug group vs 52% [41–63] in the standard group; HR 0·45 [95% CI 0·28–0·73]; p=0·0013). After 1 and 4 years, non-relapse mortality increased to 4% (95% CI 0–9) and 16% (8–24) in the triple-drug group and 16% (8–24) and 32% (21–43) in the standard group (HR 0·48 [0·26–0·90]; p=0·021). Overall survival at 1 year was 86% (95% CI 78–93) in the triple-drug group and 70% in the standard group (60–80) and at 4 years it was 64% in the triple-drug group (54–75) and 46% in the standard group (34–57%; HR 0·62 [0·40–0·97]; p=0·035). Progression-free survival at 1 year was 77% (95% CI 68–85) in the triple-drug group and 64% (53–74) in the standard drug group, and at 4 years it was 59% in the triple-drug group (49–70) and 41% in the standard group (30–53%; HR 0·64 [0·42–0·99]; p=0·045). We observed no difference in the cumulative incidence of grade 3–4 acute GVHD (2% [0–5] in the triple-drug group vs 8% [2–14] in the standard group; HR 0·55 [0·16–1·96]; p=0·36) and chronic GVHD (49% [39–59] in triple-drug group vs 50% [39–61] in the standard group; HR 0·94 [0·62–1·40]; p=0·74). In both groups the most common CTCAE grade 4 or higher toxic effects were pulmonary.

Interpretation

Adding sirolimus to cyclosporine and mycophenolate mofetil resulted in a significantly lower proportion of patients developing acute GVHD compared with patients treated with cyclosporine and mycophenolate mofetil alone. Based on these results, the combination of cyclosporine, mycophenolate mofetil, and sirolimus has become the new standard GVHD prophylaxis regimen for patients treated with non-myeloablative conditioning and HLA-matched unrelated HSCT at the Fred Hutchinson Cancer Research Center.

Funding

National Institutes of Health.

中文翻译：

---

在无关的非清髓性造血干细胞移植后患者中，将西罗莫司加到标准环孢素加基于麦考酚酸酯的移植物抗宿主病的预防上：一项多中心，随机，3期试验。

背景

非清髓性人类白细胞抗原（HLA）匹配的，无关的供体，同种异体造血干细胞移植（HSCT）后的急性移植物抗宿主病（GVHD）与相当高的发病率和死亡率有关。该试验旨在评估在标准环孢霉素和霉酚酸酯预防性治疗中添加西罗莫司预防这种情况下的急性GVHD的疗效。

方法

这项多中心，随机，3期试验在美国，丹麦和德国的9个HSCT中心进行。符合条件的患者被异基因HSCT诊断为可治疗的晚期血液系统恶性肿瘤，其Karnofsky评分大于或等于60，年龄大于50岁，或者年龄大于或等于50岁，被认为与治疗方案相关的高风险与大剂量移植前条件治疗方案相关的毒性。通过移植中心分层的适应性随机分配方案对患者进行随机分配，以接受标准的GVHD预防方案（环孢霉素和霉酚酸酯）或三药联合方案（环孢霉素，霉酚酸酯和西罗莫司）。患者和医生没有被掩盖治疗。^2个每天）在HSCT当天（第0天）接受2或3 Gy全身辐射之前的4、3和2天。在两个研究组中，从HSCT前3天开始每天两次口服5·0 mg / kg环孢素，并且从第96天到第150天逐渐减少剂量（在没有GVHD的情况下）。在标准GVHD预防组中，剂量为15 mg从第0天到第30天每天口服3次/ kg霉酚酸酯，在第180天逐渐减少剂量（无GVHD时），每天口服两次，直到第150天。与标准组相同，但在第40天停药。西罗莫司于HSCT前3天开始，每天2 mg口服一次，并调整至150天，以保持谷浓度在3–12 ng / mL之间，并且（在没有GVHD的情况下）在第180天逐渐减少。主要终点是移植后第100天的2-4级急性GVHD的累积发生率。次要终点是非复发死亡率，总生存期，无进展生存期，3-4级急性GVHD的累积发生率和慢性GVHD的累积发生率。根据方案进行疗效和安全性分析，包括所有接受调理治疗并接受移植的患者。根据不良事件通用术语标准（CTCAE）测量毒性作用。根据预先确定的无效性中期分析结果，在168名患者接受了分配的干预措施后，根据数据和安全监控委员会的建议，本研究于2016年7月27日提前结束。该研究已在ClinicalTrials.gov上注册，编号为NCT01231412。

发现

在2010年11月1日至2016年7月27日之间招募了参与者。在该研究招募的180例患者中，有167例接受了完整的研究干预，并纳入了安全性和有效性分析：标准GVHD预防组为77例，而GVHD预防组为90例。三药组。在分析时，中位随访时间为48个月（IQR 31-60）。与标准的GVHD预防组相比，三药组在第100天的2-4级急性GVHD的累积发生率要低（三药组中26％[95％CI 17-35] vs标准组中52％[41–63]；HR 0·45 [95％CI 0·28-0·73]；p = 0·0013）。1年和4年后，三药组的非复发死亡率分别上升至4％（95％CI 0-9）和16％（8-24），分别增至16％（8-24）和32％（21-21）。 43）在标准组中（HR 0·48 [0·26-0·90]； p = 0·021）。三药组在1年时的总生存率为86％（95％CI 78-93），标准药组（60-80）为70％，而4年时三药组的总生存率为64％（54）。 –75）和标准组中的46％（34–57％； HR 0·62 [0·40-0·97]； p = 0·035）。三联药物组1年无进展生存率为77％（95％CI 68-85），标准药物组为64％（53-74），4年无进展生存率为59％。药物组（49–70）和标准组的41％（30–53％； HR 0·64 [0·42-0·99]； p = 0·045）。与标准组的8％[2-14]相比；HR 0·55 [0·16-1·96]；p = 0·36）和慢性GVHD（三药组为49％[39–59] ，而标准组为50％[39–61]； HR 0·94 [0·62-1·40]； p = 0·74）。在两组中，最常见的4级CTCAE或更高的毒性作用是肺部的。

解释

与单独用环孢霉素和霉酚酸酯治疗的患者相比，将西罗莫司加到环孢霉素和霉酚酸酯中导致急性GVHD的患者比例显着降低。基于这些结果，在弗雷德·哈钦森癌症研究中心，环孢素，霉酚酸酯和西罗莫司的组合已成为接受非清髓性调理和HLA匹配无关HSCT治疗的患者的新标准GVHD预防方案。

资金

国立卫生研究院。