- Broadly, there are six groups of AML in WHO classification system:
- AML with recurrent genetic abnormalities
- AML with myelodysplasia-related features
- Therapy-related AML and MDS
- AML, not otherwise specified
- Myeloid sarcoma
- Myeloid proliferations related to Down syndrome
- There are eight subtypes of AML in FAB classification system:
- M0: Acute myeloblastic leukaemia without maturation
- M1: Acute myeloblastic leukaemia with minimal granulocyte maturation
- M2: Acute myeloblastic leukaemia with granulocyte maturation
- M3: Acute promyelocytic leukaemia (APL)
- M4: Acute myelomonocytic leukaemia
- M5: Acute monocytic leukaemia
- M6: Acute erythroid leukaemia
- M7: Acute megakaryoblastic leukaemia
- Environmental factors
- Ionizing radiation
- Chemicals (benzene)
- Pre-existing haematologic disorder
- Myelodysplastic syndromes
- Aplastic anaemia
- Myeloproliferative disorders
- Paroxysmal nocturnal haemoglobinuria
- Clonal haematopoiesis of indeterminate prognosis
- Genetic or chromosomal factors
- Trisomy 21 (Down syndrome): risk is 10–20 times higher than the general population.
- Fanconi anaemia
- Bloom's syndrome
- Familial mutations of CEBPA, DDX41, RUNX1
- Environmental or genetic factors → malignant transformation of myeloid precursor cells → clonal proliferation and arrest in maturation in early stages of haematopoiesis → further proliferation of immature/dysfunctional blasts:
- Accumulation of immature cells in the bone marrow → suppresses normal bone marrow activity → other cell lines impaired (anaemia, bleeding, and infections).
- Immature cells enter and accumulate in peripheral blood.
- Infiltration in other tissues (CNS, liver, and skin).
- Mostly due to infections but may occur solely due to leukaemia.
- Immature leucocytes predisposes to frequent infections.
- Ecchymoses or petechiae.
- Gingival bleeding, epistaxis, or menorrhagia.
- Unique to acute promyelocytic leukemia.
- Bleeding secondary to disseminated intravascular coagulation.
- Medical emergency.
- Bone pain:
- Sternal discomfort or aching in extremities.
- Due to expansion of the medullary cavity by the leukemic process.
- Leukaemia cutis:
- Nodular, violaceous lesions on the skin.
- Seen in up to 13% of patients.
- Mostly associated with acute monocytic leukaemia or acute myelomonocytic leukaemia.
- Gingival hypertrophy:
- Primarily associated with the monocytic subtype.
- Infiltration by leukaemic cells.
- CNS involvement:
- Headache, visual changes, and nerve palsies.
- Mostly associated with acute monocytic leukaemia or acute .myelomonocytic leukaemia
- Adenopathy, hepatomegaly, and splenomegaly.
- Uncommon, around 10% each.
- Infiltration of leukaemic cells.
Full blood count with differential:
Peripheral blood smear:
- Raised myeloblasts: myeloblasts are immature cells with large nuclei, usually with prominent nucleoli, and pale blue cytoplasm with Wright Giemsa stain.
- Auer rods:
- Pink/red, rod-shaped cytoplasmic granular inclusions.
- Myeloperoxidase positive.
- Pathognomonic of myeloblasts.
- Mostly seen with acute promyelocytic leukaemia.
Coagulation panel for disseminated intravascular coagulation (DIC):
- Raised prothrombin time (PT), raised activated partial thromboplastin time (APTT), low platelet count, elevated D-dimer concentration and decreased fibrinogen concentration is seen in .
- Electrolyte abnormalities are seen with increased cell lysis
- Hyperphosphatemia, hypocalcemia, hyperkalemia, and hyperuricemia
Bone marrow aspiration and biopsy:
- Confirmatory test of AML
- ≥ 20% myeloblasts in the bone marrow confirm the diagnosis
Immunophenotyping: the majority of subtypes are express CD13, CD33, CD34, CD117, and HLA-DR.
Cytogenetic features: cytogenetic abnormalities can be identified by conventional karyotypic analysis plus reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescent in situ hybridization (FISH). The abnormalities like: t (8;21)(q22;q22), inv (16)(p13;q22), t (16;16)(p13;q22), and t (15;17)(q22;q12), define AML irrespective of the blast count.
Molecular studies: abnormalities in specific genes FLT3, NPM1, KIT, CEBPA, IDH1 and IDH2, p53, or RUNX1.
- Acute lymphocytic leukaemia:
- Myelodysplastic syndrome
- Similarities: anaemia, thrombocytopenia, infections
- Differences: blasts (< 20%), pseudo–Pelger-Huet abnormality (neutrophils with bilobed nuclei)
- Myeloproliferative neoplasms:
- Similarities: infections, abnormalities in different cell lines
- Differences: JAK2 mutation, thrombocytosis.
- Chronic myeloid leukaemia in blast crisis
- Similarities; anaemia, thrombocytopenia, infections
- Differences: Philadelphia chromosome or t (9:22), raised matured cells (myelocytes)
Acute promyelocytic leukaemia (APL) is a distinct form of AML that represents a medical emergency. Treatment of APL differs significantly from that of other forms of AML. For APL, all-trans retinoic acid (ATRA) and arsenic are used to induce the maturation of immature malignant cells.
Chemotherapy: the choice of drug is based on the cytogenetics. Cytarabine and anthracyclines (daunorubicin) are commonly used. Targeted agents like midostaurin, ivosidenib, or enasidenib may be added for specific mutations.
- Induction chemotherapy:
- Intensive combination chemotherapy.
- To achieve complete remission.
- Failure of relapse may warrant re-induction therapy.
- Consolidation chemotherapy:
- An intensive treatment that follows after complete remission.
- To destroy remaining tumour cells
- Maintenance chemotherapy:
- Non-myelosuppressive treatment
- To maintain remission
Haematopoietic cell transplantation (HCT):
Indicated for patients with unfavourable prognostic factors (unfavourable cytogenetics) or patients who do not achieve remission through chemotherapy. Allogeneic HCT is preferred.
Monitoring and supportive treatment:
- Preventing and treating infections:
- Antibiotic prophylaxis (broad-spectrum IV antibiotics) for febrile neutropenia.
- Trimethoprim-sulfamethoxazole for pneumocystis pneumonia prophylaxis in neutropenic patients.
- Maintain hygiene
- Surveillance for infections.
- Nutritional support
- Antiemetics (ondansetron)
- Transfusions for severe anaemia, thrombocytopenia.
Tumour lysis syndrome: An oncologic emergency. It mostly occurs after initiating cytotoxic therapy, although it may occur spontaneously. The rapid destruction of tumour cells leads to a massive release of intracellular components (potassium, phosphate, and nucleic acid) into the circulation.
- Labs: hyperkalemia, hyperphosphatemia, hypocalcemia (secondary to phosphate binding), and hyperuricemia (nucleic acid conversion to uric acid).
- Acute kidney injury (due to calcium phosphate crystals in tubules and urate nephropathy).
- Clinical features:
- Nausea, vomiting, and diarrhoea,
- Seizures, arrhythmias
- Tetany, muscle cramps, paresthesia
Leukostasis: excessive number of leukaemic cells (hyperleukocytosis: white blood cell count greater than 50 x 109/µL) causes increased blood viscosity. It typically presents with respiratory or neurological distress. The clinical features are:
- Chest pain
- Altered mental status
Disseminated intravascular coagulation: although it may be seen with all subtypes of AML, it is especially associated with acute promyelocytic leukaemia.
Severe neutropenia: the absolute neutrophil count is <500 cells/µL, and there is a high risk of infections.
Severe thrombocytopenia: counts less than 10,000/µL or active bleeding.
Severe anaemia: normocytic, normochromic anaemia; a haemoglobin level ≤8 g/dL needs a transfusion.
Venous thromboembolism: mostly occurs during the first three months of treatment.
- Clinical characteristics:
- Age < 50 years
- Performance status: An ECOG performance status score < 3 or a Karnofsky score >60 %.
- No medical comorbidities
- No antecedent haematologic disorder (myelodysplastic syndrome or myeloproliferative neoplasm)
- No antecedent history of exposure to cytotoxic agents and radiation therapy
- Cytogenetic features:
- MDR 1-negative phenotype
- Translocations: t (8;21), inv (16), t (16;16), t (15;17)
- NPM1 mutation, CEBPA mutation