Hematology · PANCE / PANRE

Acute Myeloid Leukemia (AML)

Clonal expansion of myeloid blasts in marrow and blood — pancytopenia plus circulating blasts; APL subtype is a hemorrhagic emergency.

Also known as: AML, acute myelogenous leukemia, acute myeloblastic leukemia, APL, acute promyelocytic leukemia

Overview

Clonal hematopoietic malignancy characterized by accumulation of immature myeloid cells (myeloblasts) in the bone marrow, peripheral blood, and other tissues, with impaired differentiation. Diagnosis requires ≥20% blasts in marrow or peripheral blood (WHO criteria) — or any percentage with diagnostic cytogenetics (t(15;17), t(8;21), inv(16), t(16;16)).

Epidemiology

Most common acute leukemia in adults; median age at diagnosis ~68 years. US incidence ~4 per 100,000; rises sharply with age. Slight male predominance. Acute promyelocytic leukemia (APL) is a unique subtype that can present at any age.

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Risk factors

  • Age >60
  • Prior cytotoxic chemotherapy (alkylators, topoisomerase II inhibitors) or radiation — therapy-related AML
  • Antecedent hematologic disorder: MDS, MPN, aplastic anemia
  • Genetic syndromes: Down syndrome (transient and persistent leukemia), Fanconi anemia, Li-Fraumeni, neurofibromatosis, familial AML
  • Environmental: benzene exposure, smoking, ionizing radiation
  • Germline DDX41, RUNX1, GATA2, CEBPA mutations

Pathophysiology

Acquired genetic and epigenetic alterations (often FLT3, NPM1, CEBPA, IDH1/2, TET2, DNMT3A mutations; or recurrent translocations such as t(15;17) in APL) impair myeloid differentiation and promote proliferation. Blasts accumulate in the marrow, suppressing normal hematopoiesis (causing anemia, thrombocytopenia, neutropenia) and infiltrating extramedullary sites. APL has the unique t(15;17) PML-RARA fusion that responds dramatically to all-trans retinoic acid (ATRA).

Clinical presentation

Symptoms

  • Pancytopenia symptoms: fatigue, dyspnea, pallor (anemia); easy bruising, petechiae, mucosal bleeding (thrombocytopenia); fever, recurrent infections (neutropenia)
  • Constitutional: fever, night sweats, weight loss
  • Leukostasis (WBC >100K with blasts): dyspnea, hypoxemia, altered mental status, retinal hemorrhages — medical emergency
  • Extramedullary involvement: gum hypertrophy (M4/M5 monocytic subtypes), skin (leukemia cutis), CNS, myeloid sarcoma (granulocytic sarcoma)
  • APL: DISPROPORTIONATE BLEEDING from DIC and hyperfibrinolysis — intracranial, pulmonary, mucosal hemorrhage

Signs / physical exam

  • Pallor, petechiae, ecchymoses, mucosal bleeding
  • Hepatosplenomegaly (less prominent than in CML/CLL)
  • Lymphadenopathy uncommon
  • Gum hypertrophy (monocytic subtypes)
  • Leukemia cutis: violaceous nodules or plaques
  • Fever (sepsis or disease)

Classic findings

Older adult with pancytopenia, fatigue, petechiae, and Auer rods on blast smear. APL: severe DIC with intracranial or pulmonary hemorrhage at presentation.

Differential diagnosis

  • Acute lymphoblastic leukemia (ALL) — TdT positive, lymphoid markers (CD19, CD10); more common in children; CNS involvement more common
  • Myelodysplastic syndrome — Dysplastic features with <20% blasts; same cytopenia presentation; may evolve to AML
  • Aplastic anemia — Hypocellular marrow without blasts
  • Acute promyelocytic leukemia (APL) — AML subtype; t(15;17) PML-RARA; presents with DIC and severe bleeding; ATRA-responsive
  • Leukemoid reaction — Reactive myeloid hyperplasia, high LAP score, identifiable infection/inflammation; no blasts
  • Chronic myeloid leukemia (blast crisis) — Antecedent CML history, Philadelphia chromosome BCR-ABL1 fusion

Diagnostic workup

Diagnostic criteria

≥20% myeloid blasts in bone marrow or peripheral blood (WHO 5th edition); or any blast percentage with recurrent cytogenetic abnormality t(15;17), t(8;21), inv(16)/t(16;16). APL diagnosed by t(15;17) PML-RARA or PML-RARA fusion.

Labs

  • CBC — anemia, thrombocytopenia; WBC may be high, normal, or low; circulating blasts often visible
  • Peripheral smear — myeloblasts (large with prominent nucleoli and scant cytoplasm); AUER RODS (eosinophilic needle-like inclusions) are pathognomonic for AML; faggot cells (bundles of Auer rods) characterize APL
  • Bone marrow aspirate and biopsy — ≥20% blasts (or any % with recurrent cytogenetic abnormality)
  • Flow cytometry — myeloid markers CD13, CD33, CD117, MPO; rules out lymphoid lineage
  • Cytochemistry — myeloperoxidase (MPO) positive (myeloid lineage); nonspecific esterase positive in monocytic subtypes
  • Cytogenetics and FISH — recurrent abnormalities define WHO classification: t(15;17) PML-RARA (APL), t(8;21), inv(16)/t(16;16) (favorable), complex/monosomal karyotype (adverse), MLL/KMT2A rearrangements
  • Molecular: FLT3-ITD/TKD, NPM1, CEBPA, IDH1/2, TP53, RUNX1, ASXL1 — prognostic and therapeutic targets
  • Coagulation studies (essential in APL): PT, PTT, fibrinogen, D-dimer
  • LDH, uric acid (tumor lysis risk), tumor lysis labs (K, Ca, PO4, Cr)
  • Lumbar puncture only if CNS symptoms or selected high-risk subtypes
  • HLA typing for potential allogeneic stem cell transplant

Imaging

  • CXR if pulmonary symptoms; chest CT for febrile neutropenia evaluation
  • Echocardiogram before anthracycline therapy
  • CT or MRI head if neurologic symptoms

Diagnostic algorithm

Risk Group (ELN 2022)Genetic FindingsApproach
Favorablet(15;17) PML-RARA (APL); t(8;21); inv(16)/t(16;16); NPM1 mutated without FLT3-ITD; biallelic CEBPAChemotherapy alone; APL: ATRA + ATO
IntermediateNPM1 mutated with FLT3-ITD; wild-type NPM1 with FLT3-ITD; t(9;11); cytogenetic abnormalities not in favorable/adverseConsider HSCT in CR1
AdverseComplex karyotype, monosomy 5/7, -17/abn(17p), TP53 mutation, ASXL1, RUNX1, EZH2, BCOR mutations; KMT2A rearrangementsHSCT in CR1; targeted therapy
ELN 2022 AML risk stratification — guides post-remission strategy.

Treatment

First-line

  • Induction chemotherapy '7+3': cytarabine (continuous infusion × 7 days) + anthracycline (daunorubicin or idarubicin × 3 days) — standard for fit patients
  • Addition of midostaurin for FLT3-mutated AML (RATIFY trial); gilteritinib for FLT3-mutated relapsed/refractory
  • Older or unfit patients: venetoclax (BCL-2 inhibitor) + hypomethylating agent (azacitidine or decitabine) — standard of care for unfit/older patients (VIALE-A trial)
  • Consolidation after remission: high-dose cytarabine (HiDAC) for favorable cytogenetics; allogeneic HSCT for intermediate/adverse risk
  • APL: ALL-TRANS RETINOIC ACID (ATRA) + arsenic trioxide ± idarubicin/cytarabine — high cure rate (>90%). START ATRA EMPIRICALLY when APL suspected, before cytogenetic confirmation, to prevent fatal hemorrhage
  • Tumor lysis syndrome prophylaxis: IV fluids, allopurinol, rasburicase (avoid in G6PD deficiency)
  • Febrile neutropenia: empiric broad-spectrum antibiotics (cefepime, piperacillin-tazobactam, or carbapenem)

Second-line / adjunct

  • Allogeneic hematopoietic stem cell transplantation — definitive for intermediate/adverse-risk AML and relapsed disease
  • Targeted agents: midostaurin/gilteritinib/quizartinib (FLT3), ivosidenib/enasidenib/olutasidenib (IDH1/2), gemtuzumab ozogamicin (CD33), glasdegib (Hedgehog), magrolimab (CD47)
  • Investigational: menin inhibitors for KMT2A-rearranged AML
  • ATRA differentiation syndrome (APL): hold ATRA, give dexamethasone, supportive care
  • Maintenance: oral azacitidine (CC-486) after consolidation in fit patients (QUAZAR trial)

Complications

  • Pancytopenia complications: severe infection (bacterial, fungal — Aspergillus, Candida), bleeding (intracranial, GI, mucosal)
  • Tumor lysis syndrome: hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia, AKI
  • Leukostasis with WBC >100K — pulmonary, CNS, retinal complications
  • DIC, especially APL — leading cause of early mortality in APL
  • ATRA differentiation syndrome — fever, dyspnea, pulmonary infiltrates, hypoxia, edema, hypotension during APL induction; mortality ~10% if untreated
  • Chemotherapy toxicity: cardiotoxicity (anthracyclines), mucositis, alopecia, neuropathy, secondary malignancy
  • Allogeneic HSCT complications: GVHD (acute, chronic), graft failure, infection, transplant-related mortality

PANCE pearls

  • Auer rods on peripheral smear are PATHOGNOMONIC for AML; faggot cells (bundles of Auer rods) characterize APL.
  • APL is a medical emergency — DIC with severe bleeding kills patients within days of presentation. Start ATRA on clinical suspicion BEFORE cytogenetic confirmation.
  • APL paradoxically has the HIGHEST cure rate of any AML subtype with ATRA + arsenic trioxide (>90% long-term remission).
  • FLT3 mutations carry worse prognosis but are targetable with midostaurin (induction) and gilteritinib (relapsed).
  • Venetoclax + azacitidine has transformed outcomes for older/unfit AML patients (median OS 14.7 months vs 9.6 with azacitidine alone — VIALE-A).
  • TLS prophylaxis with allopurinol and IV fluids is mandatory; rasburicase for high-risk cases (high WBC, high LDH, high uric acid) — but check G6PD first.
  • Allogeneic stem cell transplant in CR1 is recommended for intermediate/adverse-risk AML; favorable-risk patients (CBF leukemias, mutated NPM1 without FLT3-ITD) often spared.
  • Down syndrome AML (especially megakaryoblastic, M7) has favorable outcomes with attenuated regimens — distinct biology.

References

  • ELN 2022 — Diagnosis and management of AML in adults: 2022 ELN recommendations (Döhner et al., Blood 2022)
  • VIALE-A — Azacitidine and Venetoclax in Previously Untreated AML (DiNardo et al., NEJM 2020)
  • RATIFY — Midostaurin plus Chemotherapy for AML with FLT3 Mutation (Stone et al., NEJM 2017)
  • APML4 — ATRA + arsenic trioxide for newly diagnosed APL (Lo-Coco et al., NEJM 2013)
  • WHO 5th edition — WHO Classification of Haematolymphoid Tumours, 5th edition (2022)

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Related Hematology diagnoses

Iron Deficiency AnemiaAnemia of Chronic Disease (Anemia of Inflammation)Vitamin B12 Deficiency / Pernicious AnemiaFolate Deficiency AnemiaSickle Cell DiseaseThalassemia (Alpha and Beta)G6PD DeficiencyAplastic AnemiaWarm Autoimmune Hemolytic AnemiaImmune Thrombocytopenic Purpura (ITP)Thrombotic Thrombocytopenic Purpura (TTP) / Hemolytic Uremic Syndrome (HUS)Disseminated Intravascular Coagulation (DIC)Hemophilia A and BVon Willebrand Disease

Differentials & related conditions

Acute Lymphoblastic Leukemia (ALL)Myelodysplastic Syndrome (MDS)Chronic Myeloid Leukemia (CML)

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