NPM1-mutated acute myeloid leukemia is characterized by mutations in the nucleophosmin 1 gene, occurring in approximately 30% of adult AML cases and representing the most common genetic abnormality in AML. NPM1 mutations cause aberrant cytoplasmic localization of the normally nucleolar protein, disrupting its tumor suppressor functions. In the absence of adverse cytogenetics or FLT3-ITD with high allelic ratio, NPM1-mutated AML is classified as favorable risk with good response to intensive chemotherapy and favorable overall survival. NPM1 mutation status also serves as a sensitive marker for minimal residual disease monitoring.
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name: Acute Myeloid Leukemia, NPM1-Mutated
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-05-02T07:57:06Z'
description: >-
NPM1-mutated acute myeloid leukemia is characterized by mutations in the
nucleophosmin 1 gene, occurring in approximately 30% of adult AML cases and
representing the most common genetic abnormality in AML. NPM1 mutations cause
aberrant cytoplasmic localization of the normally nucleolar protein, disrupting
its tumor suppressor functions. In the absence of adverse cytogenetics or
FLT3-ITD with high allelic ratio, NPM1-mutated AML is classified as favorable
risk with good response to intensive chemotherapy and favorable overall survival.
NPM1 mutation status also serves as a sensitive marker for minimal residual disease
monitoring.
categories:
- Hematologic Malignancy
- Acute Leukemia
- Molecularly Defined Cancer
parents:
- acute myeloid leukemia
pathophysiology:
- name: NPM1 Cytoplasmic Mislocalization
description: >-
NPM1 is a nucleolar phosphoprotein that shuttles between the nucleolus,
nucleoplasm, and cytoplasm. Wild-type NPM1 localizes predominantly to nucleoli
due to a C-terminal nucleolar localization signal. Mutations in exon 12 disrupt
this signal and create a nuclear export signal, causing aberrant cytoplasmic
accumulation (NPMc+). This depletes nucleolar NPM1, disrupting its normal
functions.
evidence:
- reference: PMID:40647396
reference_title: "NPM1-Mutated AML: Deciphering the Molecular and Clinical Puzzle in the Era of Novel Treatment Strategies."
supports: SUPPORT
snippet: "The aberrant localization of the mutated nucleophosmin (NPM1) protein in the cytoplasm is the hallmark of the development of acute myeloid leukemia (AML)"
explanation: This abstract identifies cytoplasmic NPM1 as a hallmark of NPM1-mutated AML, supporting the mislocalization mechanism.
cell_types:
- preferred_term: myeloblast
term:
id: CL:0000835
label: myeloblast
downstream:
- target: ARF-p53 Pathway Disruption
description: Cytoplasmic NPM1 sequesters ARF away from MDM2, destabilizing p53
- target: HOX Gene Dysregulation
description: NPM1 mutation upregulates HOXA and HOXB gene clusters
- name: ARF-p53 Pathway Disruption
description: >-
Wild-type NPM1 stabilizes the ARF tumor suppressor in the nucleolus. Cytoplasmic
NPM1 delocalizes ARF, reducing its ability to inhibit MDM2 and stabilize p53.
This impairs the p53-mediated response to oncogenic stress and DNA damage.
biological_processes:
- preferred_term: apoptotic process
modifier: DECREASED
term:
id: GO:0006915
label: apoptotic process
downstream:
- target: Impaired Tumor Suppression
description: Reduced p53 activity impairs cell cycle arrest and apoptosis
- name: HOX Gene Dysregulation
description: >-
NPM1-mutated AML consistently shows upregulation of HOXA and HOXB cluster genes,
including HOXA9 and MEIS1. These transcription factors promote self-renewal of
leukemic cells and block normal myeloid differentiation. This HOX signature is
a defining feature of NPM1-mutated AML.
cell_types:
- preferred_term: myeloblast
term:
id: CL:0000835
label: myeloblast
biological_processes:
- preferred_term: myeloid cell differentiation
modifier: DECREASED
term:
id: GO:0030099
label: myeloid cell differentiation
downstream:
- target: Differentiation Block
description: HOX/MEIS1 overexpression maintains immature blast phenotype
- name: Impaired Tumor Suppression
description: >-
The combined effects of ARF-p53 pathway disruption and loss of NPM1 nucleolar
functions impair the cell's ability to respond to oncogenic signals with
appropriate growth arrest or apoptosis.
biological_processes:
- preferred_term: cell cycle checkpoint signaling
modifier: DECREASED
term:
id: GO:0000075
label: cell cycle checkpoint signaling
- name: Differentiation Block
description: >-
NPM1-mutated AML blasts show a characteristic partial differentiation with
monocytic features. The HOX gene signature and NPM1 cytoplasmic localization
maintain the cells in a progenitor state while allowing some differentiation
along the myelomonocytic lineage.
cell_types:
- preferred_term: myeloid cell
term:
id: CL:0000763
label: myeloid cell
locations:
- preferred_term: bone marrow
term:
id: UBERON:0002371
label: bone marrow
histopathology:
- name: Myeloblast Predominance
finding_term:
preferred_term: Myeloblasts Present
term:
id: NCIT:C155995
label: Myeloblasts Present
frequency: VERY_FREQUENT
description: Acute myeloid leukemia features increased myeloblasts in blood or marrow.
evidence:
- reference: PMID:23590662
reference_title: "Acute myeloid leukemia: advances in diagnosis and classification."
supports: SUPPORT
snippet: "myeloblasts in the blood or bone marrow."
explanation: Abstract notes myeloblasts in the blood or bone marrow in AML.
phenotypes:
- category: Hematologic
name: Leukocytosis
frequency: FREQUENT
description: >-
Elevated white blood cell count, though less pronounced than in
FLT3-ITD mutated AML.
phenotype_term:
preferred_term: Leukocytosis
term:
id: HP:0001974
label: Increased total leukocyte count
evidence:
- reference: PMID:17076533
reference_title: "Nucleophosmin gene mutations in acute myeloid leukemia."
supports: SUPPORT
evidence_source: OTHER
snippet: "NPM1 gene mutations tend to occur more frequently in women, and also tend to be associated with a higher white blood cell count."
explanation: This review summarizes NPM1-mutated AML clinical features and supports leukocytosis as a characteristic laboratory phenotype.
- category: Hematologic
name: Anemia
frequency: VERY_FREQUENT
description: >-
Normocytic normochromic anemia from bone marrow replacement and
ineffective erythropoiesis.
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
evidence:
- reference: PMID:23901108
reference_title: "Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Rather, AML inhibits production of downstream hematopoietic cells by impeding differentiation at the HSC-progenitor transition."
explanation: The abstract supports impaired production of downstream hematopoietic cells in AML, consistent with anemia in this AML subtype.
- category: Hematologic
name: Thrombocytopenia
frequency: VERY_FREQUENT
description: >-
Low platelet count due to bone marrow infiltration by leukemic blasts.
phenotype_term:
preferred_term: Thrombocytopenia
term:
id: HP:0001873
label: Thrombocytopenia
evidence:
- reference: PMID:23901108
reference_title: "Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Rather, AML inhibits production of downstream hematopoietic cells by impeding differentiation at the HSC-progenitor transition."
explanation: The abstract supports impaired production of downstream hematopoietic cells in AML, consistent with thrombocytopenia.
- category: Constitutional
name: Fatigue
frequency: VERY_FREQUENT
description: >-
Fatigue related to anemia and systemic effects of leukemia.
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
evidence:
- reference: PMID:30131851
reference_title: "Patient-reported fatigue prior to treatment is prognostic of survival in patients with acute myeloid leukemia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fatigue is one of the most commonly reported symptoms of AML."
explanation: This prospective AML symptom study directly supports fatigue as a common clinical phenotype.
- category: Infectious
name: Recurrent Infections
frequency: FREQUENT
description: >-
Increased infection susceptibility from neutropenia and
dysfunctional myeloid cells.
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
evidence:
- reference: PMID:23901108
reference_title: "Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients, predisposing them to life-threatening infections and bleeding."
explanation: AML-associated marrow failure predisposes patients to infections, supporting recurrent infections in this AML subtype.
- category: Hematologic
name: Neutropenia
description: >-
Decreased neutrophil production from AML-associated marrow failure
contributes to infection susceptibility.
phenotype_term:
preferred_term: Neutropenia
term:
id: HP:0001875
label: Decreased total neutrophil count
evidence:
- reference: PMID:23901108
reference_title: "Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Rather, AML inhibits production of downstream hematopoietic cells by impeding differentiation at the HSC-progenitor transition."
explanation: Neutropenia is a cytopenic manifestation of impaired downstream hematopoietic cell production in AML.
- category: Hematologic
name: Abnormal Bleeding
description: >-
Bleeding tendency can occur when AML marrow failure reduces effective
platelet production.
phenotype_term:
preferred_term: Abnormal bleeding
term:
id: HP:0001892
label: Abnormal bleeding
evidence:
- reference: PMID:23901108
reference_title: "Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients, predisposing them to life-threatening infections and bleeding."
explanation: The abstract directly links AML marrow failure to bleeding risk, supporting abnormal bleeding as a phenotype.
biochemical:
- name: NPM1 Mutation Analysis
notes: >-
PCR-based assays or sequencing detect characteristic 4-base pair insertions
in exon 12. Type A mutation (TCTG duplication) accounts for 75-80% of cases.
NPM1 mutation is a sensitive MRD marker due to its stability during disease.
- name: Immunohistochemistry for Cytoplasmic NPM1
notes: >-
Antibodies detecting cytoplasmic NPM1 (NPMc+) can identify NPM1-mutated
AML on bone marrow biopsy. Nuclear-restricted staining excludes NPM1 mutation.
genetic:
- name: NPM1
association: Somatic Driver Mutation
notes: >-
NPM1 mutations are 4-base pair insertions in exon 12, most commonly type A
(TCTG duplication). Mutations disrupt the C-terminal nucleolar localization
signal and create a nuclear export signal. NPM1 mutation is mutually
exclusive with recurrent balanced translocations. When isolated (without
FLT3-ITD high ratio), confers favorable prognosis.
treatments:
- name: Intensive Chemotherapy (7+3)
description: >-
Standard induction with 7 days cytarabine and 3 days anthracycline achieves
high complete remission rates in NPM1-mutated AML. Consolidation with
high-dose cytarabine is particularly effective for this subtype.
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000647
label: chemotherapy
- name: Venetoclax plus Azacitidine
description: >-
For older or unfit patients, the combination of BCL2 inhibitor venetoclax
with hypomethylating agent azacitidine achieves high response rates in
NPM1-mutated AML, particularly in the absence of adverse features.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: venetoclax
term:
id: CHEBI:133021
label: venetoclax
- name: Allogeneic Stem Cell Transplantation
description: >-
Generally reserved for patients with NPM1 mutation plus FLT3-ITD or other
adverse features in first remission, or for patients who relapse. May not
be necessary for favorable-risk NPM1-mutated AML in first remission.
treatment_term:
preferred_term: hematopoietic stem cell transplantation
term:
id: MAXO:0000747
label: hematopoietic stem cell transplantation
- name: MRD-Guided Therapy
description: >-
NPM1 mutation transcript levels by RT-PCR provide sensitive minimal residual
disease monitoring. Rising MRD levels can guide preemptive treatment before
overt relapse.
treatment_term:
preferred_term: genetic testing
term:
id: MAXO:0000127
label: genetic testing
disease_term:
preferred_term: NPM1-mutated acute myeloid leukemia
term:
id: MONDO:0044923
label: acute myeloid leukemia with mutated NPM1
classifications:
icdo_morphology:
classification_value: Leukemia
harrisons_chapter:
- classification_value: cancer
- classification_value: hematologic malignancy
references:
- reference: DOI:10.1002/ajh.26822
title: 'Acute myeloid leukemia: 2023 update on diagnosis, risk‐stratification, and management'
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: Disease overviewAcute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell cancer characterized by unbridled proliferation of malignant marrow stem cells with associated infection, anemia, and bleeding.
supporting_text: Disease overviewAcute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell cancer characterized by unbridled proliferation of malignant marrow stem cells with associated infection, anemia, and bleeding.
evidence:
- reference: DOI:10.1002/ajh.26822
reference_title: 'Acute myeloid leukemia: 2023 update on diagnosis, risk‐stratification, and management'
supports: SUPPORT
evidence_source: OTHER
snippet: Disease overviewAcute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell cancer characterized by unbridled proliferation of malignant marrow stem cells with associated infection, anemia, and bleeding.
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.1038/s41375-023-01846-8
title: 'Outcome prediction by the 2022 European LeukemiaNet genetic-risk classification for adults with acute myeloid leukemia: an Alliance study'
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: Recently, the European LeukemiaNet (ELN) revised its genetic-risk classification of acute myeloid leukemia (AML).
supporting_text: Recently, the European LeukemiaNet (ELN) revised its genetic-risk classification of acute myeloid leukemia (AML).
evidence:
- reference: DOI:10.1038/s41375-023-01846-8
reference_title: 'Outcome prediction by the 2022 European LeukemiaNet genetic-risk classification for adults with acute myeloid leukemia: an Alliance study'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Recently, the European LeukemiaNet (ELN) revised its genetic-risk classification of acute myeloid leukemia (AML).
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.1038/s41375-023-01942-9
title: NPM1 mutation reprograms leukemic transcription network via reshaping TAD topology
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: NPM1 mutation reprograms leukemic transcription network via reshaping TAD topology
supporting_text: C-terminal mutation of Nucleophosmin 1 ( NPM1 C+ ) was thought to be a primary driving event in acute myeloid leukemia (AML) that reprograms leukemic-associated transcription programs to transform hematopoietic stem and progenitor cells (HSPCs).
evidence:
- reference: DOI:10.1038/s41375-023-01942-9
reference_title: NPM1 mutation reprograms leukemic transcription network via reshaping TAD topology
supports: SUPPORT
evidence_source: OTHER
snippet: C-terminal mutation of Nucleophosmin 1 ( NPM1 C+ ) was thought to be a primary driving event in acute myeloid leukemia (AML) that reprograms leukemic-associated transcription programs to transform hematopoietic stem and progenitor cells (HSPCs).
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.1038/s41408-023-00835-5
title: Comparison of the 2022 and 2017 European LeukemiaNet risk classifications in a real-life cohort of the PETHEMA group
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: Next-Generation Sequencing is needed for the accurate genetic risk stratification of acute myeloid leukemia according to European LeukemiaNet (ELN) guidelines.
supporting_text: Next-Generation Sequencing is needed for the accurate genetic risk stratification of acute myeloid leukemia according to European LeukemiaNet (ELN) guidelines.
evidence:
- reference: DOI:10.1038/s41408-023-00835-5
reference_title: Comparison of the 2022 and 2017 European LeukemiaNet risk classifications in a real-life cohort of the PETHEMA group
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Next-Generation Sequencing is needed for the accurate genetic risk stratification of acute myeloid leukemia according to European LeukemiaNet (ELN) guidelines.
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.1038/s41586-023-05812-3
title: The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function1–3.
supporting_text: Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function1–3.
evidence:
- reference: DOI:10.1038/s41586-023-05812-3
reference_title: The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function1–3.
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.1158/2643-3230.bcd-23-0144
title: Criteria for Diagnosis and Molecular Monitoring of <i>NPM1</i>-Mutated AML
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: NPM1-mutated acute myeloid leukemia (AML) represents the largest molecular subgroup of adult AML.
supporting_text: NPM1-mutated acute myeloid leukemia (AML) represents the largest molecular subgroup of adult AML.
evidence:
- reference: DOI:10.1158/2643-3230.bcd-23-0144
reference_title: Criteria for Diagnosis and Molecular Monitoring of <i>NPM1</i>-Mutated AML
supports: SUPPORT
evidence_source: OTHER
snippet: NPM1-mutated acute myeloid leukemia (AML) represents the largest molecular subgroup of adult AML.
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.1159/000530253
title: '<i>NPM1</i>-Mutated Acute Myeloid Leukemia: Recent Developments and Open Questions'
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: Somatic mutations in the nucleophosmin ( NPM1 ) gene occur in approximately 30% of de novo acute myeloid leukemias (AMLs) and are relatively enriched in normal karyotype AMLs.
supporting_text: Somatic mutations in the nucleophosmin ( NPM1 ) gene occur in approximately 30% of de novo acute myeloid leukemias (AMLs) and are relatively enriched in normal karyotype AMLs.
evidence:
- reference: DOI:10.1159/000530253
reference_title: '<i>NPM1</i>-Mutated Acute Myeloid Leukemia: Recent Developments and Open Questions'
supports: SUPPORT
evidence_source: OTHER
snippet: Somatic mutations in the nucleophosmin ( NPM1 ) gene occur in approximately 30% of de novo acute myeloid leukemias (AMLs) and are relatively enriched in normal karyotype AMLs.
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.1182/blood.2023021579
title: Molecular MRD is strongly prognostic in patients with <i>NPM1</i>-mutated AML receiving venetoclax-based nonintensive therapy
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: Molecular MRD is strongly prognostic in patients with <i>NPM1</i>-mutated AML receiving venetoclax-based nonintensive therapy
supporting_text: Assessment of measurable residual disease (MRD) by quantitative reverse transcription polymerase chain reaction is strongly prognostic in patients with NPM1-mutated acute myeloid leukemia (AML) treated with intensive chemotherapy; however, there are no data regarding its utility in venetoclax-based nonintensive therapy, despite high efficacy in this genotype.
evidence:
- reference: DOI:10.1182/blood.2023021579
reference_title: Molecular MRD is strongly prognostic in patients with <i>NPM1</i>-mutated AML receiving venetoclax-based nonintensive therapy
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Assessment of measurable residual disease (MRD) by quantitative reverse transcription polymerase chain reaction is strongly prognostic in patients with NPM1-mutated acute myeloid leukemia (AML) treated with intensive chemotherapy; however, there are no data regarding its utility in venetoclax-based nonintensive therapy, despite high efficacy in this genotype.
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.1182/blood.2024024310
title: Molecular, clinical, and therapeutic determinants of outcome in <i>NPM1</i>-mutated AML
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: Although NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die.
supporting_text: Although NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die.
evidence:
- reference: DOI:10.1182/blood.2024024310
reference_title: Molecular, clinical, and therapeutic determinants of outcome in <i>NPM1</i>-mutated AML
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Although NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die.
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.1182/bloodadvances.2022009010
title: Comparison and validation of the 2022 European LeukemiaNet guidelines in acute myeloid leukemia
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: Risk stratification in acute myeloid leukemia (AML) remains principle in survival prognostication and treatment selection.
supporting_text: Risk stratification in acute myeloid leukemia (AML) remains principle in survival prognostication and treatment selection.
evidence:
- reference: DOI:10.1182/bloodadvances.2022009010
reference_title: Comparison and validation of the 2022 European LeukemiaNet guidelines in acute myeloid leukemia
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Risk stratification in acute myeloid leukemia (AML) remains principle in survival prognostication and treatment selection.
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.1186/s12935-023-02877-y
title: A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: Mixed lineage leukemia 1-rearranged (MLL1-r) acute leukemia patients respond poorly to currently available treatments and there is a need to develop more effective therapies directly disrupting the Menin‒MLL1 complex.
supporting_text: Mixed lineage leukemia 1-rearranged (MLL1-r) acute leukemia patients respond poorly to currently available treatments and there is a need to develop more effective therapies directly disrupting the Menin‒MLL1 complex.
evidence:
- reference: DOI:10.1186/s12935-023-02877-y
reference_title: A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Mixed lineage leukemia 1-rearranged (MLL1-r) acute leukemia patients respond poorly to currently available treatments and there is a need to develop more effective therapies directly disrupting the Menin‒MLL1 complex.
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.1200/jco.23.01599
title: 'Targeting Molecular Measurable Residual Disease and Low-Blast Relapse in AML With Venetoclax and Low-Dose Cytarabine: A Prospective Phase II Study (VALDAC)'
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: A prospective phase II study examined the safety and efficacy of venetoclax combined with low-dose cytarabine (LDAC) in AML at first measurable residual disease (MRD) or oligoblastic relapse.
supporting_text: A prospective phase II study examined the safety and efficacy of venetoclax combined with low-dose cytarabine (LDAC) in AML at first measurable residual disease (MRD) or oligoblastic relapse.
evidence:
- reference: DOI:10.1200/jco.23.01599
reference_title: 'Targeting Molecular Measurable Residual Disease and Low-Blast Relapse in AML With Venetoclax and Low-Dose Cytarabine: A Prospective Phase II Study (VALDAC)'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A prospective phase II study examined the safety and efficacy of venetoclax combined with low-dose cytarabine (LDAC) in AML at first measurable residual disease (MRD) or oligoblastic relapse.
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.3390/biomedicines12081768
title: Molecular Features and Treatment Paradigms of Acute Myeloid Leukemia
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: Molecular Features and Treatment Paradigms of Acute Myeloid Leukemia
supporting_text: Acute myeloid leukemia (AML) is a common hematologic malignancy that is considered to be a disease of aging, and traditionally has been treated with induction chemotherapy, followed by consolidation chemotherapy and/or allogenic hematopoietic stem cell transplantation.
evidence:
- reference: DOI:10.3390/biomedicines12081768
reference_title: Molecular Features and Treatment Paradigms of Acute Myeloid Leukemia
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Acute myeloid leukemia (AML) is a common hematologic malignancy that is considered to be a disease of aging, and traditionally has been treated with induction chemotherapy, followed by consolidation chemotherapy and/or allogenic hematopoietic stem cell transplantation.
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.3390/biomedicines12102282
title: Characteristics and Prognosis of “Acute Promyelocytic Leukemia-like” Nucleophosmin-1-Mutated Acute Myeloid Leukemia in a Retrospective Patient Cohort
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: AML with NPM1 mutation is the largest subcategory of AML, representing about 35% of AML cases.
supporting_text: AML with NPM1 mutation is the largest subcategory of AML, representing about 35% of AML cases.
evidence:
- reference: DOI:10.3390/biomedicines12102282
reference_title: Characteristics and Prognosis of “Acute Promyelocytic Leukemia-like” Nucleophosmin-1-Mutated Acute Myeloid Leukemia in a Retrospective Patient Cohort
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: AML with NPM1 mutation is the largest subcategory of AML, representing about 35% of AML cases.
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.3390/cancers15041177
title: NPM 1 Mutations in AML—The Landscape in 2023
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: Acute myeloid leukemia (AML) represents 80% of acute leukemia in adults and is characterized by clonal expansion of hematopoietic stem cells secondary to genomic mutations, rendering a selective growth advantage to the mutant clones.
supporting_text: Acute myeloid leukemia (AML) represents 80% of acute leukemia in adults and is characterized by clonal expansion of hematopoietic stem cells secondary to genomic mutations, rendering a selective growth advantage to the mutant clones.
evidence:
- reference: DOI:10.3390/cancers15041177
reference_title: NPM 1 Mutations in AML—The Landscape in 2023
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Acute myeloid leukemia (AML) represents 80% of acute leukemia in adults and is characterized by clonal expansion of hematopoietic stem cells secondary to genomic mutations, rendering a selective growth advantage to the mutant clones.
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
- reference: DOI:10.3390/ijms24043161
title: Targeting and Monitoring Acute Myeloid Leukaemia with Nucleophosmin-1 (NPM1) Mutation
found_in:
- NPM1_Mutant_AML-deep-research-falcon.md
findings:
- statement: Mutations in NPM1, also known as nucleophosmin-1, B23, NO38, or numatrin, are seen in approximately one-third of patients with acute myeloid leukaemia (AML).
supporting_text: Mutations in NPM1, also known as nucleophosmin-1, B23, NO38, or numatrin, are seen in approximately one-third of patients with acute myeloid leukaemia (AML).
evidence:
- reference: DOI:10.3390/ijms24043161
reference_title: Targeting and Monitoring Acute Myeloid Leukaemia with Nucleophosmin-1 (NPM1) Mutation
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Mutations in NPM1, also known as nucleophosmin-1, B23, NO38, or numatrin, are seen in approximately one-third of patients with acute myeloid leukaemia (AML).
explanation: Deep research cited this publication as relevant literature for NPM1 Mutant AML.
NPM1-mutated AML is a genetically defined AML subtype characterized by somatic mutations in NPM1 that produce an aberrantly cytoplasmic nucleophosmin protein (“NPM1c”), and it is the largest molecular subgroup of adult AML. (falini2024criteriafordiagnosis pages 1-2)
Current classification concept: recent WHO/ICC schemes treat NPM1 mutation as AML‑defining, with differences in blast thresholds (see below). (patel2024npm1mutatedacutemyeloid pages 1-2, falini2024criteriafordiagnosis pages 5-6, shimony2023acutemyeloidleukemia pages 5-6)
Not retrieved in this run: OMIM, Orphanet, MeSH, ICD-10/ICD-11, and a disease-specific MONDO identifier for “NPM1-mutated AML”.
| Key point | Value | Source (first author, year) | URL/DOI | Publication date |
|---|---|---|---|---|
| Disease name | Acute myeloid leukemia with mutated NPM1; also written as NPM1-mutated AML | Falini, 2024 (falini2024criteriafordiagnosis pages 1-2) | https://doi.org/10.1158/2643-3230.bcd-23-0144 | 2024-12 |
| Common synonyms | AML with mutated NPM1; NPM1-mutated AML; NPM1mut AML; NPM1+ AML | Falini, 2024 (falini2024criteriafordiagnosis pages 1-2) | https://doi.org/10.1158/2643-3230.bcd-23-0144 | 2024-12 |
| Classification source | WHO 5th edition (2022) recognizes AML with mutated NPM1 as an AML-defining genetic abnormality/distinct entity | Patel, 2024 (patel2024npm1mutatedacutemyeloid pages 1-2, patel2024npm1mutatedacutemyeloid pages 4-4) | https://doi.org/10.1159/000530253 | 2024-03 |
| Classification source | ICC 2022 recognizes NPM1-mutated AML as a distinct recurrent-genetic-abnormality category | Sharma, 2023 (sharma2023npm1mutations pages 1-2); Shimony, 2023 (shimony2023acutemyeloidleukemia pages 5-6) | https://doi.org/10.3390/cancers15041177; https://doi.org/10.1002/ajh.26822 | 2023-02; 2023-01 |
| Classification source | ELN 2022 requires NPM1 and FLT3 status for genetic risk stratification | Falini, 2024 (falini2024criteriafordiagnosis pages 1-2, falini2024criteriafordiagnosis pages 5-6) | https://doi.org/10.1158/2643-3230.bcd-23-0144 | 2024-12 |
| Blast-count threshold (WHO 5th ed.) | WHO 5th edition permits diagnosis of NPM1-mutated AML irrespective of blast percentage / no blast threshold for AML defined by genetic abnormalities | Falini, 2024 (falini2024criteriafordiagnosis pages 5-6); Shimony, 2023 (shimony2023acutemyeloidleukemia pages 5-6) | https://doi.org/10.1158/2643-3230.bcd-23-0144; https://doi.org/10.1002/ajh.26822 | 2024-12; 2023-01 |
| Blast-count threshold (ICC 2022) | ICC 2022 requires ≥10% blasts for AML with mutated NPM1 | Falini, 2024 (falini2024criteriafordiagnosis pages 5-6); Patel, 2024 (patel2024npm1mutatedacutemyeloid pages 4-4) | https://doi.org/10.1158/2643-3230.bcd-23-0144; https://doi.org/10.1159/000530253 | 2024-12; 2024-03 |
| ELN 2022 risk group: NPM1-mutated, FLT3-ITD negative | Favorable risk | Falini, 2024 (falini2024criteriafordiagnosis pages 5-6) | https://doi.org/10.1158/2643-3230.bcd-23-0144 | 2024-12 |
| ELN 2022 risk group: NPM1-mutated with FLT3-ITD | Intermediate risk regardless of FLT3-ITD allelic ratio | Falini, 2024 (falini2024criteriafordiagnosis pages 5-6); Sargas, 2023 (sargas2023comparisonofthe pages 1-2); Lachowiez, 2023 (lachowiez2023comparisonandvalidation pages 1-2) | https://doi.org/10.1158/2643-3230.bcd-23-0144; https://doi.org/10.1038/s41408-023-00835-5; https://doi.org/10.1182/bloodadvances.2022009010 | 2024-12; 2023-05; 2023-05 |
| ELN 2022 adverse override | NPM1-mutated AML with adverse cytogenetic abnormalities is classified as adverse risk | Shimony, 2023 (shimony2023acutemyeloidleukemia pages 5-6); Mrózek, 2023 (mrozek2023outcomepredictionby pages 1-2) | https://doi.org/10.1002/ajh.26822; https://doi.org/10.1038/s41375-023-01846-8 | 2023-01; 2023-02 |
| ELN/MDS-related mutation note | WHO/ICC prioritize NPM1 mutation over myelodysplasia-related mutations when co-occurring; ELN discussion suggests MR mutations should not automatically overrule favorable NPM1 biology | Falini, 2024 (falini2024criteriafordiagnosis pages 5-6) | https://doi.org/10.1158/2643-3230.bcd-23-0144 | 2024-12 |
| Epidemiology: adult AML frequency | NPM1 mutations occur in ~30–35% of adult AML / about one-third of adult AML | Falini, 2024 (falini2024criteriafordiagnosis pages 1-2); Patel, 2024 (patel2024npm1mutatedacutemyeloid pages 1-2); Sharma, 2023 (sharma2023npm1mutations pages 1-2) | https://doi.org/10.1158/2643-3230.bcd-23-0144; https://doi.org/10.1159/000530253; https://doi.org/10.3390/cancers15041177 | 2024-12; 2024-03; 2023-02 |
| Epidemiology: normal-karyotype AML | NPM1 mutations are present in ~50–60% of normal-karyotype AML; Patel also notes ~60% of normal-karyotype AML | Falini, 2024 (falini2024criteriafordiagnosis pages 1-2); Patel, 2024 (patel2024npm1mutatedacutemyeloid pages 1-2) | https://doi.org/10.1158/2643-3230.bcd-23-0144; https://doi.org/10.1159/000530253 | 2024-12; 2024-03 |
| Epidemiology: pediatric AML | Less frequent in children, about 2–8% | Falini, 2024 (falini2024criteriafordiagnosis pages 1-2) | https://doi.org/10.1158/2643-3230.bcd-23-0144 | 2024-12 |
| Typical associated clinicopathologic features | Often normal karyotype, myelomonocytic/monocytic differentiation, low/absent CD34, frequent extramedullary involvement | Falini, 2024 (falini2024criteriafordiagnosis pages 1-2); Patel, 2024 (patel2024npm1mutatedacutemyeloid pages 1-2) | https://doi.org/10.1158/2643-3230.bcd-23-0144; https://doi.org/10.1159/000530253 | 2024-12; 2024-03 |
Table: This table summarizes the current naming, classification framework, blast-threshold differences, and headline epidemiology figures for acute myeloid leukemia with mutated NPM1. It is useful for quickly aligning WHO 2022, ICC 2022, and ELN 2022 terminology and risk-stratification rules.
Genetic (somatic co-mutations / disease biology modifiers) - Co-mutations are common and clinically important; across cohorts, recurrent co-mutations include FLT3 (especially FLT3-ITD), DNMT3A, WT1, and others, with prognostic impact (see Prognosis). (othman2024molecularclinicaland pages 1-5)
Environmental / iatrogenic - Therapy-related AML (t‑AML) can carry NPM1 mutations. A diagnostic-focused review notes that therapy-related NPM1‑mutated AML comprises ≈15% of therapy-related AMLs and, if FLT3-ITD negative, is considered ELN favorable with post‑remission decisions guided by MRD. (falini2024criteriafordiagnosis pages 5-6)
No specific protective (genetic or environmental) factors were retrieved in the cited evidence for the NPM1-mutated AML subtype.
No gene–environment interaction evidence specific to NPM1-mutated AML was retrieved in this run.
Common presentation overlaps with AML generally (cytopenias, infections, bleeding), but NPM1-mutated AML has recurrent clinicopathologic patterns: - Bone marrow: typically markedly hypercellular. (falini2024criteriafordiagnosis pages 1-2) - Differentiation: often myelomonocytic/monocytic (FAB M4/M5 predominance; other FAB categories can occur). (falini2024criteriafordiagnosis pages 1-2) - Immunophenotype: typically no/low CD34 expression; a 2024 cohort paper states “the vast majority of NPM1m AML cases are therefore CD34‑negative”. (falini2024criteriafordiagnosis pages 1-2, papadopoulou2024characteristicsandprognosis pages 1-2) - Extramedullary disease: commonly reported, particularly skin involvement, and IHC can help detect such involvement. (falini2024criteriafordiagnosis pages 1-2) - Demographics: “female predominance” is noted in diagnostic reviews. (falini2024criteriafordiagnosis pages 1-2)
A subset of NPM1‑mutated AML may show a “double negative” CD34−/HLA‑DR− immunophenotype that can mimic acute promyelocytic leukemia (APL) at presentation, necessitating rapid exclusion of PML::RARA rearrangement. (papadopoulou2024characteristicsandprognosis pages 1-2)
These are ontology suggestions (not direct extractions from a single cited ontology resource in this run): - Anemia (HP:0001903) - Thrombocytopenia (HP:0001873) - Leukocytosis (HP:0001974) - Neutropenia (HP:0001875) - Recurrent infections (HP:0002719) - Abnormal bleeding (HP:0001892) - Bone marrow hypercellularity (commonly mapped to marrow hypercellularity concepts; exact HPO mapping requires ontology lookup) - Extramedullary hematopoiesis / myeloid sarcoma (ontology mapping requires curation)
Somatic vs germline: the defining NPM1 lesion is described as somatic in AML series/reviews. (patel2024npm1mutatedacutemyeloid pages 1-2)
Population allele frequencies: not retrieved (these are somatic leukemia variants and are generally absent from germline population databases).
In a large prospective trial cohort (NCRI AML17/AML19; n=1357), independent adverse baseline associations for overall survival included: FLT3-ITD (HR 1.28), DNMT3A (HR 1.65), WT1 (HR 1.74), and non‑ABD NPM1 mutations (HR 1.64). (othman2024molecularclinicaland pages 1-5)
NPM1-mutated AML is enriched in normal karyotype AML (a large fraction of NK-AML cases). (patel2024npm1mutatedacutemyeloid pages 1-2, falini2024criteriafordiagnosis pages 1-2)
Recent mechanistic work supports NPM1 mutation as a chromatin-associated neomorphic driver of the HOX program, including cooperation with KMT2A/MLL1 and maintenance of active chromatin at HOX loci. (patel2024npm1mutatedacutemyeloid pages 3-4)
A 2023 primary study additionally links NPM1C+ to 3D genome architecture changes (CTCF/TAD remodeling) that strengthen TADs at HOXA/B and PBX3 loci and weaken TADs at cell-cycle inhibitor loci (e.g., Cdkn1a/p21), supporting proliferation and differentiation block. (lai2023npm1mutationreprograms pages 1-3)
Primary site: bone marrow hematopoietic tissue. (falini2024criteriafordiagnosis pages 1-2)
Peripheral blood involvement: circulating blasts/leukocytosis can occur, especially with RAS/FLT3 co-mutations. (falini2024criteriafordiagnosis pages 1-2)
Extramedullary involvement: skin and other sites (myeloid sarcoma) may be involved; mutant NPM1 IHC can support identification. (falini2024criteriafordiagnosis pages 1-2, patel2024npm1mutatedacutemyeloid pages 2-3)
Suggested UBERON terms (requires ontology lookup): bone marrow; blood; skin.
NPM1 mutant transcript burden closely tracks disease status and is suited to high-sensitivity MRD monitoring. (patel2024npm1mutatedacutemyeloid pages 1-2)
A key 2024 real-world analysis (venetoclax-based, nonintensive therapy) reported: - BM MRD negativity 25% by cycle 2; 47% by cycle 4; 50% by cycle 6. (othman2024molecularmrdis pages 1-2) - 2-year OS 84% if MRD-negative by cycle 4 vs 46% if MRD-positive. (othman2024molecularmrdis pages 1-2)
Direct abstract quote (MRD utility): “A total of 44 patients (58%) achieved bone marrow (BM) MRD negativity…” and “Patients achieving BM MRD negativity by the end of cycle 4 had 2-year overall of 84% compared with 46% if MRD was positive.” (othman2024molecularmrdis pages 1-2)
An MRD monitoring algorithm for intensive chemotherapy (including management of “MRD relapse”) is provided in Figure 4 of Falini & Dillon 2024. (falini2024criteriafordiagnosis media 3d972561)
In a large prospective analysis of NPM1-mutated AML (NCRI AML17/AML19; n=1357), independent adverse factors for overall survival included FLT3-ITD, DNMT3A, WT1, and non‑ABD NPM1 mutation classes, and these were strongly associated with MRD positivity. (othman2024molecularclinicaland pages 1-5)
The prospective VALDAC phase II study demonstrates a real-world implementation of treating molecular MRD relapse or oligoblastic relapse with venetoclax+LDAC, with mutant NPM1 comprising 77% of MRD markers and MRD-negative remission achieved in 46% by cycle 2 in the MRD cohort. (tiong2024targetingmolecularmeasurable pages 1-2)
Direct abstract quote (VALDAC): “By cycle 2 in the MRD relapse cohort, a log10 reduction in MRD was observed in 69%; 46% achieved MRD negative remission.” (tiong2024targetingmolecularmeasurable pages 1-2)
A seminal first-in-human trial established menin inhibition as an actionable strategy in susceptible leukemias (including NPM1-mutant):
Direct abstract quote (Nature 2023): “therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh)… Asymptomatic prolongation of the QT interval… was identified as the only dose-limiting toxicity.” (issa2023themenininhibitor pages 1-2)
Quantitatively, in 60 evaluable patients with KMT2A-rearranged or NPM1-mutant disease, ORR was 53%, CR/CRh 30%, and MRD negativity among CR/CRh was 78%. (issa2023themenininhibitor pages 4-4)
Multiple Phase 3 programs are actively evaluating adding menin inhibitors to standard regimens in newly diagnosed genetically selected AML: - Revumenib + intensive chemotherapy vs placebo (newly diagnosed NPM1-mutated AML): NCT07211958; Phase 3; estimated n=468; primary endpoints include event-free survival and MRD CR rate. (NCT07211958 chunk 1) - Revumenib + azacitidine + venetoclax vs placebo (newly diagnosed NPM1-mutated or KMT2A-rearranged AML, intensive-ineligible): NCT06652438; Phase 3; estimated n≈415. (NCT06652438 chunk 1) - Ziftomenib + (venetoclax+azacitidine) or + (7+3) vs placebo in untreated NPM1-mutated/KMT2A-rearranged AML: NCT07007312; Phase 3; estimated n=1300. (NCT07007312 chunk 1)
| Intervention/setting | Key outcomes/statistics | Safety notes | Evidence type | Source (first author, journal, year) | Publication date | URL/DOI or ClinicalTrials.gov URL | Notes |
|---|---|---|---|---|---|---|---|
| Venetoclax + HMA or LDAC in previously untreated NPM1-mutated AML achieving CR/CRi; molecular MRD by RT-qPCR | Bone marrow MRD negativity: 25% by end of cycle 2, 47% by end of cycle 4, 50% by end of cycle 6; best MRD-negative response 58%; additional 18% achieved >=4 log10 reduction; 2-year OS 84% if BM MRD-negative by cycle 4 vs 46% if MRD-positive; 22 patients who stopped therapy in BM MRD-negative remission after median 8 cycles had 2-year treatment-free remission 88% (othman2024molecularmrdis pages 1-2, othman2024molecularmrdis pages 7-8, othman2024molecularmrdis pages 5-6) | MRD status, not a drug-specific new toxicity signal, was the dominant prognostic discriminator in this real-world cohort; PB MRD less sensitive than BM MRD (othman2024molecularmrdis pages 7-8) | Human clinical; international real-world cohort | Othman, Blood, 2024 | 2024-01 | https://doi.org/10.1182/blood.2023021579 | Strong contemporary evidence for MRD-guided management in venetoclax-based nonintensive therapy for NPM1-mutated AML (othman2024molecularmrdis pages 1-2, othman2024molecularmrdis pages 5-6) |
| VALDAC: venetoclax + low-dose cytarabine for first molecular MRD relapse or oligoblastic relapse in AML; mutant NPM1 represented 77% of MRD markers | In MRD-relapse cohort, by cycle 2: >=1 log10 MRD reduction in 69%, MRD-negative remission in 46%; in oligoblastic relapse cohort, CR/CRh/CRi 73%; estimated 2-year OS 67% in MRD cohort and 53% in oligoblastic cohort; 44% proceeded to HCT (tiong2024targetingmolecularmeasurable pages 1-2) | Oligoblastic relapse cohort had more grade >=3 anemia (32% vs 4%) and infections (36% vs 8%); grade 4 neutropenia 32% and thrombocytopenia 27% in oligoblastic cohort (tiong2024targetingmolecularmeasurable pages 1-2) | Human clinical; prospective phase II | Tiong, J Clin Oncol, 2024 | 2024-06 | https://doi.org/10.1200/JCO.23.01599 | Demonstrates a real-world actionable use of molecular relapse detection, often driven by NPM1 RT-qPCR monitoring (tiong2024targetingmolecularmeasurable pages 1-2) |
| Revumenib (SNDX-5613), AUGMENT-101, relapsed/refractory KMT2A-rearranged or NPM1-mutant acute leukemia | In 60 evaluable patients: ORR 53% (32/60); CR/CRh 30% (18/60), including CR 20% and CRh 10%; MRD-negative rate among CR/CRh 78% (14/18); median time to CR/CRh about 1.9 months; median duration of response 9.1 months; median OS 7 months (issa2023themenininhibitor pages 1-2, issa2023themenininhibitor pages 4-4) | Dose-limiting toxicity: asymptomatic QT prolongation; any-grade TEAEs 98.5%, TRAEs 77.9%; differentiation syndrome in 11 patients (16.2%); common AEs included nausea and vomiting (issa2023themenininhibitor pages 1-2) | Human clinical; first-in-human phase I/II | Issa, Nature, 2023 | 2023-03 | https://doi.org/10.1038/s41586-023-05812-3 | Foundational proof-of-concept for menin inhibition in NPM1-mutant leukemia; included 14 NPM1-mutant patients in the enrolled population (issa2023themenininhibitor pages 1-2, issa2023themenininhibitor pages 4-4) |
| Revumenib + intensive chemotherapy in newly diagnosed NPM1-mutated AML | Phase 3, randomized, double-blind, placebo-controlled; estimated enrollment 468; compares revumenib + cytarabine/daunorubicin intensive chemotherapy vs placebo + intensive chemotherapy; primary endpoints include event-free survival and MRD complete remission rate (NCT07211958 chunk 1) | Key exclusions include significant QTc prolongation, active CNS disease, GI absorption issues, pregnancy/nursing, active viral infections with detectable viral load (NCT07211958 chunk 1) | Interventional trial; ongoing Phase 3 | ClinicalTrials.gov NCT07211958 | 2025 record | https://clinicaltrials.gov/study/NCT07211958 | Newly diagnosed, previously untreated AML with NPM1 mutation; minimum age 12 years; candidates for intensive chemotherapy (NCT07211958 chunk 1) |
| Revumenib + azacitidine + venetoclax in newly diagnosed NPM1-mutated or KMT2A-rearranged AML ineligible for intensive chemotherapy | Phase 3, randomized, double-blind, placebo-controlled; estimated enrollment ~415; revumenib or placebo added day 1-28 each cycle on top of azacitidine + venetoclax (NCT06652438 chunk 1) | Requires WBC <25 x 10^9/L before enrollment (hydroxyurea allowed); trial population defined by intensive-therapy ineligibility rather than published safety outcomes yet (NCT06652438 chunk 1) | Interventional trial; ongoing Phase 3 | ClinicalTrials.gov NCT06652438 | 2025 record | https://clinicaltrials.gov/study/NCT06652438 | Adults >=18 years; central confirmation of NPM1 mutation or KMT2A rearrangement; newly diagnosed disease, including >=10% blasts for NPM1c entry criterion (NCT06652438 chunk 1) |
| Ziftomenib program in untreated NPM1-mutated or KMT2A-rearranged AML: nonintensive venetoclax/azacitidine +/- ziftomenib and intensive 7+3 +/- ziftomenib | Phase 3, randomized, double-blind, placebo-controlled; estimated enrollment 1,300; nonintensive study primary endpoint OS; intensive study primary endpoint EFS, with CR/MRD-related endpoints also specified (NCT07007312 chunk 1) | No mature efficacy/safety results yet in this registration excerpt; standard backbone toxicities expected from venetoclax/azacitidine or 7+3, with ziftomenib under blinded evaluation (NCT07007312 chunk 1) | Interventional trial; ongoing Phase 3 | ClinicalTrials.gov NCT07007312 | 2025 record | https://clinicaltrials.gov/study/NCT07007312 | Nonintensive arm targets untreated adults with NPM1-mut AML; intensive arm includes untreated adults with NPM1-mut or KMT2A-rearranged AML (NCT07007312 chunk 1) |
Table: This table summarizes high-value recent clinical evidence and current Phase 3 implementation studies for NPM1-mutated AML, spanning MRD-guided venetoclax use, preemptive relapse treatment, menin inhibition with revumenib, and active registrational trials. It is useful for comparing outcomes, safety signals, and real-world translational applications across the rapidly evolving 2023-2025 landscape.
Primary prevention of de novo NPM1-mutated AML is not established. Practical prevention in AML largely focuses on reducing therapy-related AML risk (when feasible) and optimizing supportive care to reduce infectious/hemorrhagic mortality; no NPM1-specific preventive interventions were retrieved in the evidence set for this run.
No naturally occurring NPM1-mutated AML analogs in non-human species were retrieved in this run.
A 2023 primary study used a hematopoietic-specific conditional knock-in NPM1C+ mouse model and showed that NPM1C+ alters TAD topology and induces an MPN/MDS-like condition (long latency, splenomegaly, leukocytosis, thrombocytopenia), supporting its use as a mechanistic model for leukemogenesis and differentiation block. (lai2023npm1mutationreprograms pages 1-3)
References
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(NCT07211958 chunk 1): Study of Revumenib in Combination With Intensive Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia (AML) With a NPM1 Mutation. Syndax Pharmaceuticals. 2025. ClinicalTrials.gov Identifier: NCT07211958
(NCT06652438 chunk 1): Revumenib in Combination With Azacitidine + Venetoclax in Patients NPM1-mutated or KMT2A-rearranged AML. Stichting Hemato-Oncologie voor Volwassenen Nederland. 2025. ClinicalTrials.gov Identifier: NCT06652438
(NCT07007312 chunk 1): Studies to Assess Ziftomenib in Combination With Ven+Aza or 7+3 in Patients With Untreated NPM1-m or KMT2A-r AML. Kura Oncology, Inc.. 2025. ClinicalTrials.gov Identifier: NCT07007312
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