Acute Myeloid Leukaemia (AML)
Pathophysiology
AML is a malignancy of immature myeloid haematopoietic stem cells. This results in increased production of myeloid blast cells, which accumulate in the bone marrow, blood and invade other tissues.
AML can be the result of a random new (de novo) mutation, or it can be secondary to an existing blood disorders such as myelodysplasia.
Epidemiology
It is the most common acute leukaemia in adults, with an annual incidece of 3 in 100,000. The incidence of AML is increasing. The median age of presentation is 69-70.(1)
Signs and Symptoms
Due to the accumulation of immature cells, the bone marrow in unable to produce sufficient red blood cells or platelets. Though white cells are produced in large QUANTITIES, they lack QUALITY. As a result, features of AML include:
-
Infection - poor quality white blood cells
-
Anaemia - insufficient red blood cells
-
Bleeding/easy bruising - insufficient platelets
Additionally, leukemic cells infiltrate other organs/tissues including the spleen, liver, testes, and skin, and gums.(2)
When there is a very high blast count, it can cause symptoms of leucostasis. Leucostasis is the term to describe the accumulation of white blood cells in blood vessels, which blocks oxygen and blood flow to organs. Examples of symptoms/signs include retinal haemorrhage, confusion, hypoxia, and diffuse pulmonary infiltrates.(1)
Investigations
Peripheral Blood Film in AML. Image courtesy: Dr Pip Nicolson
WHO Classification of AML
The WHO classifies AML into 7 subheadings(1):
1. Acute myeloid leukaemia with recurrent genetic abnormalities
2. Acute myeloid leukaemia with myelodysplasia-related changes
3. Therapy-related myeloid neoplasms
4. Acute myeloid leukaemia, not otherwise specified
5. Myeloid sarcoma
6. Myeloid proliferations related to Down’s syndrome
7. Blastic plasmacytoid dendritic cell neoplasm
Management
Supportive care
-
Blood transfusions for low Hb
-
Broad-spectrum antibiotics and anti-fungals for prophylaxis against infections
-
Platelet transfusions if thrombocytopenic with bleeding
-
Allopurinol for prophylaxis of gout due to rapid cell turnover(1)
Chemotherapy
Treatment occurs in 2 phases: 1) Remission induction, and 2) Consolidation.
Remission Induction
The aim of remission induction is to achieve complete haematological remission: normal bone marrow cellularity and normal blood counts with no blast cells. Typically, this phase includes 2 courses of anthracycline combination therapy (ex. daunorubicin and cytarabine).(1,2)
Consolidation
The purpose of consolidation is to reduce the risk of relapse (1,2).
Stem Cell Transplantation
This is offered to patients with poor risk AML, who have achieved complete remission. The type of transplant used is allogenic stem cell transplantation, where donor cells come from someone else (1,2).
Relapse
50% of patients will relapse after chemotherapy. Majority of relapses occur within 2-3 years of stopping chemotherapy. Further chemotherapy can help attain 2nd complete remission. Good prognostic factors for 2nd complete remission include young age and longer duration of the first complete response (greater than 6 months). Stem cell transplantation can be offered to patients after 2nd complete response.(1)
Acute Promyelocytic Leukemia (APML)
APML is a subtype of AML which requires a different approach. In this subtype, the blood contains a very high number of promyelocytes.(1)
It is important to know about APML because these patients are at high risk of Disseminated Intravascular Coagulopathy (DIC), which could lead to fatal intracranial haemorrhages. The mechanism by which APML causes DIC is through leukemic cells releasing pro-coagulants and proteins which increase the fibrinogen deposition (3).
APML is due to translocation t(15,17), resulting in the production of a fusion protein called PML-RARA. This fusion protein binds to DNA in the cell, preventing the maturation of granulocytes. Treatment with All-trans retinoic acid (ATRA) allows DNA transcription and maturation of granulocytes to occur. Therefore ATRA does not acutally kill the leukemia cells, but rather it allows these cells to complete differentiation, after which they will undergo apoptosis themselves. ATRA is given in combination with arsenic trioxide (ATO). (4)
References
-
Provan D, Dokal I, Vos J, Baglin T. Oxford Handbook of Clinical Haematology. 4th ed. Oxford: Oxford University Press; 2015.
-
Tidy C. Acute Myeloid Leukaemia. 2016; Available at: https://patient.info/doctor/acute-myeloid-leukaemia-pro.
-
Mistry AR, Pedersen EW, Solomon E, Grimwade D. The molecular pathogenesis of acute promyelocytic leukaemia: implications for the clinical management of the disease. Blood Reviews ;17(2):71-97.
-
Ikezoe T. Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin. International Journal of Haematology 2014;100(1):27-37.