Emma Cammann, Sindha Madhav, Lloyd Hutchinson, Jan Cerny, Muthalagu Ramanathan, Jacob R Bledsoe, Vladislav Makarenko, Shyam A Patel, Xiuling Meng, Keith Tomaszewicz, Rajneesh Nath, Benjamin Chen, Bruce Woda, William Selove
{"title":"白血病相关基因的帧移位突变与接受异基因干细胞移植治疗新发急性髓性白血病患者的良好疗效相关。","authors":"Emma Cammann, Sindha Madhav, Lloyd Hutchinson, Jan Cerny, Muthalagu Ramanathan, Jacob R Bledsoe, Vladislav Makarenko, Shyam A Patel, Xiuling Meng, Keith Tomaszewicz, Rajneesh Nath, Benjamin Chen, Bruce Woda, William Selove","doi":"10.14740/jh1276","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 <i>de novo</i> AML patients, who had at least one FS mutation (other than <i>NPM1</i>) in one of the 42 assessed genes versus those with only non-FS mutations.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":15964,"journal":{"name":"Journal of hematology","volume":null,"pages":null},"PeriodicalIF":1.3000,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11236359/pdf/","citationCount":"0","resultStr":"{\"title\":\"Frameshift Mutations in Leukemia-Associated Genes Correlate With Superior Outcomes in Patients Undergoing Allogeneic Stem Cell Transplant for <i>De Novo</i> Acute Myeloid Leukemia.\",\"authors\":\"Emma Cammann, Sindha Madhav, Lloyd Hutchinson, Jan Cerny, Muthalagu Ramanathan, Jacob R Bledsoe, Vladislav Makarenko, Shyam A Patel, Xiuling Meng, Keith Tomaszewicz, Rajneesh Nath, Benjamin Chen, Bruce Woda, William Selove\",\"doi\":\"10.14740/jh1276\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 <i>de novo</i> AML patients, who had at least one FS mutation (other than <i>NPM1</i>) in one of the 42 assessed genes versus those with only non-FS mutations.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":15964,\"journal\":{\"name\":\"Journal of hematology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.3000,\"publicationDate\":\"2024-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11236359/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of hematology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.14740/jh1276\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/28 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q4\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of hematology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.14740/jh1276","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/28 0:00:00","PubModel":"Epub","JCR":"Q4","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Frameshift Mutations in Leukemia-Associated Genes Correlate With Superior Outcomes in Patients Undergoing Allogeneic Stem Cell Transplant for De Novo Acute Myeloid Leukemia.
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.