Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial
Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial
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DOI：
10.1016/s1470-2045(12)70349-2
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发表时间：
2012-10-01
期刊：
影响因子：
51.1
通讯作者：
Stelljes, Matthias
中科院分区：
文献类型：
--
作者：
Bornhaeuser, Martin;Kienast, Joachim;Stelljes, Matthias
背景：为了最大限度地减少同种异体造血细胞移植后的早期毒性作用和死亡，已经开发了低强度调理方案。然而，在此之前，这些方案的有效性尚未在随机试验中进行调查。在这项前瞻性、开放标签随机3期试验中，我们比较了首次完全缓解的急性髓性白血病患者的低强度氟达拉滨调节方案和标准方案。方法首次完全缓解的患者年龄为18-60岁，患有中危或高危急性髓性白血病（由细胞遗传学定义）；可用的HLA匹配的兄弟姐妹供体或至少具有10个HLA等位基因中的9个的非亲属供体；肾，心，肺和神经功能正常。在2004年11月15日至2009年12月31日期间，患者被随机分配（1:1，通过基于计算机的最小化程序，平衡患者的年龄，细胞遗传风险，诱导治疗和供体类型），接受4剂量2gy全身照射和150mg /m氟达拉滨(2)的降低强度调节或6剂量2gy全身照射和120mg /kg环磷酰胺的标准调节。所有患者均给予环孢素和甲氨蝶呤预防移植物抗宿主病。研究人员和患者都没有盲法研究治疗。我们的主要终点是在意向治疗人群中分析的非复发死亡率发生率。该试验已在ClinicalTrials.gov注册，注册号为NCT00150878。由于患者累积缓慢，该试验于2009年12月31日提前终止。99名患者被随机分配接受低强度训练，96名患者接受标准训练。降低强度组和标准条件组的非复发死亡率没有差异（3年累积发病率为13% [95% CI 6-21] vs 18% [10-26]； HR 0.62 [95% CI 0.30-1.31]）。复发率（3年累计发病率28% [95% CI 19-38] vs 26% [17-36]； HR 1.10 [95% CI 0.63-1.90]）、无病生存率（3年无病生存率58% [95% CI 49-70] vs 56% [46-67]； HR 0.85 [95% CI 0.55-1.32]）和总生存率（3年总生存率61% [95% CI 50-74] vs 58% [47-70]； HR 0.77 [95% CI 0.48-1.25]）在组间无显著差异。低强度训练组3-4级口腔黏膜炎的发生率低于标准训练组（低强度训练组为50例，标准训练组为73例）；其他副作用如移植物抗宿主病和胆红素和肌酐浓度升高的频率在两组之间没有显著差异。与标准调节相比，低强度调节导致相似的非复发死亡率发生率和毒性作用降低，而不影响生存结果，因此可优先用于60岁以下首次完全缓解的急性髓性白血病移植患者。
Background Reduced-intensity conditioning regimens have been developed to minimise early toxic effects and deaths after allogeneic haemopoietic cell transplantation. However, the efficacy of these regimens before this procedure has not been investigated in a randomised trial. In this prospective, open-label randomised phase 3 trial we compared a reduced-intensity fludarabine-based conditioning regimen with a standard regimen in patients with acute myeloid leukaemia in first complete remission.Methods Patients were aged 18-60 years and had intermediate-risk or high-risk acute myeloid leukaemia (defined by cytogenetics) in first complete remission; an available HLA-matched sibling donor or an unrelated donor with at least nine of ten HLA alleles; and adequate renal, cardiac, pulmonary, and neurological function. Between Nov 15, 2004, and Dec 31, 2009, patients were randomly assigned (1:1, by a computer-based minimisation procedure that balanced patients for age, cytogenetic risk, induction therapy, and donor type) to receive either reduced-intensity conditioning of four doses of 2 Gy of total-body irradiation and 150 mg/m(2) fludarabine or standard conditioning of six doses of 2 Gy of total-body irradiation and 120 mg/kg cyclophosphamide. All patients were given ciclosporin and methotrexate as prophylaxis against graft-versus-host disease. Neither investigators nor patients were blinded to study treatment. Our primary endpoint was the incidence of non-relapse mortality, analysed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00150878.Findings The trial was stopped early on Dec 31, 2009, because of slow accrual of patients. 99 patients were randomly assigned to receive reduced-intensity conditioning and 96 to receive standard conditioning. The incidence of non-relapse mortality did not differ between the reduced-intensity and standard conditioning groups (cumulative incidence at 3 years 13% [95% CI 6-21] vs 18% [10-26]; HR 0.62 [95% CI 0.30-1.31]). Relapse incidence (cumulative incidence 3 years 28% [95% CI 19-38] vs 26% [17-36]; HR 1.10 [95% CI 0.63-1.90]), disease-free survival (3 year disease-free survival 58% [95% CI 49-70] vs 56% [46-67]; HR 0.85 [95% CI 0.55-1.32]), and overall survival (3 year overall survival 61% [95% CI 50-74] vs 58% [47-70]; HR 0.77 [95% CI 0.48-1.25]) did not differ significantly between groups. Grade 3-4 of oral mucositis was less common in the reduced-intensity group than in the standard conditioning group (50 patients in the reduced-intensity conditioning group vs 73 patients in the standard conditioning group); the frequency of other side-effects such as graft-versus-host disease and increased concentrations of bilirubin and creatinine did not differ significantly between groups.Interpretation Reduced-intensity conditioning results in a similar incidence of non-relapse mortality and reduced toxic effects compared with standard conditioning without affecting survival outcomes, and thus could be preferentially used in patients younger than 60 years with acute myeloid leukaemia transplanted in first complete remission.