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Acute Myeloid Leukemia (C92.00)

Advancements in the mechanistic understanding of acute myeloid leukemia (AML) have redefined it from a morphologic diagnosis to a genomically and epigenetically stratified clonal stem-cell disorder characterized by disrupted differentiation, aberrant self-renewal, and maladaptive metabolic rewiring. High-throughput sequencing has elucidated recurrent driver lesions in transcription factors (e.g., RUNX1), epigenetic modifiers (DNMT3A, TET2, ASXL1), spliceosome components (SRSF2, SF3B1), cohesin complex genes, and signaling kinases such as FLT3 and KIT, revealing convergent pathogenic programs centered on impaired hematopoietic maturation and constitutive survival signaling. Mutant IDH1/2–mediated 2-hydroxyglutarate accumulation highlighted oncometabolite-driven epigenetic dysregulation as a druggable node, while dependence on anti-apoptotic BCL-2 exposed mitochondrial priming as a therapeutic vulnerability. These insights have translated into targeted agents including FLT3 inhibitors (midostaurin, gilteritinib), IDH1/2 inhibitors (ivosidenib, enasidenib), BCL-2 inhibition with venetoclax in combination regimens, and antibody-drug conjugates such as gemtuzumab ozogamicin targeting CD33. Emerging strategies are now focused on menin inhibitors for KMT2A-rearranged and NPM1-mutant AML, CD123-directed immunotherapies, TP53-reactivation approaches, and combinatorial regimens that exploit synthetic lethality within DNA damage repair and metabolic pathways. Increasingly, measurable residual disease (MRD) monitoring and single-cell multi-omics are refining risk stratification and dynamic treatment adaptation, signaling a shift toward temporally informed, precision-guided intervention in AML.

Causes

The etiology of acute myeloid leukemia (AML) is multifactorial, arising from the stepwise acquisition of somatic mutations within hematopoietic stem and progenitor cells that confer clonal fitness, impaired differentiation, and survival advantage. Age-related clonal hematopoiesis—particularly involving mutations in DNMT3A, TET2, and ASXL1—creates a preleukemic substrate upon which additional transforming events (e.g., FLT3-ITD, NPM1 mutation, KMT2A rearrangements, TP53 loss) accumulate. Exogenous leukemogenic exposures include prior cytotoxic chemotherapy (especially alkylating agents and topoisomerase II inhibitors), ionizing radiation, and environmental toxins such as benzene, which promote DNA damage and genomic instability. Inherited predisposition syndromes—such as germline RUNX1, CEBPA, GATA2, or DDX41 mutations—further demonstrate that impaired transcriptional regulation and hematopoietic stem-cell maintenance can prime for malignant transformation. Therapy-related AML and AML arising from antecedent myelodysplastic syndromes represent distinct biological entities characterized by complex karyotypes, chromosomal aneuploidy, and TP53 pathway disruption. Ultimately, AML emerges when accumulated genetic and epigenetic insults overwhelm normal hematopoietic regulatory networks, tipping the balance from controlled self-renewal and differentiation toward unchecked clonal expansion.

Pathophysiology

The pathophysiology of acute myeloid leukemia (AML) is defined by a hierarchical disruption of normal hematopoiesis in which genetically and epigenetically altered hematopoietic stem or progenitor cells acquire aberrant self-renewal capacity, impaired differentiation, and resistance to apoptosis. Foundational “class II” lesions typically impair transcriptional programs governing myeloid maturation (e.g., NPM1 mutations, core-binding factor rearrangements, RUNX1 alterations), while “class I” signaling mutations (e.g., FLT3-ITD, RAS pathway activation, KIT mutations) drive proliferative and survival signaling through constitutive MAPK, PI3K/AKT, and STAT pathway activation. Concurrent mutations in epigenetic regulators (DNMT3A, TET2, IDH1/2, ASXL1) reprogram chromatin accessibility and DNA methylation landscapes, locking cells into an undifferentiated, blast phenotype. Metabolically, AML cells demonstrate altered mitochondrial priming and increased reliance on oxidative phosphorylation, creating vulnerability to BCL-2 inhibition. The leukemic clone expands within the bone marrow niche, suppressing normal hematopoiesis through cytokine dysregulation, stromal remodeling, and competition for growth factors, leading to cytopenias. At a systems level, AML reflects a convergence of transcriptional arrest, constitutive growth signaling, metabolic adaptation, and microenvironmental co-option that collectively sustain malignant clonal dominance.

Clinical features

The clinical features of acute myeloid leukemia (AML) primarily reflect bone marrow failure and, in some cases, leukemic infiltration of extramedullary tissues. Patients commonly present with symptoms of anemia (fatigue, dyspnea, pallor), thrombocytopenia (easy bruising, petechiae, mucosal bleeding), and neutropenia (recurrent or severe infections), often developing over weeks. Constitutional symptoms such as fever, weight loss, and night sweats may occur. Hyperleukocytosis in aggressive subtypes can lead to leukostasis, manifesting as respiratory distress or neurologic deficits due to microvascular obstruction. Gingival hypertrophy, skin infiltration (leukemia cutis), lymphadenopathy, or hepatosplenomegaly may be seen, particularly in monocytic variants. Acute promyelocytic leukemia is notable for a high risk of disseminated intravascular coagulation at presentation. Bone pain and laboratory evidence of elevated lactate dehydrogenase may reflect rapid cellular turnover. Overall, the clinical phenotype mirrors the underlying pathobiology: clonal expansion of immature myeloid blasts suppressing normal hematopoiesis while, in some cases, infiltrating peripheral tissues and triggering systemic inflammatory responses.

Diagnosis

The diagnosis of acute myeloid leukemia (AML) is established through integrated morphologic, immunophenotypic, cytogenetic, and molecular evaluation. It is typically suspected in the setting of unexplained cytopenias or circulating blasts on peripheral smear and confirmed by bone marrow aspiration and biopsy demonstrating ≥20% myeloid blasts, or by the presence of specific defining genetic abnormalities irrespective of blast percentage (e.g., PML::RARA, RUNX1::RUNX1T1, CBFB::MYH11). Flow cytometry characterizes aberrant myeloid immunophenotypes (commonly CD13, CD33, CD34, CD117, HLA-DR with variable lineage infidelity), distinguishing AML from acute lymphoblastic leukemia and identifying subtypes such as acute promyelocytic leukemia. Conventional karyotyping and fluorescence in situ hybridization (FISH) detect recurrent chromosomal rearrangements and complex cytogenetics, while next-generation sequencing panels identify actionable mutations in FLT3, NPM1, IDH1/2, TP53, and others that inform risk stratification and therapeutic selection. Increasingly, measurable residual disease (MRD) assessment using multiparameter flow cytometry or molecular assays (e.g., PCR for NPM1 transcripts) refines prognostication and guides post-remission management. Thus, AML diagnosis is no longer purely morphologic but represents a genomically stratified framework that directly links biology to treatment strategy.

Mechanism of action videos

Biological pathways

  • PI3K-Akt signaling pathway
  • MAPK signaling pathway
  • JAK-STAT signaling pathway
  • Imatinib and chronic myeloid leukemia
  • Hematopoietic cell lineage
  • FLT3 signaling by CBL mutants
  • Drug resistance of FLT3 mutants
  • Cell cycle
  • Apoptosis
  • Acute myeloid leukemia
  • Polymerase switching
  • Leading Strand Synthesis
  • Removal of the Flap Intermediate
  • Processive synthesis on the lagging strand
  • DNA replication initiation
  • Polymerase switching on the C-strand of the telomere
  • Synthesis of DNA
  • DNA strand elongation
  • PCNA-Dependent Long Patch Base Excision Repair
  • S Phase
  • Extension of Telomeres
  • Gap-filling DNA repair synthesis and ligation in GG-NER
  • Telomere C-strand (Lagging Strand) Synthesis
  • Recognition of DNA damage by PCNA-containing replication complex
  • Resolution of AP sites via the multiple-nucleotide patch replacement pathway
  • Mitotic G1 phase and G1/S transition
  • Termination of translesion DNA synthesis
  • Diseases of signal transduction by growth factor receptors and second messengers
  • Activation of the pre-replicative complex
  • DNA Replication
  • Downstream signal transduction
  • Chromosome Maintenance
  • Dual Incision in GG-NER
  • Cell Cycle, Mitotic
  • Telomere Maintenance
  • Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template
  • Resolution of Abasic Sites (AP sites)
  • Signaling by PDGFR in disease
  • Defective pyroptosis
  • DNA Damage Bypass

Clinical trials

  • Phase 1 Dose Escalation and Expansion of Ziftomenib in Combination With Quizartinib in Acute Myeloid Leukemia
  • Quality of Life-based Transfusion in Refractory MDS or AML Under Advanced Palliative Care and Supportive Treatment.
  • SENTI-202-101: A Phase 1, Multicenter, Open-Label Study of SENTI-202, a Selective Off-the-Shelf Logic Gated CAR NK Cell Therapy, in Subjects With CD33 and/or FLT3 Expressing Malignancies
  • Phase 1 Trial of Iadademstat in Combination With Venetoclax and Azacitidine in Patients With Treatment Naive AML
  • A Phase 1/2 Study of Vorinostat [Suberoylanilide Hydroxamic Acid (SAHA)] in Combination With Azacitidine in Patients With the Myelodysplastic Syndrome (MDS)
  • RELION Study: Characteristics and Outcomes of the Patient Population With Acute Myeloid Leukemia in Remission, Treated With Oral Azacitidine Maintenance in France
  • Randomized Phase II Study of Epigenetic Priming Using Decitabine With Induction Chemotherapy in Patients With Acute Myelogenous Leukemia (AML)
  • Cancer Moonshot Biobank Research Protocol
  • A Phase 1 Study of TAK-243 for Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes With Increased Blasts
  • Shortened Venetoclax Duration Based on Bone Marrow Blasts on Day 14 Versus Standard Therapy in Elderly or Frail Patients With Acute Myeloid Leukemia Treated With Azacitidine Plus Venetoclax: A Multicenter Prospective Randomized Controlled Study
  • A Randomized Phase II Study Comparing Cytarabine + Daunorubicin (7+3) vs (Daunorubicin and Cytarabine) Liposome, Cytarabine + Daunorubicin + Venetoclax, Azacitidine + Venetoclax, and (Daunorubicin and Cytarabine) Liposome + Venetoclax in Patients Aged 59 or Younger Who Are Considered High-Risk (Adverse) Acute Myeloid Leukemia As Determined by MYELOMATCH; A MYELOMATCH Clinical Trial
  • A Phase 1 Study of M3814 in Combination With MEC in Patients With Relapsed or Refractory Acute Myeloid Leukemia
  • A Phase 1b Study With Expansion Cohort of Escalating Doses of KRT-232 (AMG 232) Administered in Combination With Standard Induction Chemotherapy (Cytarabine and Idarubicin) in Newly Diagnosed Acute Myelogenous Leukemia (AML)
  • A Phase 1 Study of ICP-248 in Combination With Azacitidine for the Treatment in Patients With Myeloid Malignancies.
  • Phase II Study of Cytarabine + Daunorubicin (7 + 3) + Gemtuzumab Ozogamicin vs. Cytarabine + Daunorubicin (7 + 3) + Venetoclax for the Treatment of Newly Diagnosed Core Binding Factor Acute Myeloid Leukemia (CBF-AML) in Younger Adults: A MyeloMATCH Substudy
  • A Randomized Phase II Study of Venetoclax and HMA-Based Therapies for the Treatment of Older and Unfit Adults With Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia (AML): A MyeloMATCH Treatment Trial
  • A Multicenter Access and Distribution Protocol for Unlicensed Cryopreserved Cord Blood Units (CBUs) for Transplantation in Pediatric and Adult Patients With Hematologic Malignancies and Other Indications
  • A Phase 1b Study of Menin Inhibitor SNDX-5613 in Combination With Daunorubicin and Cytarabine in Newly Diagnosed Patients With Acute Myeloid Leukemia and NPM1 Mutated/FLT3 Wildtype or MLL/KMT2A Rearranged Disease.
  • Study of Precursor Hematological Malignancies to Assess the Relationship Between Molecular Events of Progression and Clinical Outcome
  • A Two Cohort, Randomized, Double-Blind, Placebo-Controlled, Phase II Multi-Center Signal-Finding Study of Venetoclax Combined With Reduced-Intensity Conditioning Followed by Allogeneic Hematopoietic Cell Transplantation Then Venetoclax Maintenance in Adult Patients With Acute Myeloid Leukemia in First Complete Remission: A MyeloMATCH Sub-Study
  • A Phase I Study Evaluating the Safety of Cirtuvivint as Monotherapy and in Combination With ASTX727 in Patients With Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)
  • A Multicenter, Single-Arm Phase I/II Clinical Study of the Venetoclax, Ivosidenib, and Azacitidine Triple-Drug Regimen in the Treatment of Chemotherapy-eligible Adult Patients With IDH1-Mutated Acute Myeloid Leukemia.
  • Efficacy Analysis of Comparison of CAMS-2005 Trial and CAMS-2009 Trial for Pediatric Acute Myeloid Leukemia
  • National Longitudinal Cohort of Hematological Diseases (NICHE)
  • A Randomized Phase 2 Trial of Olutasidenib-Based Therapies in Patients With Newly Diagnosed IDH1-Mutant Myeloid Malignancies: A MyeloMATCH Substudy
  • A Measurable Residual Disease (MRD) Focused, Phase II Study of Venetoclax Plus Chemotherapy for Newly Diagnosed Younger Patients With Intermediate Risk Acute Myeloid Leukemia: A Tier 1 MYELOMATCH SubStudy
  • A Multicenter, Randomized, Controlled Trial of a Triple-Drug Regimen (Venetoclax, Azacitidine, Gilteritinib) Followed by Intensive Chemotherapy, Versus Standard Chemotherapy Plus Gilteritinib, in Fit Adults With Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia.
  • Electronic Health Mindfulness-based Music Therapy Intervention for Patients Undergoing Allogeneic Stem Cell Transplantation
  • Red Blood Cell Transfusion Threshold-Specific Bleeding, Quality of Life and Functional Outcomes in Acute Leukemia Patients With Thrombocytopenia: a Randomized Feasibility Study
  • Eradicating Measurable Residual Disease in Patients With Acute Myeloid Leukemia (AML) Prior to StEm Cell Transplantation (ERASE): A MyeloMATCH Treatment Trial
  • Master Screening and Reassessment Protocol (MSRP) for the NCI MyeloMATCH Clinical Trials
  • A Phase 2, Randomized, Double-Blind, Placebo-controlled Study to Compare Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care Versus Best Supportive Care as Maintenance Therapy in Japanese Subjects With Acute Myeloid Leukemia in Complete Remission
  • An Exploratory Clinical Study on the Safety and Efficacy of LILRB4 STAR-T Cells in the Treatment of Monocytic Leukemia
  • Phase I Study to Evaluate the Safety and Efficacy of NK Cell Therapy in Acute Myeloid Leukemia (AML).
  • A Phase I Study of ADCLEC.syn1 CAR T Cells in Adult Patients With Relapsed or Refractory Acute Myeloid Leukemia
  • Ivosidenib in Combination With Azacitidine as First-line Treatment for Adult Patients With Newly Diagnosed AML With an IDH1 R132 Mutation Who Are Not Eligible to Receive Standard Induction Chemotherapy
  • A Phase 1, Open-Label, Dose Escalation and Expansion Study of STX-0712 in Patients With Advanced Hematologic Malignancies
  • IMPACT-AML: A Randomized Pragmatic Clinical Trial for Relapsed or Refractory Acute Myeloid Leukemia. IMPACT-AML RPCT
  • Phase 1/1b Trial of Donor γδ T--Cell Infusion for Treatment of Patients With Acute Myeloid Leukemia at High Risk of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation
  • Familial Investigations of Childhood Cancer Predisposition

Therapeutic area: Oncology

Acute Myeloid Leukemia (C92.00)