{"doi":"10.1038/s41408-024-01077-9","title":"Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>\n                    Current therapies for high-grade\n                    <jats:italic>TP53</jats:italic>\n                    -mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with\n                    <jats:italic>TP53</jats:italic>\n                    -mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 &amp; 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (\n                    <jats:italic>P</jats:italic>\n                     = 0.026), ≥2 autosomal monosomies (\n                    <jats:italic>P</jats:italic>\n                     &lt; 0.001), −17/17p (\n                    <jats:italic>P</jats:italic>\n                     = 0.011), multi-hit\n                    <jats:italic>TP53</jats:italic>\n                    allelic state (\n                    <jats:italic>P</jats:italic>\n                     &lt; 0.001) and\n                    <jats:italic>CUX1</jats:italic>\n                    co-alterations (\n                    <jats:italic>P</jats:italic>\n                     = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (\n                    <jats:italic>P</jats:italic>\n                     = 0.004),\n                    <jats:italic>TP53</jats:italic>\n                    VAF &gt; 25% (\n                    <jats:italic>P</jats:italic>\n                     = 0.002),\n                    <jats:italic>TP53</jats:italic>\n                    splice junction mutations (\n                    <jats:italic>P</jats:italic>\n                     = 0.007) and antecedent treated myeloid neoplasm (\n                    <jats:italic>P</jats:italic>\n                     = 0.001). In addition, mutations/deletions in\n                    <jats:italic>CUX1</jats:italic>\n                    ,\n                    <jats:italic>U2AF1</jats:italic>\n                    ,\n                    <jats:italic>EZH2</jats:italic>\n                    ,\n                    <jats:italic>TET2</jats:italic>\n                    ,\n                    <jats:italic>CBL</jats:italic>\n                    , or\n                    <jats:italic>KRAS</jats:italic>\n                    (‘\n                    <jats:italic>EPI6</jats:italic>\n                    ’ signature) predicted inferior OS24 (HR = 2.0 [1.5–2.8];\n                    <jats:italic>P</jats:italic>\n                     &lt; 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (\n                    <jats:italic>N</jats:italic>\n                     = 144),\n                    <jats:italic>TP53</jats:italic>\n                    VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including\n                    <jats:italic>TP53</jats:italic>\n                    splice junction mutations,\n                    <jats:italic>EPI6</jats:italic>\n                    and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (\n                    <jats:italic>P</jats:italic>\n                     &lt; 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.\n                  </jats:p>","journal":"Blood Cancer Journal","year":2024,"id":608950,"datarank":0.48584321315413326,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.052287449469708515,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.052287449469708515,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":10,"citers_with_citation_signal":4,"citers_with_endowment":4,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":638758,"name":"Alexandra E. Rojek","orcid":"0000-0003-1615-1447","position":1,"is_corresponding":false},{"id":1141516,"name":"Emily Symes","orcid":"0000-0002-5795-7183","position":2,"is_corresponding":false},{"id":397589,"name":"Mariam T. Nawas","orcid":"0000-0001-5161-0878","position":3,"is_corresponding":false},{"id":1564673,"name":"Anand A. Patel","orcid":null,"position":4,"is_corresponding":false},{"id":1564674,"name":"Jay L. Patel","orcid":null,"position":5,"is_corresponding":false},{"id":981413,"name":"Payal Sojitra","orcid":"0000-0001-7936-4058","position":6,"is_corresponding":false},{"id":1564675,"name":"Barina Aqil","orcid":null,"position":7,"is_corresponding":false},{"id":570997,"name":"Madina Sukhanova","orcid":"0000-0002-1843-7038","position":8,"is_corresponding":false},{"id":340436,"name":"Megan E. McNerney","orcid":"0000-0002-8260-3598","position":9,"is_corresponding":false},{"id":1564676,"name":"Leo P. Wu","orcid":null,"position":10,"is_corresponding":false},{"id":1564677,"name":"Aibek Akmatbekov","orcid":null,"position":11,"is_corresponding":false},{"id":555123,"name":"Jeremy Segal","orcid":null,"position":12,"is_corresponding":false},{"id":1011708,"name":"Melissa Y. Tjota","orcid":"0000-0002-5869-3175","position":13,"is_corresponding":false},{"id":679943,"name":"Sandeep Gurbuxani","orcid":"0000-0003-0716-8730","position":14,"is_corresponding":false},{"id":340435,"name":"Jason X. Cheng","orcid":"0000-0002-4626-770X","position":15,"is_corresponding":false},{"id":1485506,"name":"Su Yeon Yeon","orcid":"0000-0003-2600-4133","position":16,"is_corresponding":false},{"id":1564678,"name":"Harini V. Ravisankar","orcid":null,"position":17,"is_corresponding":false},{"id":1041713,"name":"Carrie Fitzpatrick","orcid":"0000-0002-6237-9293","position":18,"is_corresponding":false},{"id":1564679,"name":"Angela Lager","orcid":null,"position":19,"is_corresponding":false},{"id":660472,"name":"Michael W. Drazer","orcid":"0000-0002-8171-4106","position":20,"is_corresponding":false},{"id":1182404,"name":"Caner Saygin","orcid":"0000-0003-1315-0377","position":21,"is_corresponding":false},{"id":1041711,"name":"Pankhuri Wanjari","orcid":"0000-0001-6228-8431","position":22,"is_corresponding":false},{"id":317861,"name":"Panagiotis Katsonis","orcid":"0000-0002-7172-1644","position":23,"is_corresponding":false},{"id":317863,"name":"Olivier Lichtarge","orcid":"0000-0003-4057-7122","position":24,"is_corresponding":false},{"id":561561,"name":"Jane E. Churpek","orcid":"0000-0001-7998-5479","position":25,"is_corresponding":false},{"id":1564680,"name":"Sharmila B. Ghosh","orcid":null,"position":26,"is_corresponding":false},{"id":724042,"name":"Ami B. Patel","orcid":"0000-0002-0626-4248","position":27,"is_corresponding":false},{"id":1564681,"name":"Madhu P. Menon","orcid":null,"position":28,"is_corresponding":false},{"id":1041715,"name":"Daniel A. Arber","orcid":"0000-0002-2160-9689","position":29,"is_corresponding":false},{"id":1272069,"name":"Peng Wang","orcid":"0000-0002-5699-3676","position":30,"is_corresponding":false},{"id":446856,"name":"Girish Venkataraman","orcid":"0000-0002-8674-2608","position":31,"is_corresponding":false},{"id":1083999,"name":"Amandeep Kaur","orcid":"0000-0002-8761-6806","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>\n                    Current therapies for high-grade\n                    <jats:italic>TP53</jats:italic>\n                    -mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with\n                    <jats:italic>TP53</jats:italic>\n                    -mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 &amp; 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (\n                    <jats:italic>P</jats:italic>\n                     = 0.026), ≥2 autosomal monosomies (\n                    <jats:italic>P</jats:italic>\n                     &lt; 0.001), −17/17p (\n                    <jats:italic>P</jats:italic>\n                     = 0.011), multi-hit\n                    <jats:italic>TP53</jats:italic>\n                    allelic state (\n                    <jats:italic>P</jats:italic>\n                     &lt; 0.001) and\n                    <jats:italic>CUX1</jats:italic>\n                    co-alterations (\n                    <jats:italic>P</jats:italic>\n                     = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (\n                    <jats:italic>P</jats:italic>\n                     = 0.004),\n                    <jats:italic>TP53</jats:italic>\n                    VAF &gt; 25% (\n                    <jats:italic>P</jats:italic>\n                     = 0.002),\n                    <jats:italic>TP53</jats:italic>\n                    splice junction mutations (\n                    <jats:italic>P</jats:italic>\n                     = 0.007) and antecedent treated myeloid neoplasm (\n                    <jats:italic>P</jats:italic>\n                     = 0.001). In addition, mutations/deletions in\n                    <jats:italic>CUX1</jats:italic>\n                    ,\n                    <jats:italic>U2AF1</jats:italic>\n                    ,\n                    <jats:italic>EZH2</jats:italic>\n                    ,\n                    <jats:italic>TET2</jats:italic>\n                    ,\n                    <jats:italic>CBL</jats:italic>\n                    , or\n                    <jats:italic>KRAS</jats:italic>\n                    (‘\n                    <jats:italic>EPI6</jats:italic>\n                    ’ signature) predicted inferior OS24 (HR = 2.0 [1.5–2.8];\n                    <jats:italic>P</jats:italic>\n                     &lt; 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (\n                    <jats:italic>N</jats:italic>\n                     = 144),\n                    <jats:italic>TP53</jats:italic>\n                    VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including\n                    <jats:italic>TP53</jats:italic>\n                    splice junction mutations,\n                    <jats:italic>EPI6</jats:italic>\n                    and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (\n                    <jats:italic>P</jats:italic>\n                     &lt; 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.\n                  </jats:p>","is_dataset_classified":null,"base_score":2.833213344056216,"endowment":2.833213344056216,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38890297","pmcid":"PMC11189545","openalex_id":"https://openalex.org/W4399783590","authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"T32 CA009566","title":null}],"total_grants":1,"fwci":4.8053,"citation_percentile":0.95735648,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":10},{"year":2026,"count":5}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.nature.com/articles/s41408-024-01077-9.pdf","host_type":"journal"},{"url":"https://www.nature.com/articles/s41408-024-01077-9.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/s41408-024-01077-9","host_type":"publisher"},{"url":"https://doi.org/10.1038/s41408-024-01077-9","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38890297","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11189545","host_type":"repository"},{"url":"https://digitalcommons.library.tmc.edu/baylor_docs/2221","host_type":"repository"},{"url":"https://doaj.org/article/c0e050742d8c498c9f4fc3640be68aa0","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11189545/pdf/41408_2024_Article_1077.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11189545","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11189545?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Acute Myeloid Leukemia Research","Epigenetics and DNA Methylation","Lymphoma Diagnosis and Treatment","Humans","Male","Female","Aged","Tumor Suppressor Protein p53","Mutation","Middle Aged","Aged, 80 and over","Adult","Prognosis","Treatment Outcome"],"mesh_terms":["Adult","Aged","Aged, 80 and over","Female","Humans","Male","Middle Aged","Mutation","Prognosis","Tumor Suppressor Protein p53","Treatment Outcome"],"keywords":["Medicine","KRAS","Cohort","Internal medicine","Myeloid","Oncology","Venetoclax","Cytarabine","Transplantation","Myeloid leukemia","Gastroenterology","Leukemia","Cancer","Chronic lymphocytic leukemia","Colorectal cancer"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-31T01:01:20.062460Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}