Background

The effect of systemic iron overload on outcomes after allogeneic haemopoietic cell transplantation (HCT) has been a matter of substantial debate. We aimed to investigate the predictive value of both stored (MRI-derived liver iron content) and biologically active iron (enhanced labile plasma iron; eLPI) on post-transplantation outcomes in patients with acute myeloid leukaemia or myelodysplastic syndrome undergoing allogenic HCT.

Methods

The prospective, multicentre, observational, ALLogeneic Iron inVEstigators (ALLIVE) trial recruited patients at five centres in Germany. We enrolled patients with acute myeloid leukaemia or myelodysplastic syndrome undergoing allogeneic HCT. Patients underwent cytotoxic conditioning for a median of 6 days (IQR 6–7) before undergoing allogeneic HCT and were followed up for up to 1 year (±3 months) post-transplantation. eLPI was measured in serum samples with the FeROS eLPI kit (Aferrix, Tel-Aviv, Israel) and values greater than 0·4 μmol/L were considered to represent raised eLPI. Liver iron content was measured by MRI. The primary endpoints were the quantitative delineation of eLPI dynamics during allogeneic HCT and the correlation coefficient between liver iron content before HCT and dynamic eLPI (eLPI_dyn; maximum eLPI minus baseline eLPI). All patients with available data were included in all analyses. This is the final analysis of this completed trial, which is registered with ClinicalTrials.gov, number NCT01746147.

Findings

Between Dec 13, 2012, and Dec 23, 2014, 112 patients underwent allogeneic HCT. Liver iron content before allogeneic HCT was not significantly correlated with eLPI_dyn (ρ=0·116, p=0·22). Serum eLPI concentrations rapidly increased during conditioning, and most (79 [73%] of 108) patients had raised eLPI by the day of transplantation. Patients with a pretransplant liver iron content greater than or equal to 125 μmol/g had an increased incidence of non-relapse mortality (20%, 95% CI 14–26) compared with those with lower concentrations (7%, 2–12; p=0·039) at day 100. Patients who had raised eLPI at baseline also had a significantly increased incidence of non-relapse mortality at day 100 (33%, 15–52) compared with those who had normal eLPI at baseline (7%, 2–13; p=0·00034).

Interpretation

eLPI is a possible biological mediator of iron-related toxicity. Peritransplantation eLPI-scavenging strategies could be explored in prospective interventional clinical trials for patients with systemic iron overload.

Funding

The Technical University of Dresden and Novartis.

中文翻译：

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同种异体造血细胞移植（ALLIVE）后急性髓细胞白血病和骨髓增生异常综合症中不稳定血浆铁的增强和结果：一项前瞻性，多中心，观察性试验

背景

异体造血细胞移植（HCT）后全身铁超负荷对预后的影响一直是一个有争议的问题。我们旨在调查在异基因HCT的急性髓样白血病或骨髓增生异常综合征患者中，储存的（MRI衍生的肝铁含量）和生物活性铁（增强的不稳定血浆铁； eLPI）对移植后结局的预测价值。

方法

前瞻性，多中心，观察性的异基因铁研究者（ALLIVE）试验在德国的五个中心招募了患者。我们招募了接受异基因HCT的急性髓细胞性白血病或骨髓增生异常综合症患者。接受异基因HCT之前，患者接受了6天（IQR 6-7）的细胞毒性调节，并在移植后进行了长达1年（±3个月）的随访。用FeROS eLPI试剂盒（Aferrix，特拉维夫，以色列）测量血清样品中的eLPI，认为大于0·4μmol/ L的值代表eLPI升高。肝铁含量通过MRI测量。主要终点是异基因HCT期间eLPI动态的定量描述以及HCT之前肝铁含量与动态eLPI（eLPI _dyn）之间的相关系数; 最大eLPI减去基线eLPI）。所有具有可用数据的患者均包括在所有分析中。这是对该完成的试验的最终分析，该试验已在ClinicalTrials.gov注册，编号为NCT01746147。

发现

在2012年12月13日至2014年12月23日期间，有112例患者接受了异基因HCT。异基因HCT前的肝铁含量与eLPI _dyn无显着相关性（ρ= 0·116，p = 0·22）。在调理过程中，血清eLPI浓度迅速增加，并且大多数（108位中的79名[73％]）患者在移植当天就已经升高了eLPI。移植前肝铁含量大于或等于125μmol/ g的患者的非复发死亡率（20％，95％CI 14–26）与较低浓度的患者（7％，2-12）相比有所增加。 p = 0·039）在第100天时。与在基线时eLPI正常的患者相比，在基线时eLPI升高的患者在100天时非复发死亡率的发生率也显着增加（33％，15–52）。 ％，2–13; p = 0·00034）。

解释

eLPI可能是铁相关毒性的生物介质。对于系统性铁超负荷患者，可以在前瞻性介入临床试验中探索围手术期eLPI清除策略。

资金

德累斯顿和诺华技术大学。