{"id":"ef1f7b32-88ea-5a9c-b94e-93ce394c6257","stable_key":"a2968a2f-5b00-5212-8b8c-8a4262bcb149:ascorbate-no-response-in-ccus-trial","predicate":"did_not_change","statement":"In a phase 2 trial of high-dose intravenous ascorbic acid in TET2-mutant clonal cytopenia of undetermined significance, none of the eight patients evaluable for response met International Working Group Myelodysplasia Syndromes/Neoplasms criteria at week 20.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"neutral","is_public":true,"mechanism_event_id":"5405418f-4dc1-51cc-9e2f-8675d78e1fb6","mechanism_event_label":"In a phase 2 trial of high-dose intravenous ascorbic acid in TET2-mutant clonal cytopenia of undetermined significance, none of the eight patients evaluable for response met International Working Group Myelodysplasia Syndromes/Neoplasms criteria at week 20.","subject":{"id":"38d0c4d9-53d1-5239-bfe3-c1b5e9b79085","slug":"ascorbate","display_name":"L-Ascorbate","entity_type_key":"small_molecule"},"object":{"id":"5a931020-e53b-5046-8c1d-abef773f33b2","slug":"human-ccus-haematologic-response","display_name":"Haematologic response in TET2-mutant clonal cytopenia of undetermined significance","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"5405418f-4dc1-51cc-9e2f-8675d78e1fb6","stable_key":"a2968a2f-5b00-5212-8b8c-8a4262bcb149:ascorbate-no-response-in-ccus-trial-event","event_type":"observed_relationship","label":"In a phase 2 trial of high-dose intravenous ascorbic acid in TET2-mutant clonal cytopenia of undetermined significance, none of the eight patients evaluable for response met International Working Group Myelodysplasia Syndromes/Neoplasms criteria at week 20.","description":"In the one published trial of this idea in patients, nobody responded.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"38d0c4d9-53d1-5239-bfe3-c1b5e9b79085","slug":"ascorbate","display_name":"L-Ascorbate","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"5a931020-e53b-5046-8c1d-abef773f33b2","slug":"human-ccus-haematologic-response","display_name":"Haematologic response in TET2-mutant clonal cytopenia of undetermined significance","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"duration","value_text":"Response assessed at week 20","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Phase 2 single-arm trial, 10 enrolled and 8 evaluable; NCT03418038","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"High-dose intravenous ascorbic acid","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Eight evaluable patients and a 20-week assessment. A null in clonal cytopenia does not test prevention over years, nor treatment of established leukaemia, and the trial did not report whether TET2 activity or 5hmC changed.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"organism","value_text":"Homo sapiens","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"In the one published trial of this idea in patients, nobody responded.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[guarnera-2024] High-dose IV ascorbic acid therapy for patients with CCUS with TET2 mutations (2024). https://pubmed.ncbi.nlm.nih.gov/39352751/ DOI: 10.1182/blood.2024024962","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue","value_text":"Blood and bone marrow","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null}],"evidence":[{"id":"f8cbce9f-7f67-5835-94b2-b4ce9b62ebad","evidence_kind":"source_excerpt","locator":"Lines 203-211","start_line":203,"end_line":211,"excerpt":"## ascorbate-no-response-in-ccus-trial\nIn a phase 2 trial of high-dose intravenous ascorbic acid in TET2-mutant clonal cytopenia of undetermined significance, none of the eight patients evaluable for response met International Working Group Myelodysplasia Syndromes/Neoplasms criteria at week 20.\nModel/species: Phase 2 single-arm trial, 10 enrolled and 8 evaluable; NCT03418038\nOrganism: Homo sapiens\nTissue/system: Blood and bone marrow\nExposure: High-dose intravenous ascorbic acid\nDuration: Response assessed at week 20\nLimits: Eight evaluable patients and a 20-week assessment. A null in clonal cytopenia does not test prevention over years, nor treatment of established leukaemia, and the trial did not report whether TET2 activity or 5hmC changed.\nPrimary reference: [guarnera-2024] High-dose IV ascorbic acid therapy for patients with CCUS with TET2 mutations (2024). https://pubmed.ncbi.nlm.nih.gov/39352751/ DOI: 10.1182/blood.2024024962","model_system":"Phase 2 single-arm trial, 10 enrolled and 8 evaluable; NCT03418038","directness":"reported_statement","verification_status":"source_derived_draft","notes":"","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"c0b9b176-985b-55c7-b8f5-f3ca16a7ddfe","stable_key":"import-a2968a2f-5b00-5212-8b8c-8a4262bcb149","title":"TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23)","document_type":"imported_text","citation_label":"Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text.","file_path":"","sha256":"22e2c8388d4f0c1813546ba6a9ccee3fa14c0c8f578bd9bd80103c1390b2536b","revision_id":"fbc29d8d-0420-562c-bfdb-1b5af42f2d08","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"dd434963-3ac9-5b7b-993b-9eb20345cd56","title":"Vitamin C suppresses leukaemia in animals and cells, but the published patient trial found no response","kind":"context_difference","status":"open","why":"Preclinical work restores TET2 function with vitamin C and slows leukaemia in mice and xenografts. The one registered phase 2 trial in TET2-mutant clonal cytopenia found no haematologic responses at week 20. The studies differ in species, disease stage, endpoint and duration, so this is recorded as a difference in what was tested rather than as a refutation of the mechanism. It is kept visible because the mechanistic records alone would otherwise read as clinical support.","resolution":"Unresolved; needs review. A trial measuring TET2 activity or 5hmC alongside a clinical endpoint, in a population selected for adequate transporter expression and a responsive mutation, would separate the explanations.","created_at":"2026-09-23 21:18:02","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/dd434963-3ac9-5b7b-993b-9eb20345cd56","sides":[{"conflict_id":"dd434963-3ac9-5b7b-993b-9eb20345cd56","ordinal":0,"label":"Vitamin C suppressed leukaemia progression in human AML xenografts","revision_id":"fbc29d8d-0420-562c-bfdb-1b5af42f2d08","start_line":113,"end_line":121,"quote":"## ascorbate-suppresses-aml-colony-formation\nVitamin C treatment suppressed leukaemic colony formation by human leukaemia cells and slowed leukaemia progression in primary human acute-myeloid-leukaemia patient-derived xenografts.\nModel/species: Human leukaemia cell lines and primary human AML patient-derived xenografts\nOrganism: Homo sapiens cells in mouse xenograft hosts\nTissue/system: Leukaemic blasts\nExposure: Pharmacological vitamin C\nDuration: Colony assays and xenograft progression\nLimits: Pharmacological vitamin C in a xenograft is not dietary intake, and a xenograft host lacks an intact immune system.\nPrimary reference: [cimmino-2017] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression (2017). https://pubmed.ncbi.nlm.nih.gov/28823558/ DOI: 10.1016/j.cell.2017.07.032","source_key":"import-a2968a2f-5b00-5212-8b8c-8a4262bcb149","source_title":"TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23)","claim_ids":["10bd5cbc-d7ac-5e5b-9468-a631ad978b20"]},{"conflict_id":"dd434963-3ac9-5b7b-993b-9eb20345cd56","ordinal":1,"label":"No patient met response criteria in the phase 2 clonal cytopenia trial","revision_id":"fbc29d8d-0420-562c-bfdb-1b5af42f2d08","start_line":203,"end_line":211,"quote":"## ascorbate-no-response-in-ccus-trial\nIn a phase 2 trial of high-dose intravenous ascorbic acid in TET2-mutant clonal cytopenia of undetermined significance, none of the eight patients evaluable for response met International Working Group Myelodysplasia Syndromes/Neoplasms criteria at week 20.\nModel/species: Phase 2 single-arm trial, 10 enrolled and 8 evaluable; NCT03418038\nOrganism: Homo sapiens\nTissue/system: Blood and bone marrow\nExposure: High-dose intravenous ascorbic acid\nDuration: Response assessed at week 20\nLimits: Eight evaluable patients and a 20-week assessment. A null in clonal cytopenia does not test prevention over years, nor treatment of established leukaemia, and the trial did not report whether TET2 activity or 5hmC changed.\nPrimary reference: [guarnera-2024] High-dose IV ascorbic acid therapy for patients with CCUS with TET2 mutations (2024). https://pubmed.ncbi.nlm.nih.gov/39352751/ DOI: 10.1182/blood.2024024962","source_key":"import-a2968a2f-5b00-5212-8b8c-8a4262bcb149","source_title":"TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23)","claim_ids":["ef1f7b32-88ea-5a9c-b94e-93ce394c6257"]}]}],"corrections":[],"research":null}