建议对严重再生障碍性贫血（SAA）患者进行种系基因检测来指导治疗，包括使用免疫抑制治疗和/或调整造血细胞移植（HCT）方式。噬血细胞性淋巴组织细胞增多症 (HLH) 是一种危及生命的高炎症性疾病，通常与常染色体隐性 (AR) 或 X 连锁隐性 (XLR) 遗传的血细胞减少症相关。 HLH 是 SAA 鉴别诊断的一部分，基因检测可以识别 SAA 患者的 HLH 基因变异。 HLH 基因中致病性/可能致病性 (P/LP) 变异对 SAA 中 HCT 结局的影响尚不清楚。我们的目的是确定大量获得性 SAA 患者中 HLH 基因变异的频率，并评估其关联性。再生障碍性贫血移植结果项目是美国国家癌症研究所和国际血液和骨髓移植研究中心之间的合作项目，包含 1989 年至 2015 年间因 SAA 接受 HCT 的 824 名患者的基因组和临床数据。我们排除了 140 名患有遗传性骨髓衰竭综合征的患者，并使用其余 684 名获得性 SAA 患者的外显子组测序数据来识别使用 ACMG/AMP 标准筛选的 14 个 HLH 相关基因（11 个 AR、3 个 XLR）中的 P/LP 变异。意义不确定的有害变异 (del-VUS) 被定义为不符合 ACMG/AMP P/LP 标准但在 ≥3/5 元预测变量（BayesDel、REVEL、CADD、MetaSVM 和/或 EIGEN）中具有破坏性预测的变异。 Kaplan-Meier 估计器用于计算 HCT 后总生存 (OS) 的概率，累积发生率计算器用于考虑相关竞争风险的其他 HCT 结果。49 名患者中有 46 种 HLH 变异（7.2%；N 总数= 684）。 19 名患者 (2.8%) 中的 17 种变异为 P/LP；其中 8 个是功能丧失变异。在 19 名 P/LP HLH 变异患者中，16 名 (84%) 存在 AR 遗传基因单等位基因变异，3 名存在 XLR 基因变异。 PRF1 是最常受影响的基因（8/19 名患者）。我们发现有和没有 P/LP HLH 变异的患者之间移植相关因素没有统计学上的显着差异。与对照组相比，P/LP 和 del-VUS HLH 变异患者的 5 年生存率分别为 89% (95% CI=72-99) 和 70% (95% CI=53-85%)。没有变异的患者中为 66% (95% CI=62-70) (p-log-rank=0.16)。具有 P/LP HLH 变异的患者中性粒细胞植入的中位时间为 16 天，而具有 del-VUS 或无变异的患者则为 18 天（p-Gray 检验 = 0.01）。 P/LP HLH 变异与急性或慢性移植物抗宿主病风险之间没有统计学上显着的关联。在这一大型获得性 SAA 队列中，我们发现 2.8% 的患者在 HLH 中携带 P/LP 变异基因。 HLH 基因变异对 HCT 后的生存没有负面影响。患有 P/LP HLH 变异的患者数量较少限制了研究提供确凿证据的能力。然而，我们的数据表明，携带 P/LP 变异的 SAA 患者不需要特殊的移植考虑。版权所有 © 2024。由 Elsevier Inc. 出版。

Germline genetic testing for patients with severe aplastic anemia (SAA) is recommended to guide treatment, including the use of immunosuppressive therapy and/or adjustment of hematopoietic cell transplantation (HCT) modalities. Hemophagocytic lymphohistiocytosis (HLH) is a life threatening hyperinflammatory condition often associated with cytopenias with autosomal recessive (AR) or X-linked recessive (XLR) inheritance. HLH is part of the SAA differential diagnosis and genetic testing may identify variants in HLH genes in patients with SAA. The impact of pathogenic/likely pathogenic (P/LP) variants in HLH genes on HCT outcomes in SAA is unclear.We aimed to determine the frequency of HLH gene variants in a large cohort of patients with acquired SAA and to evaluate their association(s) with HCT outcomes.The Transplant Outcomes in Aplastic Anemia project, a collaboration between the National Cancer Institute and the Center for International Blood and Marrow Transplant Research, consists of genomic and clinical data from 824 patients who underwent HCT for SAA between 1989 and 2015. We excluded 140 patients with inherited bone marrow failure syndromes and used exome sequencing data from the remaining 684 patients with acquired SAA to identify P/LP variants in 14 HLH-associated genes (11 AR, 3 XLR) curated using ACMG/AMP criteria. Deleterious variants of uncertain significance (del-VUS) were defined as those not meeting ACMG/AMP P/LP criteria but with damaging predictions in ≥3/5 meta-predictors (BayesDel, REVEL, CADD, MetaSVM and/or EIGEN). Kaplan-Meier estimator was used to calculate the probability of overall survival (OS) after HCT, and cumulative incidence calculator was used for other HCT outcomes accounting for relevant competing risks.There were 46 HLH variants in 49 patients (7.2%; N total=684). Seventeen variants in 19 patients (2.8%) were P/LP; 8 of these were loss of function variants. Among 19 patients with P/LP HLH variants, 16 (84%) had monoallelic variants in genes with AR inheritance, and three had variants in XLR genes. PRF1 was the most frequently affected gene (8/19 patients). We found no statistically significant differences in transplant-related factors between patients with and without P/LP HLH variants. The 5-year survival probabilities were 89% (95% CI=72-99), and 70% (95% CI=53-85%) in patients with P/LP and del-VUS HLH variants, respectively, as compared with 66% (95% CI=62-70) in those without variants (p-log-rank=0.16). The median time to neutrophil engraftment was 16 days for patients with P/LP HLH variants versus 18 days in those with del-VUS or without variants, combined (p-Gray's test=0.01). No statistically significant associations between P/LP HLH variants and the risk of acute or chronic graft-versus-host disease were noted.In this large cohort of acquired SAA, we found that 2.8% of patients harbor a P/LP variant in an HLH gene. No negative effect on post-HCT survival was noted with HLH gene variants. The small number of patients with P/LP HLH variants limit the study ability to provide conclusive evidence. Yet, our data suggest no need for special transplant considerations for patients with SAA carrying P/LP variants.Copyright © 2024. Published by Elsevier Inc.