Cammann Emma, Madhav Sindha, Hutchinson Lloyd, Cerny Jan, Ramanathan Muthalagu, Bledsoe Jacob R, Makarenko Vladislav, Patel Shyam A, Meng Xiuling, Tomaszewicz Keith, Nath Rajneesh, Chen Benjamin, Woda Bruce, Selove William
UMass Medical School, Worcester, MA, USA.
Department of Pathology, UMass Memorial Medical Center, University of Massachusetts, Worcester, MA, USA.
J Hematol. 2024 Jun;13(3):86-93. doi: 10.14740/jh1276. Epub 2024 Jun 28.
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 AML patients, who had at least one FS mutation (other than ) 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.
异基因干细胞移植（allo-SCT）是急性髓系白血病（AML）治疗的主要手段。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新抗原的免疫反应。先前在实体瘤中的研究表明，移码（FS）衍生肽比非同义单核苷酸变异（SNV）衍生肽具有更强的免疫原性。因此，我们假设白血病相关基因中携带FS突变的AML病例比仅具有其他类型突变（非FS）的病例具有更强的免疫原性，从而通过更强大的GvL效应从allo-SCT中获益更多。
我们确定了2010年至2022年间接受allo-SCT且诊断标本有使用42基因热点 panel进行的下一代测序数据的AML患者。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和无复发生存的影响。
确定了95例AML allo-SCT患者。我们观察到，在42个评估基因中至少有一个（除外）携带FS突变的AML患者移植后无复发生存期更佳（P = 0.038，风险比（HR）：0.24），总生存期有边缘性优势（P = 0.058，HR：0.55），而仅具有非FS突变的患者则不然。
我们的研究结果表明，FS突变的AML病例可能比仅具有非FS突变的病例从allo-SCT中获益更多，这可能是由于免疫原性新表位的产生增加。如果在一项扩大的研究中得到验证，将体细胞FS突变状态纳入AML中可以改善骨髓移植的患者选择算法，从而带来更好的结果。
