The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
Hematology, Oncology and Transplant, University of Minnesota, Minneapolis, MN.
Blood Adv. 2024 Jun 25;8(12):3284-3292. doi: 10.1182/bloodadvances.2023011049.
Graft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [REG3α]) when measured at GVHD diagnosis are validated predictors of NRM risk but have never been assessed in the same patients using identical statistical methods. We measured the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n = 374). All algorithms were strong discriminators of 12-month NRM, whether or not patients were systemically treated (n = 321). An algorithm containing only ST2 + REG3α had the highest area under the receiver operating characteristics curve (0.757), correctly classified the most patients (75%), and more accurately risk-stratified those who developed Minnesota standard-risk GVHD and for patients who received posttransplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk-stratified patients with Minnesota high-risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance.
移植物抗宿主病（GVHD）是异基因造血细胞移植后非复发死亡率（NRM）的主要原因。在GVHD 诊断时测量的包含胃肠道（GI）GVHD 生物标志物 Amphiregulin（AREG）或 2 种 GI GVHD 生物标志物（肿瘤抑制因子 2 [ST2] + 再生家族成员 3 alpha [REG3α]）的算法是 NRM 风险的验证预测因子，但从未使用相同的统计方法在相同的患者中进行评估。我们通过酶联免疫吸附试验测量了 715 名患者在 GVHD 诊断时的血清 ST2、REG3α 和 AREG 浓度，根据移植日期将患者分为训练（2004-2015 年）和验证（2015-2017 年）队列。使用训练队列（n=341）开发了预测 12 个月 NRM 概率的算法，这些算法包含 1 至 3 种生物标志物的所有可能组合，以及与一致性概率相对应的阈值，用于分层患者的 NRM 风险。使用仅验证队列（n=374），根据多个指标比较了算法之间的差异，包括接收者操作特征曲线下的面积、正确分类患者的比例、敏感性和特异性。所有算法均能很好地区分 12 个月 NRM，无论患者是否接受系统性治疗（n=321）。仅包含 ST2+REG3α 的算法具有最高的接收者操作特征曲线下面积（0.757），正确分类了最多的患者（75%），并且更准确地分层了发生明尼苏达州标准风险 GVHD 的患者和接受移植后环磷酰胺为基础的预防治疗的患者。仅包含 AREG 的算法更准确地分层了发生明尼苏达州高危 GVHD 的患者。将 ST2、REG3α 和 AREG 组合成单个算法并不能提高性能。
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