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

Acute myeloid leukemia (AML) is a rapidly progressive malignant disorder of hematopoietic progenitor cells characterized by the clonal expansion of immature myeloid blast cells that arrest in early stages of differentiation. AML is the most common acute leukemia in adults, accounting for approximately 80% of adult acute leukemia cases, with an incidence of 4 per 100,000 per year and a marked increase in incidence with age (median age at diagnosis 65–70 years). AML is defined by ≥20% myeloblasts in the bone marrow or peripheral blood, though certain AML-defining cytogenetic or molecular abnormalities (t(8;21), inv(16)/t(16;16), t(15;17) — APL, and specific NPM1 mutations) diagnose AML regardless of blast percentage per the 2022 WHO and ELN 2022 classifications. The 5-year overall survival remains approximately 30% across all patient groups; however, outcomes vary dramatically by risk category: favorable-risk patients (e.g., NPM1-mutated without FLT3-ITD, biallelic CEBPA) may achieve 5-year survival of 60–70%, while adverse-risk patients with TP53 mutations or complex karyotype have median survival under 12 months.

AML arises from the sequential acquisition of somatic driver mutations in hematopoietic stem cells. Clonal hematopoiesis of indeterminate potential (CHIP) — somatic mutations in DNMT3A, TET2, ASXL1, TP53 detectable in the blood of healthy individuals — is the recognized precursor state. Prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) progresses to AML in 20–30% of cases. Therapy-related AML (t-AML) follows prior cytotoxic chemotherapy (alkylating agents: melphalan, cyclophosphamide; topoisomerase II inhibitors: etoposide, anthracyclines) or radiation therapy after 2–10 years latency; t-AML typically has adverse cytogenetics (del5q, del7, complex karyotype) and poor prognosis. Benzene exposure causes AML through bone marrow myelotoxicity. Hereditary predispositions include: Down syndrome (21-fold elevated risk of AML in children <4 years; GATA1-mutated acute megakaryoblastic leukemia, AML-M7), Fanconi's anemia, Shwachman-Diamond syndrome, RUNX1 familial platelet disorder, GATA2 deficiency, and CEBPA germline mutations. Advanced age, male sex, and prior radiation are non-modifiable risk factors.

AML typically presents acutely over days to weeks with symptoms of bone marrow failure. Anaemia (normocytic) causes fatigue, dyspnoea on exertion, pallor, and tachycardia. Neutropenia leads to recurrent bacterial infections — pneumonia, perirectal abscess, pharyngitis — and fever; invasive fungal infections (Aspergillus, Candida) are particular risks in prolonged neutropenia. Thrombocytopenia causes mucosal bleeding (epistaxis, gingival bleeding, menorrhagia), petechiae, ecchymoses, and — in severe thrombocytopenia — spontaneous intracranial haemorrhage. Acute promyelocytic leukemia (APL) causes severe, life-threatening disseminated intravascular coagulation (DIC) with catastrophic bleeding. Leukostasis — hyperleukocytosis with blast count >100×10⁹/L — causes pulmonary infiltrates (dyspnoea, hypoxia), CNS dysfunction (confusion, focal deficits), renal failure, and priapism; it is a haematological emergency. Extramedullary disease: gum infiltration and hypertrophy (particularly AML-M4/M5, monocytic), chloroma (myeloid sarcoma — a soft-tissue mass of blasts, typically orbital, epidural, or cutaneous), and sweet's syndrome (neutrophilic dermatosis associated with AML).

Peripheral blood film demonstrates circulating blasts with Auer rods — pathognomonic of myeloid lineage differentiation — particularly in AML-M2 (t(8;21)) and APL. Bone marrow aspiration and trephine biopsy confirm ≥20% blasts (or lower with AML-defining abnormalities). Multiparameter flow cytometry immunophenotypes the blast population by myeloid markers (CD33, CD13, CD117, CD34, MPO, NSE). Cytogenetics (karyotype) and fluorescence in situ hybridization (FISH) for t(8;21), inv(16), t(15;17) (PML-RARA) define favorable-risk cytogenetics. Next-generation sequencing (NGS) for AML-relevant mutations is mandatory: NPM1 (favorable prognosis), FLT3-ITD (allelic ratio matters: high ratio = adverse; FLT3-TKD = intermediate), CEBPA (biallelic = favorable), IDH1/IDH2, DNMT3A, TET2, RUNX1, TP53, WT1, ASXL1, KIT (in core binding factor AML). ELN 2022 classifies AML as favorable, intermediate, or adverse risk — this determines post-remission strategy. Minimal residual disease (MRD) assessment by flow cytometry, RT-PCR (NPM1), or NGS guides consolidation decisions.

Treatment is determined by patient fitness (performance status, comorbidities, organ function) and ELN risk classification. Fit patients aged <60–65 years: induction with '7+3' (cytarabine 100–200 mg/m²/day × 7 days continuous infusion + idarubicin 12 mg/m²/day × 3 days). Gemtuzumab ozogamicin (anti-CD33 antibody-drug conjugate) added to 7+3 improves outcomes in favorable/intermediate risk (ALFA-0701 and AML17 trials). Targeted additions: midostaurin 50 mg BID to 7+3 for FLT3-mutated AML (RATIFY trial: 4-year OS 51% vs 44%); quizartinib for FLT3-ITD. Complete remission is achieved in 70–80% after one induction cycle. Post-remission consolidation: allogeneic SCT for intermediate and adverse risk in CR1 — the only potentially curative treatment for most AML; high-dose cytarabine (HiDAC) for favorable-risk (biallelic CEBPA, NPM1+/FLT3-ITDlow) without transplant. Older/unfit patients: azacitidine + venetoclax (VIALE-A) is the current standard with CR/CRi rate 66%; enasidenib (IDH2), ivosidenib (IDH1), or glasdegib are further options. Relapsed/refractory AML: salvage chemotherapy (MEC, FLAG-Ida) + allogeneic SCT; gilteritinib for FLT3-mutated R/R AML (ADMIRAL trial).

Five-year overall survival for AML is approximately 30% across all patient groups, with dramatic variation by age and ELN risk category. Favorable-risk AML patients (NPM1 mutated without FLT3-ITD high; biallelic CEBPA; core binding factor leukemia t(8;21), inv(16)) treated with intensive induction plus consolidation achieve 5-year OS of 60–70%. Intermediate-risk AML achieves 40–60% with allogeneic SCT as consolidation in complete remission. Adverse-risk AML (TP53 mutation, complex karyotype, FLT3-ITD high with adverse co-mutations) has 5-year OS of 10–20% despite intensive therapy and allogeneic transplant. Older patients (>65 years) have considerably worse outcomes — 5-year OS is approximately 10–15% with azacitidine plus venetoclax versus less than 5% with prior hypomethylating agent monotherapy. MRD negativity after induction (assessed by NPM1 PCR or multiparameter flow cytometry) is the strongest predictor of favorable long-term outcome — MRD-negative patients have significantly lower relapse rates and better OS in prospective studies. Allogeneic SCT in complete remission for intermediate/adverse-risk AML improves long-term outcomes but carries 10–25% transplant-related mortality, necessitating careful risk-benefit assessment. Relapsed/refractory AML has a median survival of 4–8 months without transplant; salvage rates with gilteritinib in FLT3-mutated relapsed AML (ADMIRAL trial) are approximately 50% for initial remission but durable responses require transplant. Long-term survivors require monitoring for treatment-related sequelae including secondary MDS and graft-versus-host disease.

Avoidance of known leukemogenic exposures: benzene and other organic solvents should be minimized with occupational health measures. In oncology, limiting cumulative alkylating agent and topoisomerase II inhibitor doses where possible — using non-myelotoxic equivalents for solid tumor treatment — reduces t-AML risk. Patients receiving AML-risk chemotherapy (CHOP for lymphoma, high-dose alkylators) should have CBC monitoring every 6 months for 5–10 years post-treatment. Patients with CHIP mutations detected incidentally on NGS do not require treatment but should avoid additional myelotoxic exposures and have annual haematological review. Germline predisposition syndromes (RUNX1, GATA2) should be identified early through genetic counselling, enabling donor identification and preparatory steps for possible allogeneic SCT before AML transformation occurs.

AML is a haematological emergency requiring same-day admission and haematology review. Attend the emergency department immediately if: fever in a patient with known neutropenia (febrile neutropenia — empirical antibiotics must be administered within 60 minutes); unexplained mucosal bleeding, heavy menorrhagia, or petechiae with any constitutional symptoms; or extreme fatigue with pallor developing over days. A full blood count showing blasts, thrombocytopenia below 20×10⁹/L, or extreme leukocytosis requires immediate haematology referral. Do not delay: AML treated with even a 24-hour delay in the setting of leukostasis, DIC (particularly APL), or febrile neutropenia carries significant increase in early mortality. ATRA must be started on clinical suspicion of APL — before waiting for molecular confirmation.