同种异体干细胞移植（allo-SCT）是治疗急性髓系白血病（AML）的主要方法。其成功很大程度上取决于供体 T 淋巴细胞对白血病细胞的反应，即移植物抗白血病 (GvL) 效应。 GvL 的一个关键潜在驱动因素是对突变衍生的新抗原的免疫反应。先前针对实体瘤的研究已证明移码 (FS) 衍生肽与非同义单核苷酸变体 (SNV) 衍生的肽相比具有增强的免疫原性。因此，我们假设白血病相关基因中携带 FS 突变的 AML 病例比仅携带其他类型突变（非 FS）的 AML 病例更具免疫原性，因此通过更强大的 GvL 从异基因 SCT 中获益更多。在 2010 年至 2022 年间接受了异基因 SCT，并使用 42 基因热点面板获得了诊断样本的下一代测序数据。我们根据 FS 与非 FS 状态比较了诊断时存在的肿瘤突变对总生存期和无复发生存期的影响。确定了 95 名 AML 同种异体 SCT 患者。我们观察到至少有一种 FS 突变的新发 AML 患者移植后具有较高的无复发生存率（P = 0.038，风险比 (HR)：0.24）和临界总体生存率较高（P = 0.058，HR：0.55） （NPM1 除外）与仅具有非 FS 突变的 42 个评估基因之一相比。我们的研究结果表明，与仅具有非 FS 突变的患者相比，FS 突变的 AML 病例可能从异体 SCT 中获益更多，这可能是由于免疫原性新表位的产生。如果在一项扩展研究中得到验证，将体细胞 FS 突变状态纳入 AML 可以改善骨髓移植的患者选择算法，从而获得更好的结果。版权所有 2024，Cammann 等人。

Allogeneic stem cell transplant (allo-SCT) is a mainstay of treatment for acute myeloid leukemia (AML). Its success depends largely on response of donor T lymphocytes against leukemia cells, known as graft-vs-leukemia (GvL) effect. A key potential driver of GvL is immune response to mutation-derived neoantigens. Previous studies in solid tumors have demonstrated enhanced immunogenicity of frameshift (FS)-derived peptides vs. those from non-synonymous single nucleotide variants (SNVs). We therefore hypothesized that AML cases bearing FS mutations in leukemia-associated genes would be more immunogenic than those with only other types of mutations (non-FS), and thus benefit more from allo-SCT via more robust GvL.We identified AML patients who had undergone allo-SCT between 2010 and 2022 and had next-generation sequencing data available on diagnostic specimens using a 42-gene hot spot panel. We compared the impact of tumor mutations present at diagnosis on overall survival and relapse-free survival based on FS versus non-FS status.Ninety-five AML allo-SCT patients were identified. We observed superior relapse-free survival (P = 0.038, hazard ratio (HR): 0.24) and borderline superior overall survival (P = 0.058, HR: 0.55) post-transplant in de novo AML patients, who had at least one FS mutation (other than NPM1) in one of the 42 assessed genes versus those with only non-FS mutations.Our findings suggest that FS-mutated AML cases may benefit more from allo-SCT than those with only non-FS mutations, possibly due to increased generation of immunogenic neoepitopes. If validated in an expanded study, incorporation of somatic FS mutation status in AML could improve patient selection algorithms for bone marrow transplant and thereby lead to superior outcomes.Copyright 2024, Cammann et al.