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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Question 1HematologyMedium
A 45-year-old male presents with fatigue, easy bruising, and bone pain. Labs reveal pancytopenia, blasts on peripheral smear with Auer rods. Bone marrow biopsy shows >20% myeloblasts. Which of the following cytogenetic findings carries the most favorable prognosis?
At(9;22) Philadelphia chromosome
BComplex karyotype
Ct(15;17) PML-RARA
DFLT3-ITD mutation
Reveal answer & full explanation
Correct answer: C — t(15;17) PML-RARA
At(9;22) Philadelphia chromosome
BComplex karyotype
Ct(15;17) PML-RARA✓
DFLT3-ITD mutation
Why t(15;17) PML-RARA is correct
The t(15;17) translocation produces the PML-RARA fusion gene, which defines acute promyelocytic leukemia (APL) — the most favorable cytogenetic subtype of acute myeloid leukemia (AML).
APL is uniquely treated with all-trans retinoic acid (ATRA) and arsenic trioxide, achieving cure rates >90% without traditional chemotherapy.
Why the others are wrong
t(9;22) Philadelphia chromosome — is the defining abnormality of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL); in AML it confers unfavorable prognosis.
Complex karyotype — carries an unfavorable prognosis in AML.
FLT3-ITD mutation — is an unfavorable prognostic marker in AML, associated with high relapse risk.
Additional high-yield points
AML diagnosis requires at least 20% blasts in marrow or blood; Auer rods (azurophilic crystalline rods in the cytoplasm) are pathognomonic for AML.
APL-specific risk: high risk of disseminated intravascular coagulation (DIC) at diagnosis.
Standard AML induction (non-APL): 7+3 regimen (cytarabine + daunorubicin), followed by consolidation with or without allogeneic stem cell transplant (SCT).
Question 2HematologyMedium
A 67-year-old man presents with 3 weeks of progressive fatigue, dyspnea on exertion, and easy bruising. On exam he has conjunctival pallor and scattered petechiae over both shins. A CBC shows hemoglobin 7.8 g/dL, platelets 22,000/µL, and a WBC of 38,000/µL with circulating large immature cells. A peripheral blood smear is reviewed. Which of the following findings on the smear best supports a diagnosis of acute myeloid leukemia?
AAuer rods within the immature blasts
BTdT-positive lymphoblasts on the smear
CTeardrop cells with nucleated red cells
DSmudge cells filling the entire field
Reveal answer & full explanation
Correct answer: A — Auer rods within the immature blasts
AAuer rods within the immature blasts✓
BTdT-positive lymphoblasts on the smear
CTeardrop cells with nucleated red cells
DSmudge cells filling the entire field
Why Auer rods within the immature blasts is correct
Auer rods are eosinophilic, needle-like cytoplasmic inclusions of fused azurophilic (primary) granules seen within myeloblasts; they are pathognomonic for acute myeloid leukemia (AML) and confirm myeloid lineage.
In an older adult with pancytopenia, circulating blasts, and Auer rods, AML is the diagnosis; bundles of Auer rods (faggot cells) specifically characterize acute promyelocytic leukemia (APL).
Diagnosis is then confirmed with bone marrow showing >=20% myeloid blasts (WHO 5th edition), flow cytometry (CD13, CD33, CD117, MPO), and cytogenetics/molecular testing.
Why the others are wrong
TdT-positive lymphoblasts on the smear — TdT positivity and lymphoid markers (CD19, CD10) indicate acute lymphoblastic leukemia, not AML, which is MPO-positive and TdT-negative.
Smudge cells filling the entire field — fragile lymphocytes that rupture on smear preparation are the classic clue to chronic lymphocytic leukemia, a mature B-cell disorder of older adults, not an acute myeloid blast process.
Teardrop cells with nucleated red cells — a leukoerythroblastic smear with dacrocytes suggests marrow infiltration/fibrosis such as primary myelofibrosis, not the blast-driven pancytopenia of AML.
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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).
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
≥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)
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
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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