Background

In recipients of allogeneic hematopoietic stem cell transplantation (HSCT), organ toxicity is a barrier to administering high-intensity conditioning. We hypothesized that determinants of acute organ toxicity are specific to individual regimens. We sought to characterize these toxicities, evaluate their prognostic implication, and derive predictors of severe toxicity at the regimen level.

Methods

This retrospective study included adults undergoing first allogeneic HSCT at a single center between 2001 and 2014. Patients received grafts from matched sibling or unrelated donors and received any of the following regimens: Cy/TBI, Bu/Cy, Flu/Bu 12.8 mg, Flu/Bu 6.4 mg, Flu/Treosulfan 36-42 gr/m², and Flu/Mel 100-140 mg/m². Studied toxicities included acute kidney injury (AKI) per KDIGO definition and increases in total bilirubin, AST, ALT, and alkaline phosphatase (Alk Phos) per CTCAE grading. The incidence of toxicities from conditioning through 30-days post-HSCT was tabulated. Risk factors for severe organ toxicity were assessed within each regimen using multivariable logistic regressions.

Results

In a cohort of 707 patients, the main indications were acute leukemia (57%), myelodysplastic syndrome (13%), and aggressive lymphoma (9%). GvHD prophylaxis included methotrexate in 80% of patients, and 56% received ATG. The incidence of AKI and increased serum bilirubin in each regimen is shown in Figure 1A/B, respectively. Sinusoidal-obstructive syndrome (6% overall) accounted for only 17% of gr. ≥ 3 bilirubinemia in the entire cohort. Elevations in AST, ALT, and Alk Phos of gr ≥ 3 were not common (<8%). AKI gr ≥ 2, increased bilirubin gr ≥ 3, AST gr ≥ 3, and Alk Phos gr ≥ 2 were associated with increased 100-day mortality (p < 0.05). Acute severe organ toxicity (ASOT) was defined as the occurrence of any of these toxicities. ASOT had an odds ratio (OR) of 3.4 (95% CI: 2.2-5.3) for 100-day mortality. Within each regimen, we studied the relationship between ASOT and transplant/patient characteristics (Figure 1C). Elevations in baseline bilirubin were predictive of ASOT in Cy/TBI (OR: 1.7 [1.2-2.4]), while increasing creatinine was predictive in patients conditioned with Flu/Mel (OR: 1.4 [1.1-1.9]). In patients treated with Bu/Cy, administration of ATG increased the risk of ASOT (1.3 [1.1-1.6]).

Conclusion

Allogeneic transplantation recipients are at high risk for acute organ damage. We describe patterns of renal and liver toxicity across several regimens. Determinants of acute severe organ toxicity, defined as those associated with short-term mortality, are regimen dependent. Our findings suggest these factors should be considered in selecting the preparative regimen. While requiring validation, the newly-defined composite endpoint of acute severe organ toxicity (ASOT) may be valuable in studying transplantation strategies.

中文翻译：

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同种异体移植后急性重度器官毒性的条件养护模式和决定因素

背景

在同种异体造血干细胞移植（HSCT）的接受者中，器官毒性是进行高强度调节的障碍。我们假设急性器官毒性的决定因素是个别方案所特有的。我们试图表征这些毒性，评估其预后意义，并在治疗水平上得出严重毒性的预测指标。

方法

这项回顾性研究包括在2001年至2014年间在单个中心进行首次异基因HSCT的成年人。患者从相匹配的同胞或无关亲戚的供体那里接受了移植，并接受了以下任何一种治疗方案：Cy / TBI，Bu / Cy，Flu / Bu 12.8 mg，Flu / Bu 6.4毫克，Flu / Treosulfanan 36-42 gr / m ²，Flu / Mel 100-140 mg / m ²。研究的毒性包括根据KDIGO定义的急性肾损伤（AKI），以及根据CTCAE分级增加的总胆红素，AST，ALT和碱性磷酸酶（Alk Phos）。记录了HSCT后至30天从调节产生的毒性发生率。在每个方案中，使用多变量logistic回归评估严重器官毒性的危险因素。

结果

在707名患者中，主要适应症为急性白血病（57％），骨髓增生异常综合症（13％）和侵袭性淋巴瘤（9％）。GvHD预防措施包括80％的患者接受甲氨蝶呤，而56％的患者接受ATG。每种方案中AKI的发生率和血清胆红素升高分别如图1A / B所示。鼻窦阻塞综合征（占总体的6％）仅占gr的17％。整个队列中≥3胆红素血症。gr≥3的AST，ALT和Alk Phos升高并不常见（<8％）。AKI gr≥2，胆红素gr≥3增加，AST gr≥3和Alk Phos gr≥2与100天死亡率增加相关（p <0.05）。急性重度器官毒性（ASOT）定义为任何这些毒性的发生。对于100天死亡率，ASOT的优势比（OR）为3.4（95％CI：2.2-5.3）。在每个方案中 我们研究了ASOT与移植/患者特征之间的关系（图1C）。基线胆红素升高可预测Cy / TBI中的ASOT（OR：1.7 [1.2-2.4]），而肌酐增加则可预测患有Flu / Mel的患者（OR：1.4 [1.1-1.9]）。在接受Bu / Cy治疗的患者中，ATG的使用增加了ASOT的风险（1.3 [1.1-1.6]）。

结论

同种异体移植受者有急性器官损伤的高风险。我们描述了几种治疗方案中肾脏和肝脏毒性的模式。急性严重器官毒性的决定因素（与短期死亡率相关的决定因素）取决于治疗方案。我们的研究结果表明，在选择制备方案时应考虑这些因素。在需要验证的同时，新定义的急性重度器官毒性（ASOT）复合终点在研究移植策略中可能很有价值。