Makindo Medical Notes

Related Subjects: | Leukaemias in General | Acute Promyelocytic Leukaemia | Acute Myeloblastic Leukaemia (AML) | Acute Lymphoblastic Leukaemia (ALL) | Chronic Lymphocytic Leukaemia (CLL) | Chronic Myeloid Leukaemia (CML) | Hairy Cell Leukaemia | Differentiation Syndrome | Tretinoin (All-trans-retinoic acid (ATRA)) | Haemolytic Anaemia | Immune (Idiopathic) Thrombocytopenic Purpura (ITP)

Acute Myeloid Leukaemia (AML) is a type of cancer originating in the bone marrow, characterized by the rapid proliferation of abnormal myeloblasts (immature white blood cells). These abnormal cells accumulate in the bone marrow, interfering with the production of normal blood cells, and can spread to other parts of the body. AML is an aggressive form of leukaemia that requires prompt treatment. Symptoms include fever, weakness, pallor, infections, bleeding, bone pain, and splenomegaly.

About

• AML is a neoplastic clone of immature myeloid precursors, predominantly affecting older patients.
• The presence of Auer rods is a characteristic finding.
• Can be primary or secondary to some pre-existing cause e.g. myelodysplasia.

Types

• Primary: no pre-existing disease
• Secondary to some pre-existing cause e.g. myelodysplasia.

Aetiology

• AML results from clonal proliferation of myeloid precursors with a reduced capacity to differentiate into mature cellular elements.
• This leads to the accumulation of leukaemic cells in the bone marrow, peripheral blood, and other tissues, causing a marked reduction in red cells, platelets, and neutrophils.
• The increased production of malignant cells and the reduction in mature elements result in systemic symptoms, anaemia, bleeding, and an increased risk of infection.

Genetic Translocations

• t(8;21): Occurs in a subset of AML patients.
• t(15;17): Associated with Acute Promyelocytic Leukaemia (APL; M3 subtype).

Risk Factors

• Primarily a malignancy of adults, more common in older adults.
• Genetic conditions:
  • Down's syndrome (especially associated with M7 type; 400-fold increased risk).
  • Fanconi anaemia.
• Exposure to benzene or radiation.
• Secondary to myelodysplasia and other myeloid malignancies.
• Previous chemotherapy or radiation therapy.
• Myelodysplastic syndromes.

Classification (FAB Classification)

• M0: Undifferentiated blasts; CD13+, CD33+, CD117+; less than 3% of cells show MPO/SBB positivity.
• M1: Minimally differentiated AML; lightly granulated blasts.
• M2: AML with maturation; granulated blasts often with Auer rods.
• M3: Acute Promyelocytic Leukaemia (APL); associated with t(15;17) translocation.
• M4: Acute myelomonocytic leukaemia.
• M5: Acute monocytic leukaemia.
• M6: Erythroleukaemia; Auer rods and dysplasia may be seen; PAS positivity in erythroblasts.
• M7: Acute megakaryocytic leukaemia; positive for CD41 and CD61 (platelet markers).

Acute Promyelocytic Leukaemia (APL; M3 Subtype)

• Notable for:
  • Risk of Disseminated Intravascular Coagulation (DIC), even after treatment initiation.
  • Responsiveness to All-Trans-Retinoic Acid (ATRA), a vitamin A derivative.

WHO Classification

• AML with recurrent genetic abnormalities: e.g., t(8;21), inv(16), t(15;17); mostly in younger patients.
• AML with multilineage dysplasia: Evolving from a myelodysplastic disorder.
• Therapy-related AML: Related to alkylating agents or topoisomerase II inhibitors (e.g., etoposide); very poor prognosis.
• AML not otherwise categorized: Classified morphologically according to cell of origin.

Clinical Features

• Symptoms of marrow failure:
  • Anaemia: Weakness, lethargy.
  • Bleeding and petechiae due to low platelet counts.
  • Infections due to neutropenia or increased immature WBCs (blasts).
• DIC can occur, especially associated with the M3 subtype (APL).
• Gum and lung infiltration more common in M4 and M5 subtypes.
• Possible progression from a pre-existing myelodysplastic syndrome.
• Extramedullary masses (myeloblastomas) can occur in skin, bone, paravertebral areas, leading to CNS signs.
• Splenomegaly and hepatomegaly may be present.

Investigations

• Blood Tests:
  • FBC: Low Hb, low platelets, WBC may be low or high with circulating blasts.
  • Electrolytes: Elevated potassium (may be spurious if WBC is high).
  • Elevated uric acid, LDH, and creatinine levels.
  • Coagulation studies: To check for DIC.
• Peripheral Blood Film/Bone Marrow Biopsy: Presence of Auer rods within blast cells is diagnostic.
• Bone Marrow Biopsy/Aspirate: Blast count >20% is diagnostic (WHO criteria).
• Flow Cytometry and Cytogenetics: To identify immunophenotype (e.g., CD13, CD15, CD33, CD34, CD117) and genetic abnormalities.
• Imaging: Chest X-ray, lumbar puncture if CNS involvement is suspected.
• Cardiac Evaluation: Echocardiogram or MUGA scan prior to anthracycline use.

Management

• Supportive Care:
  • Address airway, breathing, circulation (ABCs).
  • Manage sepsis and anaemia; initiate transfusions and antibiotics as needed.
  • Central venous catheter placement for chemotherapy administration.
  • Prevent tumour lysis syndrome with hydration and allopurinol or rasburicase.
• Induction Chemotherapy:
  • Combination of cytarabine (ara-C) and an anthracycline (e.g., daunorubicin).
  • Leads to severe transient neutropenia and thrombocytopenia.
• Consolidation Chemotherapy: To eliminate residual disease after remission is achieved.
• APL (M3) Specific Treatment:
  • All-Trans-Retinoic Acid (ATRA) combined with anthracycline-based chemotherapy.
  • Monitor for Differentiation Syndrome (formerly known as ATRA syndrome).
• Management of Neutropenia:
  • Prompt initiation of broad-spectrum antibiotics for febrile neutropenia.
  • Antifungal agents if fungal infections are suspected (e.g., aspergillus, candida).
  • Support with platelet and red cell transfusions as needed.
• Targeted Therapy: Use of FLT3 inhibitors (e.g., midostaurin) or IDH inhibitors for patients with specific genetic mutations.
• Stem cell Transplantation: Considered for patients with high-risk disease or those who relapse.

References

• Cancer Research UK: Acute Myeloid Leukaemia (AML)
• NHS UK: Acute Myeloid Leukaemia
• Leukaemia Care: Acute Myeloid Leukaemia