Acute Myeloid Leukemia (AML): Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Acute myeloid leukemia (AML) is an aggressive malignancy arising from clonal expansion of immature myeloid progenitor cells (myeloblasts) that accumulate in the bone marrow, blood, and extramedullary sites while suppressing normal hematopoiesis. AML comprises approximately 80% of acute leukemias in adults, with approximately 20,000 new US cases annually. Median age at diagnosis is 68 years, making it primarily a disease of older adults; only approximately 15% of cases occur in individuals under 40. AML is highly heterogeneous — WHO 2022 classification defines distinct entities by cytogenetics and molecular mutations, which determine prognosis and therapy. The overall 5-year survival is approximately 28%, but outcomes vary dramatically: acute promyelocytic leukemia (APL) — defined by PML-RARA fusion from t(15;17) — is now cured with ATRA plus arsenic trioxide in over 90% of cases, while AML with complex karyotype or TP53 mutation carries a 5-year survival below 10%. The introduction of targeted therapies — midostaurin for FLT3-mutated AML (RATIFY trial), venetoclax plus azacitidine for older patients (VIALE-A trial), ivosidenib and enasidenib for IDH-mutated AML — has meaningfully expanded treatment options beyond the 7+3 cytarabine-anthracycline backbone.

AML arises from clonal selection of hematopoietic stem or progenitor cells that acquire somatic driver mutations conferring survival, proliferative, and differentiation block advantages. Recognized risk factors include: prior cytotoxic chemotherapy — alkylating agents (cyclophosphamide, melphalan) cause therapy-related AML with monosomy 5/7 (latency 5-7 years); topoisomerase II inhibitors (etoposide, anthracyclines) cause AML with KMT2A rearrangements (latency 1-3 years); prior radiotherapy; benzene and petroleum product exposure; cigarette smoking (contributes via benzene exposure); myelodysplastic syndrome (MDS, myeloproliferative neoplasms, aplastic anemia) progressing to AML; and inherited predisposition syndromes: Down syndrome (trisomy 21), Fanconi anemia (FANC genes), Diamond-Blackfan anemia, GATA2 deficiency, and germline RUNX1 or CEBPA mutations. Key somatic driver mutations in AML: FLT3-ITD or TKD (~30%); NPM1 (~30%); DNMT3A (~20%); IDH1 (~7%) and IDH2 (~11%); RUNX1; ASXL1; TP53 (adverse); and core-binding factor translocations inv(16)/t(8;21) (favorable). Clonal hematopoiesis of indeterminate potential (CHIP) — somatic DNMT3A, TET2, or ASXL1 mutations in aging hematopoietic stem cells — is a precursor state with approximately 0.5-1% annual AML transformation risk.

AML typically presents with rapid-onset symptoms over days to weeks, reflecting bone marrow failure and blast organ infiltration. Anemia: severe progressive fatigue, dyspnea on minimal exertion, pallor, palpitations, and dizziness — often the earliest and most prominent symptom. Neutropenia: unexplained fever (temperature above 38°C), recurrent or refractory bacterial infections (pneumonia, sinusitis, perirectal abscess), fungal infections (particularly Aspergillus and Candida in severely neutropenic patients), and oral mucosal ulcers. Thrombocytopenia: spontaneous bruising, petechiae (pinpoint skin hemorrhages), mucosal bleeding including gingival bleeding and epistaxis, and potentially life-threatening intracranial hemorrhage. AML-specific signs: gingival hypertrophy (marked swelling of the gums from leukemic infiltration — characteristic of monocytic AML subtypes M4-M5); leukemia cutis (violaceous skin nodules or rash from cutaneous blast infiltration); lymphadenopathy (less common than in ALL); hepatosplenomegaly with abdominal fullness. Acute promyelocytic leukemia (APL): presents with severe disseminated intravascular coagulation (DIC) causing life-threatening hemorrhage — this is an oncological emergency requiring immediate initiation of ATRA before confirmatory testing. Hyperleukocytosis (WBC above 100,000/μL): leukostasis causing respiratory failure, altered consciousness, and retinal hemorrhage — emergency management required.

AML diagnosis requires 20% or more myeloblasts in peripheral blood or bone marrow (WHO 2022 criteria), or any percentage if a defining AML-related genetic abnormality is present (e.g., t(8;21), inv(16), t(15;17)). Peripheral blood smear demonstrates circulating blasts, often with Auer rods (pathognomonic crystallized azurophilic granules — especially in AML with NPM1 mutation and core-binding factor AML). Bone marrow aspirate and trephine biopsy: morphological classification, cellularity, fibrosis assessment. Immunophenotyping by multiparameter flow cytometry: characterizes blast lineage (myeloid: CD33, CD13, CD117, MPO) and detects aberrant antigen expression enabling MRD monitoring. Cytogenetic analysis (karyotype by G-banding): essential for ELN 2022 risk stratification — favorable [t(8;21), inv(16)/t(16;16), t(15;17)], intermediate [normal karyotype, +8, del(7q)], or adverse [monosomy 5/7, complex karyotype, del(17p), t(6;9)]. Comprehensive molecular testing by NGS panel: FLT3-ITD allelic ratio and TKD, NPM1, IDH1, IDH2, DNMT3A, RUNX1, ASXL1, TP53, CEBPA (biallelic favorable) — all guide treatment and transplant decisions. ELN 2022 risk stratification drives consolidation and transplant planning.

Fit younger patients (under 60-65 with adequate organ function): induction chemotherapy with the 7+3 regimen — cytarabine 100-200 mg/m2 continuous infusion for 7 days plus idarubicin 12 mg/m2 for 3 days (or daunorubicin 60-90 mg/m2). FLT3-mutated AML: add midostaurin 50 mg BD to induction and consolidation (RATIFY trial: improved 5-year OS from 26% to 51% in FLT3+ AML). Induction achieves complete remission in 60-80% of younger patients. Consolidation therapy: high-dose cytarabine (HiDAC) 3 g/m2 every 12 hours, days 1, 3, 5 — 3-4 cycles for favorable-risk AML (NPM1+/FLT3-negative, CBF AML); allogeneic stem cell transplantation in first complete remission for intermediate- and adverse-risk AML. Older or unfit patients: venetoclax 400 mg daily plus azacitidine 75 mg/m2 SC days 1-7 — achieves complete remission in 65% of treatment-naive patients (VIALE-A trial: median OS 14.7 vs 9.6 months vs azacitidine alone, particularly in NPM1-mutated and IDH-mutated AML). Low-intensity decitabine or azacitidine monotherapy for very frail patients. Acute promyelocytic leukemia (APL): ATRA 45 mg/m2/day plus arsenic trioxide 0.15 mg/kg IV — achieves over 90% cure rate; ATRA must be started immediately upon morphological or clinical APL suspicion before molecular confirmation to prevent fatal DIC hemorrhage. Relapsed/refractory AML: gilteritinib (FLT3+ relapsed, ADMIRAL trial); ivosidenib (IDH1+ relapsed); enasidenib (IDH2+ relapsed); CPX-351 for secondary AML; gemtuzumab ozogamicin (anti-CD33 antibody-drug conjugate) for CD33+ AML; allogeneic SCT in second complete remission for eligible patients.

Overall 5-year survival for AML is approximately 28%, but outcomes vary dramatically by molecular subgroup, age, and treatment response. Acute promyelocytic leukemia (APL) is the most curable AML subtype — ATRA plus arsenic trioxide achieves cure rates exceeding 90% in low-to-intermediate-risk APL. Favorable-risk AML (NPM1-mutated without FLT3-ITD, CBF leukemia) treated with intensive chemotherapy achieves 5-year survival of approximately 55-65%. Intermediate-risk AML (normal karyotype, isolated FLT3-ITD) achieves 5-year survival of approximately 35-45% with intensive treatment including allogeneic SCT in high-risk cases. Adverse-risk AML (complex karyotype, TP53 mutation, monosomy 5/7, FLT3-ITD with high allelic ratio) carries 5-year survival below 15-20% even with transplantation. By ELN 2022 risk group, roughly: favorable-risk ~55-65% 5-year OS; intermediate-risk ~35-45%; adverse-risk ~10-20%. Age is a critical prognostic factor — patients over 60 have substantially worse outcomes from reduced treatment tolerance and less favorable molecular profiles. Venetoclax plus azacitidine for older or unfit patients achieves median overall survival of approximately 14.7 months versus 9.6 months for azacitidine alone, representing a meaningful improvement. Achievement of measurable residual disease (MRD) negativity after induction is the strongest independent predictor of sustained remission and survival across all risk groups. Relapsed AML carries poor prognosis — median survival after relapse is approximately 3-6 months without allogeneic SCT. Patients achieving second complete remission and proceeding to allogeneic SCT achieve 3-year survival of approximately 20-30%.

Most AML is not preventable; however, several risk-reducing measures exist. Avoiding benzene exposure — through workplace safety measures in rubber, oil, and chemical industries — reduces occupational AML risk. Individuals who have received alkylating chemotherapy or topoisomerase II inhibitors for prior malignancies are at elevated risk for therapy-related AML and require surveillance with periodic blood counts. Minimising unnecessary therapeutic radiation exposure is prudent. Patients with myelodysplastic syndrome (MDS), aplastic anaemia, or clonal haematopoiesis of indeterminate potential (CHIP) require regular haematological monitoring as these conditions predispose to AML development. Prompt genetic testing in families with Li-Fraumeni syndrome, Fanconi anaemia, or other inherited predisposition syndromes enables proactive surveillance.

AML frequently presents with a rapid onset of symptoms over days to weeks — any sudden unexplained fatigue, pallor, persistent fever not responding to standard antibiotics, or easy bruising and bleeding (including bleeding gums, nosebleeds, or petechiae) warrants urgent medical assessment. Because AML can be rapidly life-threatening through bone marrow failure, a complete blood count should be obtained without delay in anyone presenting with these symptoms. Gum swelling or skin nodules in the context of systemic illness may indicate monocytic AML. Any patient with prior MDS, aplastic anaemia, or prior cancer treatment who develops new cytopenias or constitutional symptoms requires urgent haematological review. APL specifically can present with severe coagulopathy (DIC) — any patient with abnormal bleeding and suspected leukemia requires emergency evaluation.