Acute Myeloid Leukaemia Flashcards
Acute Myeloid Leukaemia
Acute myeloid leukaemia is the more common form of acute leukaemia in adults. It may occur as a primary disease or following a secondary transformation of a myeloproliferative disorder.
AML - Poor Prognostic Features
Poor prognostic features
> 60 years
> 20% blasts after first course of chemo
cytogenetics: deletions of chromosome 5 or 7
Acute Promyelocytic Leukaemia M3
Acute promyelocytic leukaemia M3
associated with t(15;17)
fusion of PML and RAR-alpha genes
presents younger than other types of AML (average = 25 years old)
Auer rods (seen with myeloperoxidase stain)
DIC or thrombocytopenia often at presentation
good prognosis
AML- Classification
Classification - French-American-British (FAB) MO - undifferentiated M1 - without maturation M2 - with granulocytic maturation M3 - acute promyelocytic M4 - granulocytic and monocytic maturation M5 - monocytic M6 - erythroleukaemia M7 - megakaryoblastic
AML - Diagnosis: Example Question
A 57 year old presents with recurrent episodes of bleeding gums, nosebleeds and intermittent haematuria over the past 6 weeks. He works as an accountant, does not have any past medical history but is an active smoker of 20 pack years. He drinks occasional alcohol.
On examination, scabs and dried blood is noted on mucous membranes. No arthritis or cutaneous abnormalities are noted. The nasal bridge is unremarkable. His conjunctiva appeared pale, respiratory, abdominal and cardiovascular examination was unremarkable. His blood tests are as follows:
Hb 3.7 g/dl MCV 87 fl Platelets 17 * 109/l WBC 44.0 * 109/l Blood film myeloblasts with elongated, needle-like cytoplasmic inclusions
Na+ 147 mmol/l
K+ 3.2 mmol/l
Urea 7.8 mmol/l
Creatinine 70 µmol/l
What is the underlying diagnosis?
> Acute myeloid leukaemia Acute lymphocytic leukaemia Chronic myeloid leukaemia Chronic lymphoid leukaemia Myelofibrosis
The diagnosis is made on blood film description of needle-like elongated cytoplasmic inclusions, known as Auer rods that are pathognomonic of acute myeloid leukaemia, with myeloblasts typical of myeloid leukaemias. Clinical features are frequently typical of cell line abnormalities secondary to marrow infiltration (shortness of breath on exertion, pallor caused by anaemia; bruising or bleeding caused by thrombocytopaenia) and infections secondary to dysfunctional white cells. Diagnosis is confirmed by bone marrow biopsy, with blast cells accounting for greater than 20% of marrow cellularity. Immunophenotyping, cytogenetic and morphological analysis guides subsequent treatment options.
AML and Tumour Lysis Syndrome: Example Question
A 26-year-old gentleman presents to haematology clinic one week prior to starting chemotherapy for acute myeloid leukaemia (AML). He is currently feeling fatigued, suffering from night sweats, and has chronic lower back pain. He is anxious to start treatment.His past medical history includes ankylosing spondylitis and a clavicular fracture. His current medications include paracetamol and ibuprofen.
Blood tests: Hb 113 g/l Platelets 156 * 109/l WBC 57 * 109/l Na+ 140 mmol/l K+ 3.6 mmol/l Urea 4.2 mmol/l Creatinine 63 µmol/l
What measure is the least useful to prevent tumour lysis syndrome?
IV fluids prior to chemotherapy > Urine alkalization Prophylactic allopurinol Prophylactic rasburicase Stopping NSAID use
This patient has AML with a high white cell count and is about to start chemotherapy, and is therefore at high risk of tumour lysis syndrome (TLS).The key is to prevent TLS, which is done by ensuring good renal perfusion. Commonly this can be done by aggressive intravenous hydration prior to the start of treatment and stop NSAIDs, such as ibuprofen for this patient. Allopurinol and rasburicase both prevent uric acid accumulation and can, therefore, be used as well. Urine alkalization has not shown to be effective.
APML
You are not normally expected to be able to differentiate the different subtypes of acute myeloid leukaemia (AML) for the MRCP. An exception to this is acute promyelocytic leukaemia (APML, the M3 subtype of AML). The importance of identifying APML lies in both the presentation (classically disseminated intravascular coagulation) and management
APML is associated with the t(15;17) translocation which causes fusion of the PML and RAR-alpha genes.
Features
presents younger than other types of AML (average = 25 years old)
DIC or thrombocytopenia often at presentation
good prognosis
This diagnosis is considered a haematological emergency.
Approximately 10% of patients with an acute leukaemia are ultimately diagnosed with APML but it is a largely unconsidered diagnosis. If diagnosed, it is one of the most treatable leukaemias, however in one third of cases the initial presentation is of catastrophic haemorrhage.
The average age of presentation with APML is 30-40 which distinguishes it from other acute myeloid leukaemias which present in the seventh decade typically. Other presenting symptoms are similar however with fatigue and weakness due to anaemia, coryzal or influenza symptoms and easy bruising due to thrombocytopaenia and coagulopathy. Myeloid leukaemia may cause splenomegaly which is usually absent in APML. Lymphadenopathy does not occur in leukaemias of myeloid line.
Blood film may show characteristic Auer rods in both myeloid leukaemia and APML. The film will show abnormal myeloid precursor cells or granulocytes in APML which are often bilobar or multilobar, whereas leukaemic mature myeloid cells are present in other forms of myeloid leukaemia although distinguishing these is difficult. Automated counters may fail to determine a differential white cell count. Confirmation of AMPL is via polymerase chain reaction or fluorescent in-situ hybridisation (FISH) of the bone marrow which demonstrates translocation of chromosomes 15 and 17.
A gene on chromosome 17 codes for the retinoic acid receptor alpha protein and in APML patients with this translocation, administration of all-trans retinoic acid forces the immature myeloid cell to mature and it then undergoes apoptosis. ATRA is considered an emergency treatment for an APML blast crisis in those with coagulopathy or severe anaemia or sepsis. ATRA is considered only an emergency drug to force cell maturation; ongoing chemotherapy is required to maintain remission. Current guidelines recommend arsenic trioxide as the first line agent to achieve remission once ATRA therapy is commenced and also in refractory disease.
NB ATRA Therapy = All Trans Retinoid Acid
APML - Example Question
A 40 year old man presents to the Emergency Department with non-specific symptoms of lethargy, malaise, headache, body aches, a low grade fever and a sore throat. Examination is essentially normal aside from multiple limb petechiae. Tympanic temperature is 37.6°C. Blood pressure, heart rate and pulse oximetry is normal.
Blood tests show:
Haemoglobin 112g/L Sodium 136mmol/L MCV 82fL Potassium 4.5mmol/L Platelets 77x10^9/L Urea 6.9mmol/L White cells 32x10^9/L Creatinine 111mol/L Prothrombin time 23secs CRP 54mg/L Fibrinogen 0.45g/L HIV test Negative Liver enzymes normal
Automated counter is unable to supply differential white cell count.
Manual blood film shows immature granulocytes with bilobed nuclei and Auer rods.
What is the most important immediate therapy to institute?
> All trans retinoic acid (ATRA) [tretinoin] Methotrexate Imatinib Rituximab Arsenic trioxide
APML is a haematological emergency. Treatment is with all-trans retinoic acid (ATRA) to force immature granulocytes into maturation to resolve a blast crisis prior to more definitive chemotherapy
The above vignette gives a classical description of acute promyelocytic leukaemia (APML). This diagnosis is considered a haematological emergency. Approximately 10% of patients with an acute leukaemia are ultimately diagnosed with APML but it is a largely unconsidered diagnosis. If diagnosed, it is one of the most treatable leukaemias, however in one third of cases the initial presentation is of catastrophic haemorrhage.
The average age of presentation with APML is 30-40 which distinguishes it from other acute myeloid leukaemias which present in the seventh decade typically. Other presenting symptoms are similar however with fatigue and weakness due to anaemia, coryzal or influenza symptoms and easy bruising due to thrombocytopaenia and coagulopathy. Myeloid leukaemia may cause splenomegaly which is usually absent in APML. Lymphadenopathy does not occur in leukaemias of myeloid line.
Blood film may show characteristic Auer rods in both myeloid leukaemia and APML. The film will show abnormal myeloid precursor cells or granulocytes in APML which are often bilobar or multilobar, whereas leukaemic mature myeloid cells are present in other forms of myeloid leukaemia although distinguishing these is difficult. Automated counters may fail to determine a differential white cell count. Confirmation of AMPL is via polymerase chain reaction or fluorescent in-situ hybridisation (FISH) of the bone marrow which demonstrates translocation of chromosomes 15 and 17. A gene on chromosome 17 codes for the retinoic acid receptor alpha protein and in APML patients with this translocation, administration of all-trans retinoic acid forces the immature myeloid cell to mature and it then undergoes apoptosis. ATRA is considered an emergency treatment for an APML blast crisis in those with coagulopathy or severe anaemia or sepsis. ATRA is considered only an emergency drug to force cell maturation; ongoing chemotherapy is required to maintain remission. Current guidelines recommend arsenic trioxide as the first line agent to achieve remission once ATRA therapy is commenced and also in refractory disease.
Methotrexate may sometimes be used to maintain remission in some APML patients although it is not helpful in the acute presentation.
Imatinib is a tyrosine kinase inhibitor used in the treatment of chronic myeloid leukaemia, particularly those with the Philadelphia translocation. It is not commonly used in this scenario.
Rituximab is a monoclonal antibody against CD20 on B cells. It has many uses in inflammatory diseases, lymphoma and lymphocytic leukaemia but is rarely used in APML or myeloid leukaemia (since B cells are of lymphoid, not myeloid lineage). There are some studies which have suggested a link between rituximab usage and the development of APML.
APML - Mx
APML is a haematological emergency. Treatment is with all-trans retinoic acid (ATRA) to force immature granulocytes into maturation to resolve a blast crisis prior to more definitive chemotherapy
A gene on chromosome 17 codes for the retinoic acid receptor alpha protein and in APML patients with this translocation, administration of all-trans retinoic acid forces the immature myeloid cell to mature and it then undergoes apoptosis. ATRA is considered an emergency treatment for an APML blast crisis in those with coagulopathy or severe anaemia or sepsis. ATRA is considered only an emergency drug to force cell maturation; ongoing chemotherapy is required to maintain remission. Current guidelines recommend arsenic trioxide as the first line agent to achieve remission once ATRA therapy is commenced and also in refractory disease.
APML - Example Question
A 23-year-old man presents to the emergency department acutely unwell for the last 72 hours. He has been fatigued for the last month and has been having night sweats and has had several colds. Over the last 3 days, he has become more unwell, shivery and vomiting. He has noticed bruising on forearms and thighs. On examination, he is drowsy and has a temperature of 38.5ºC. His blood pressure is 90/50 mmHg, heart rate 120/min. He is peripherally shut down with a cap refill time of 5 seconds. He has conjunctival pallor. He is given IV fluids and antibiotics by the emergency department. His blood results show:
Hb 89 g/l Platelets 43 * 109/l WBC 13.0 * 109/l Neutrophils 9.0 * 109/l D-Dimer 5.8mg/L (<0.5) INR 8.5 PT 89 seconds (9-12) APTT ratio 1.7 (0.8-1.2) Fibrinogen 0.1g/L (1.5 - 4.5) Blood film Faggot cells seen
Na+ 138 mmol/l K+ 5.8 mmol/l Urea 18 mmol/l Creatinine 195 µmol/l CRP 170 mg/l
Bilirubin 8 µmol/l
ALP 102 u/l
ALT 300 u/l
Albumin 38 g/l
He is transferred to ITU for ionotropic support. He is treated with fresh frozen plasma which corrects his coagulopathy. Haematology is involved and he has a bone marrow analysis performed. Cytogenetics shows a translocation of chromosomes 15 and 17. What is the appropriate treatment to give?
> All-trans retinoic acid R-CHOP Chlorambucil High dose prednisolone Ribavirin
This patient has acute promyelocytic leukaemia (M3 subclass). This can present with DIC in young patients the prolonged prothrombin time, with platelets consumption and low fibrinogen. Faggot cells are hypergranular promyelocytes, so called because the high concentrations of Auer rods in the cytoplasm give the cells a bundle of sticks appearance. The gene translocation of 15:17 results in a fusion gene of PML:RARa (retinoic acid receptor). The exact process by which this gene fusion results in AML is unclear but the condition responds well to retinoic acid therapy hence this is the correct answer here. The other options are for other types of haematological malignancy.
AML Poor Prognostic Factors
- Gene expression
- Immunophenotyping
- WCC at diagnosis
- LDH
AML - Blood Film
AML:
The diagnosis is made on blood film description of needle-like elongated cytoplasmic inclusions, known as Auer rods that are pathognomonic of acute myeloid leukaemia, with myeloblasts typical of myeloid leukaemia.
Diagnosis is confirmed by bone marrow biopsy, with blast cells accounting for greater than 20% of marrow cellularity.
APML:
Faggot cells are hypergranular promyelocytes, so called because the high concentrations of Auer rods in the cytoplasm give the cells a bundle of sticks appearance.
AML - Clinical Features
Clinical features are frequently typical of cell line abnormalities secondary to marrow infiltration (shortness of breath on exertion, pallor caused by anaemia; bruising or bleeding caused by thrombocytopaenia) and infections secondary to dysfunctional white cells.
AML w High WCC - High risk of TLS
AML with a high white cell count about to start chemotherapy, = high risk of tumour lysis syndrome (TLS).
The key is to prevent TLS, which is done by ensuring good renal perfusion.
Commonly this can be done by aggressive intravenous hydration prior to the start of treatment and stopping NSAIDs such as Ibuprofen. Allopurinol and rasburicase both prevent uric acid accumulation and can, therefore, be used as well.
APML - Presentation
DIC (prolonged PT, platelet consumption, low fibrinogen) or Thrombocytopenia
Can present with catastrophic haemorrhage!
