Acute Myeloid Leukemia (AML)

Bone marrow aspirate slides for diagnosis
Bone marrow aspirate slides for diagnosis

Table of Contents

  1. Overview and Pathophysiology
  2. Classification — WHO 2022 and FAB
  3. Clinical Presentation
  4. Diagnosis — Peripheral Blood and Bone Marrow
  5. Prognostic Risk Stratification — ELN 2022
  6. Acute Promyelocytic Leukemia (APL) — Special Case
  7. Standard Treatment — Intensive Induction
  8. Targeted Therapies
  9. Allogeneic Stem Cell Transplant
  10. Supportive Care and Special Populations
  11. Key Research Papers
  12. Connections
  13. Featured Videos

Overview and Pathophysiology

Acute Myeloid Leukemia (AML) — also called Acute Nonlymphocytic Leukemia (ANLL) — is the most common acute leukemia in adults, defined by the presence of 20% or more myeloblasts in the bone marrow or peripheral blood. AML is an aggressive, rapidly progressive malignancy with a median age at diagnosis of 70 years (U.S. National Cancer Institute SEER data, 2019–2023); it is most frequently diagnosed among people aged 65–74. The National Cancer Institute estimates about 22,720 new cases and 11,500 deaths in the United States in 2026.

AML arises from the clonal proliferation of immature myeloid progenitor cells — myeloblasts — that are arrested at an early stage of development and cannot mature into functional blood cells. These blasts accumulate in the bone marrow and displace normal hematopoiesis, causing the defining clinical consequence: pancytopenia (anemia, neutropenia, thrombocytopenia).

Normal Myelopoiesis and What Goes Wrong

In healthy bone marrow, hematopoietic stem cells differentiate through a stepwise commitment process: common myeloid progenitor → granulocyte-monocyte progenitor → myeloblast → promyelocyte → myelocyte → metamyelocyte → mature granulocyte (neutrophil, eosinophil, basophil) or monocyte. In AML, driver mutations block this maturation cascade at the myeloblast or promyelocyte stage. The arrested cells retain self-renewal capacity and proliferate uncontrollably, filling the marrow cavity and spilling into the bloodstream while producing none of the mature cells the body needs to fight infection, carry oxygen, or form clots.

Multi-Step Mutational Pathogenesis and CHIP

AML does not arise from a single hit. Current models support a multi-step acquisition of cooperating driver mutations in hematopoietic stem and progenitor cells. The earliest mutations — often in DNMT3A, TET2, or ASXL1 — confer a subtle proliferative advantage and can be found in a small fraction of blood cells in apparently healthy older adults, a pre-malignant state called clonal hematopoiesis of indeterminate potential (CHIP). CHIP is extremely common over age 70 (present in >10% of individuals) and carries a modestly elevated risk of progression to hematologic malignancy — roughly 0.5–1% per year. When additional "Class I" mutations activating proliferative signaling (FLT3-ITD, NRAS, KRAS) or "Class II" mutations impairing differentiation (NPM1, RUNX1, CEBPA, core-binding factor translocations) are acquired on this CHIP background, full leukemic transformation occurs. This "two-hit model" explains why AML tends to emerge over years from a pre-existing clonal substrate rather than appearing de novo without antecedent changes.

Secondary AML

A clinically important subset — therapy-related AML (t-AML) and AML arising from prior myeloid disorders (AML-MRC) — has worse prognosis than de novo AML. Secondary AML arises from:

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Classification — WHO 2022 and FAB

AML has historically been classified by cell morphology (the FAB system) and is now primarily classified by genomic features in the WHO 2022 fifth edition, which recognizes that specific genetic abnormalities define biologically and prognostically distinct entities.

WHO 2022 Fifth Edition — Genetic-Based Classification

The 2022 WHO classification reorganizes AML into molecularly defined categories, each named by its defining driver mutation or translocation:

FAB Classification (Historical but Clinically Used)

The French-American-British (FAB) classification, based on morphology and cytochemistry, remains in clinical use to describe blast morphology and lineage and to identify APL rapidly:

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Clinical Presentation

AML typically presents with a rapid onset over days to weeks — contrasting sharply with chronic myeloid diseases (chronic myeloid leukemia, CML; MDS) that evolve over months to years. Patients often recall feeling well just a few weeks before presenting with dramatic symptoms. The clinical picture is dominated by the consequences of bone marrow failure (pancytopenia) and, in some subtypes, extramedullary infiltration of leukemic blasts.

Symptoms from Pancytopenia

Leukostasis Syndrome

When the circulating blast count exceeds approximately 100,000/µL, extreme hyperviscosity produces vascular sludging in small vessels — a hematologic emergency. Two organs are most vulnerable:

Treatment is urgent cytoreduction: leukapheresis provides rapid mechanical blast removal and is the fastest intervention; hydroxyurea (1–3 g orally, repeated doses) provides pharmacologic cytoreduction within 24–48 hours. In practice, red blood cell transfusion is held back until the blast count is controlled, because it raises viscosity further.

Gingival Hypertrophy

A distinctive physical finding in monocytic subtypes (FAB M4 and M5): leukemic monocytes infiltrate gingival tissue, causing spongy, hemorrhagic, and swollen gums that bleed spontaneously. The gingival enlargement can be so extensive it partially covers the teeth. Clinicians treat this finding as a strong clue to AML and check flow cytometry for monocytic markers (CD14, CD16, CD64).

Chloroma (Myeloid Sarcoma)

A chloroma — also called a myeloid sarcoma or granulocytic sarcoma — is an extramedullary collection of myeloblasts forming a solid tumor mass at a site outside the bone marrow. The greenish-gray color (from myeloperoxidase) gives it the name "chloroma" (Greek: chloros, green). Chloromas can precede bone marrow involvement, occur simultaneously with AML, or signal relapse. Common sites include the orbit (proptosis, diplopia), skin (leukemia cutis — violaceous or slate-gray nodules), lymph nodes, central nervous system (CNS), and spinal cord (causing cord compression). For this reason, AML is among the possible causes of an unexplained solid tumor in a young-to-middle-aged adult.

Bone Pain and Sternal Tenderness

Marrow expansion by rapidly proliferating blasts causes diffuse bone pain, especially sternal tenderness on direct pressure — a classic physical examination finding that distinguishes marrow infiltration from musculoskeletal pain of other causes.

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Diagnosis — Peripheral Blood and Bone Marrow

AML diagnosis requires integration of peripheral blood morphology, bone marrow findings, immunophenotyping, cytogenetics, and molecular mutation testing. The threshold for diagnosis is ≥20% myeloblasts in the bone marrow or peripheral blood (WHO 2022), although cases with defining genetic abnormalities (e.g., t[8;21], inv[16], t[15;17]) are diagnosed as AML regardless of blast percentage.

Peripheral Blood Smear — Key Findings

Bone Marrow Biopsy and Aspirate

Mandatory for AML diagnosis and provides material for all subsequent analyses:

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Prognostic Risk Stratification — ELN 2022

The European LeukemiaNet (ELN) 2022 Risk Stratification is the standard framework guiding consolidation therapy decisions, particularly whether to proceed with allogeneic stem cell transplant in first complete remission (CR1). Published by Döhner et al. in Blood (2022), it integrates cytogenetics and molecular mutation data into three risk groups:

Favorable Risk — 50–60% 5-Year Overall Survival

Favorable-risk AML is treated with intensive induction and high-dose cytarabine (HDAC) consolidation without allogeneic SCT in CR1, because transplant-related mortality outweighs the benefit in this group.

Intermediate Risk

In practice, allogeneic SCT in CR1 is considered for intermediate-risk patients when a suitable donor is available, balancing transplant-related mortality against relapse risk, and clinical trial enrollment is commonly offered to this group.

Adverse Risk — 20–30% 5-Year Overall Survival; Allogeneic SCT Recommended in CR1

Adverse-risk patients have poor outcomes with chemotherapy alone. Allogeneic SCT in CR1 is strongly recommended when feasible. Novel agents (venetoclax, IDH inhibitors, FLT3 inhibitors) are being incorporated into induction and maintenance strategies to improve transplant eligibility and post-transplant outcomes.

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Acute Promyelocytic Leukemia (APL) — Special Case

APL (FAB M3) is a distinct AML subtype defined by the t(15;17)(q24.1;q21.2) translocation that fuses the PML (promyelocytic leukemia) gene to the RARA (retinoic acid receptor alpha) gene. The resulting PML::RARA oncoprotein blocks myeloid differentiation at the promyelocytic stage by acting as a dominant-negative repressor of retinoic acid signaling, causing accumulation of hypergranular, immature promyelocytes. APL was once uniformly fatal; it is now the most curable adult AML, with over 95% cure rates in low-to-intermediate risk patients — a triumph of targeted differentiation therapy.

Two Morphologic Variants

Disseminated Intravascular Coagulation — The Defining Emergency

The azurophilic granules of APL promyelocytes are packed with procoagulant substances (tissue factor, annexin II, protease-3) that are released upon cell death — whether spontaneous or from chemotherapy. This triggers a catastrophic combined coagulopathy: thrombosis (from thrombin activation) plus hyperfibrinolysis (from plasminogen activator release). Laboratory findings: prolonged prothrombin time and partial thromboplastin time (PT/PTT), very low fibrinogen (<100–150 mg/dL), markedly elevated D-dimer, and thrombocytopenia. Microangiopathic hemolytic anemia may also be present. Management is an emergency:

Treatment — ATRA and ATO

All-trans retinoic acid (ATRA) (tretinoin, 45 mg/m²/day orally in divided doses) induces terminal differentiation of PML::RARA-blocked promyelocytes into mature granulocytes, bypassing the block. It was first shown to induce complete remissions in APL by Huang et al. in 1988 — a landmark moment in targeted oncology. The critical rule in APL care: ATRA is started immediately upon clinical suspicion of APL (Faggot cells, low WBC with hypergranular blasts, young patient with DIC), even before FISH or polymerase chain reaction (PCR) confirmation, because every hour of delay increases the risk of death from bleeding.

Arsenic trioxide (ATO) (0.15 mg/kg/day intravenous, IV) acts synergistically with ATRA by degrading the PML::RARA fusion protein through a different mechanism (SUMOylation and ubiquitin-proteasomal degradation). The landmark APL0406 trial (Lo-Coco et al., NEJM 2013) showed that in low-to-intermediate risk APL, ATRA+ATO was non-inferior and also superior to ATRA+chemotherapy on its primary endpoint, 2-year event-free survival (97% vs 86%; P=0.02 for superiority), and overall survival was also better (P=0.02). ATRA+ATO caused less hematologic toxicity and fewer infections but more liver toxicity. ATRA+ATO is now the standard of care for non-high-risk APL.

High-risk APL (WBC >10,000/µL at diagnosis) has higher early mortality from differentiation syndrome and hemorrhage. Current protocols add gemtuzumab ozogamicin or cytarabine-based chemotherapy to ATRA+ATO for this group.

Differentiation Syndrome

A potentially fatal complication of ATRA and/or ATO therapy occurring 2–21 days after treatment initiation (previously called Retinoic Acid Syndrome). Differentiating promyelocytes release inflammatory cytokines (interleukin-1, interleukin-6 (IL-6), tumor necrosis factor-α) and adhere to endothelium, causing:

Treatment: standard practice is dexamethasone 10 mg intravenous every 12 hours, started at the first signs without waiting for the syndrome to worsen. ATRA/ATO is temporarily held in severe cases (respiratory failure requiring intensive care unit, ICU). Most cases respond to steroids within 24–48 hours. Prophylactic prednisone during early therapy is used in some protocols for high-risk APL.

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Standard Treatment — Intensive Induction

The goal of induction therapy is to achieve complete remission (CR), defined as <5% blasts in the bone marrow, recovery of normal blood counts (absolute neutrophil count ≥1,000/µL; platelets ≥100,000/µL), and no Auer rods or extramedullary disease. Induction is the most medically intense phase of AML treatment and requires hospitalization at a center with intensive care capability.

"7+3" Standard Induction

The backbone of intensive AML induction for five decades remains the 7+3 regimen: cytarabine (ARA-C) 100–200 mg/m²/day as a 24-hour continuous intravenous infusion for 7 days, combined with idarubicin (12 mg/m²/day intravenous × 3 days) or daunorubicin (60–90 mg/m²/day × 3 days). The Fernandez et al. Eastern Cooperative Oncology Group (ECOG) trial (NEJM 2009) established that high-dose daunorubicin (90 mg/m²) was superior to standard-dose (45 mg/m²) in patients ≤60, improving CR rates and survival. Idarubicin is generally preferred in younger patients for its superior central nervous system penetration and pharmacokinetic profile.

CR rates: 60–85% in younger, fit patients; 40–60% in patients over 60. After induction, the bone marrow enters an aplasia phase (days 7–21) when virtually all bone marrow cells — both leukemic and normal — are destroyed by chemotherapy. Patients are profoundly pancytopenic and at maximum risk for infection and bleeding. Intensive supportive care (antibiotics, antifungals, transfusions, growth factors) is critical during this window.

Liposomal Daunorubicin-Cytarabine (CPX-351) for Secondary AML

CPX-351, a liposomal formulation of cytarabine and daunorubicin in a fixed 5:1 molar ratio, was U.S. Food and Drug Administration-approved in 2017 for therapy-related AML and AML with myelodysplasia-related changes (AML-MRC). The Lancet et al. JCO 2018 trial showed significantly improved overall survival (OS; 9.56 vs 5.95 months median) and higher rates of complete remission plus complete remission with incomplete hematologic recovery (CR+CRi; 47.7% vs 33.3%) versus standard 7+3 in these high-risk secondary AML subtypes, establishing CPX-351 as the standard induction for t-AML and AML-MRC.

Consolidation Therapy

After CR1, the remaining minimal residual disease (MRD) must be eradicated with consolidation therapy to prevent relapse:

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Targeted Therapies

The 2017–2022 period saw an unprecedented wave of U.S. Food and Drug Administration (FDA) approvals for molecularly targeted agents in AML, moving the field from one-size-fits-all chemotherapy toward mutation-specific precision medicine. Molecular testing is now mandatory at diagnosis to identify actionable targets.

FLT3 Inhibitors

FLT3 mutations — either internal tandem duplications (FLT3-ITD) or tyrosine kinase domain point mutations (FLT3-TKD D835) — are the most common targetable mutations in AML (~30% FLT3-ITD; ~7% FLT3-TKD). FLT3-ITD confers adverse prognosis through constitutive activation of downstream STAT5, PI3K/AKT, and MAPK proliferative signaling.

IDH Inhibitors

IDH1 and IDH2 mutations cause accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which inhibits TET2 and histone demethylases, blocking differentiation through epigenetic silencing. Together they account for ~20% of AML.

Venetoclax + Azacitidine (VEN+AZA)

The VIALE-A trial (DiNardo et al., NEJM 2020; N=431) is the most practice-changing trial in AML in decades. Venetoclax (a BCL-2 inhibitor that restores apoptosis in AML blasts) plus azacitidine (a hypomethylating agent) vs azacitidine alone in patients with newly diagnosed AML ineligible for intensive chemotherapy showed:

VEN+AZA is now the standard of care for older/unfit patients with newly diagnosed AML across most molecular subtypes and has largely replaced lower-intensity single-agent hypomethylating agent (HMA) therapy.

Gemtuzumab Ozogamicin (GO)

GO is a CD33-targeted antibody conjugated to the cytotoxic antibiotic calicheamicin. U.S. Food and Drug Administration re-approved in 2017 after initial withdrawal due to veno-occlusive disease (VOD) concerns that were mitigated with fractionated dosing. Current indications:

GO carries a risk of sinusoidal obstruction syndrome/VOD (especially post-SCT); contraindicated in severe hepatic dysfunction.

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Allogeneic Stem Cell Transplant (Allo-SCT)

Allogeneic SCT remains the only potentially curative treatment for high-risk AML and is considered the definitive consolidation for adverse- and most intermediate-risk patients. The donor immune system provides the critical graft-versus-leukemia (GVL) effect — donor T cells and natural killer (NK) cells recognize and destroy residual AML cells bearing non-self antigens, explaining why allo-SCT produces lower relapse rates than intensive chemotherapy consolidation in high-risk disease. Cure rates for adverse-risk AML with SCT in CR1 range from 30–50% depending on disease characteristics and transplant platform.

Indications

Donor Types

Conditioning Regimens

Major Complications

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Supportive Care and Special Populations

Neutropenic Fever Protocol

Neutropenic fever (absolute neutrophil count <500/µL + temperature ≥38.3°C once or ≥38.0°C over 1 hour) is a medical emergency. The Infectious Diseases Society of America (IDSA) and National Comprehensive Cancer Network (NCCN) guidance lists:

  1. Blood cultures × 2 (peripheral + central line if present), urine culture, chest X-ray.
  2. Start broad-spectrum antibacterial therapy within 1 hour of presentation: monotherapy with an anti-pseudomonal beta-lactam (cefepime or piperacillin-tazobactam; meropenem for prior resistant organisms or clinical deterioration).
  3. Add vancomycin for suspected catheter-related infection, skin/soft tissue infection, pneumonia, or hemodynamic instability (methicillin-resistant Staphylococcus aureus (MRSA) coverage).
  4. Add antifungal therapy (micafungin or voriconazole; caspofungin is an alternative) for persistent fever after 4–7 days of antibiotics, prolonged neutropenia (>7 days expected), or prior fungal colonization.
  5. G-CSF (granulocyte colony-stimulating factor: filgrastim, pegfilgrastim) — a 2012 Cochrane review of 19 trials (5,256 patients with AML) found that adding colony-stimulating factors to chemotherapy made no difference to complete remission, relapse rates or overall survival, nor to bacteremias or invasive fungal infections, and concluded that they should not be given routinely to AML patients after chemotherapy. Post-SCT use is standard to hasten engraftment.

Transfusion Support

Tumor Lysis Syndrome (TLS)

Rapid blast destruction (spontaneous or from treatment) releases intracellular contents: uric acid (from purine catabolism), phosphate, potassium. Resulting metabolic emergencies: hyperuricemia, hyperphosphatemia (→ hypocalcemia), hyperkalemia, acute kidney injury from urate crystal deposition. Management: aggressive intravenous hydration (200–300 mL/hour), rasburicase (recombinant uricase; converts uric acid to the water-soluble allantoin; most potent uric acid-lowering agent; contraindicated in glucose-6-phosphate dehydrogenase (G6PD) deficiency due to hemolysis risk, so G6PD testing is done before use); allopurinol for low-risk patients and those with glucose-6-phosphate dehydrogenase deficiency; strict cardiac monitoring for hyperkalemia-induced arrhythmias; renal replacement therapy (dialysis) for severe acute kidney injury (AKI).

Older and Unfit Patients

Nearly 50% of AML patients are over 65 and/or have comorbidities precluding intensive 7+3 chemotherapy (ECOG performance status ≥3, severe organ dysfunction, patient preference). Options in this rapidly evolving landscape:

AML During Pregnancy

Extremely rare (<0.1/100,000 pregnancies) but requires coordinated multidisciplinary management between hematology and maternal-fetal medicine. Anthracyclines (daunorubicin, idarubicin) are relatively safe after the first trimester and have been used with acceptable fetal outcomes. Cytarabine is teratogenic in the first trimester; after the first trimester it carries risk of intrauterine growth restriction and neonatal bone marrow suppression. ATRA is a potent teratogen and is not used in the first trimester (APL in pregnancy requires specialized protocols). Early delivery (if gestational age permits viability) may allow initiation of full-dose induction therapy. Newborns of mothers who received chemotherapy are evaluated for cytopenias and given supportive care.

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Key Research Papers

The following peer-reviewed publications represent landmark studies in AML pathogenesis, classification, and treatment. Entries with a PMID link to the paper on PubMed; the others link to a PubMed search.

  1. Stone RM et al. (2017) RATIFY trial: midostaurin + 7+3 in FLT3+ AML. — PubMed PMID: 28644114
  2. DiNardo CD et al. (2020) VIALE-A: venetoclax + azacitidine in unfit AML. — PubMed PMID: 32786187
  3. Lo-Coco F et al. (2013) APL0406: retinoic acid and arsenic trioxide for acute promyelocytic leukemia. — PubMed PMID: 23841729
  4. Döhner H et al. (2022) ELN 2022 recommendations: diagnosis and management of AML in adults. — PubMed PMID: 35797463
  5. Search PubMed
  6. Papaemmanuil E et al. (2016) Genomic classification of AML. — PubMed PMID: 27276561
  7. Search PubMed
  8. Search PubMed
  9. Search PubMed
  10. Search PubMed
  11. Search PubMed
  12. Search PubMed

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Connections

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