HIS Case 3: Acute Promyelocytic Leukaemia Flashcards
List the causes of bleeding tendency
See lecture
- Coagulation factors / Coagulopathy
- Inherited
—> Haemophilia A/B
—> VWD
- Acquired
—> Vit K deficiency
—> Vit K antagonism
—> Liver disease
—> DIC
—> Haemorrhagic disease of newborn
—> Uraemia - Platelet disorder
- Numerical / Functional
- Inherited / Acquired (Autoimmune/Alloimmune/Consumptive/Sequestration/Drugs) - Vascular disease
- CT problems e.g. Tissue hyperlaxity, Steroid use, CT thinning - Drugs
- Antiplatelets
- Anticoagulants
Causes of Pancytopenia
Production / Marrow
- APL
- MDS
- Aplastic anaemia
- Megaloblastic anaemia
- Marrow infiltration
Consumption
- Infection
- Autoimmune
- Splenomegaly
- Drug
Investigations required in patient with newly diagnosed acute leukaemia
See lecture
Investigations for Leukaemia / Lymphoma
基本:
- CBC with manual blood film review + differential count (D/C)
- Diagnostic BM aspiration, Trephine biopsy
- CXR
- LFT, RFT
- Serum electrolytes (K, PO4)
- LDH, urate levels
其他:
- Clotting profile, d-dimer, fibrinogen (Leukaemia)
- Serum protein electrophoresis, Serum immunoglobulin assay, ESR, β2 microglobulin, Whole body PET-CT (Lymphoma)
Diagnostic:
BM examination:
1. Morphology on PB/BM —> PB smear, BM aspiration, Trephine biopsy
2. Cytochemistry —> Myeloperoxidase, Sudan Black B
3. Immunophenotype —> Flow cytometry + Immunohistochemistry
4. Cytogenetics —> Karyotyping + FISH
5. Molecular genetics —> PCR
Pre-treatment investigations:
- ECG, transthoracic echocardiogram
- Lung function
- Hepatitis B, C serology
- HIV serology
- G6PD assay
- HLA-typing of patients, siblings for allogeneic HSCT
Classification of acute leukaemia
See lecture
Interpret peripheral blood and BM features in a patient with APL
Clinical features, Pathogenesis, Natural history of APL
Clinical features
- Anaemia (e.g. SOB, palpitation, postural dizziness)
- Bleeding tendency (e.g. Easy bruising)
- Leukopenia (e.g. Infection, sore throat)
- Poor appetite
CBC (Pancytopenia):
- Anaemia
- Leukopenia
- Thrombocytopenia
Peripheral blood film:
- Pink Granules, Bilobed Promyelocytes —> Abundant azurophilic granules
- Faggot cell (Promyelocytes) with many Auer rods
- High N/C ratio
Clotting profile:
- ↑ PT + APTT
- Low Fibrinogen
- ↑ D-dimer
Cytochemistry:
1. Strongly positive for Sudan Black B + Myeloperoxidase
Cytogenetics:
- t(15;17)
—> PML-RARA fusion gene (PML:15, RARA:17)
—> PML-RARA cause differentiation block
Natural history:
- Fast progression
- Fatal intracranial bleeding secondary to **thrombocytopenia and **DIC
Mechanisms of bleeding in APL
- Reduced platelet production
- result of BM infiltration by abnormal promyelocytes - Increased consumption due to DIC
- APL cells express ***Tissue factor
—> activate coagulation
—> intense widespread DIC
—> consume most clotting factors - Hyper-fibrinolysis
- APL cells express Annexin II
—> activate plasminogen
—> fibrinolysis
—> hypofibrinogenaemia
Management of APL
Treatment:
1. Start ATRA (all-trans retinoic acid) at first suspicion
—> induce cells to differentiate to lessen damaging effects
- Correct coagulopathy and thrombocytopenia (blood transfusion)
—> supportive infusion esp. platelets, plasma (to prevent DIC) - Treat any infection
- Treatment and prevention of tumour lysis syndrome
- Xanthine oxidase inhibitors
- Adequate hydration
Monitoring:
- CBC, LRFT, LDH, urate, electrolytes, clotting profile (daily)
- Keep platelet count >50, fibrinogen >1.5 (Ensure no spontaneous bleeding)
- ECG monitoring, QTc determination (Arsenic trioxide prolong QT interval)
- Avoid QTc prolonging agents if possible (quinolones, azoles)
- Correct electrolytes (K, Mg, Ca) (arrhythmia)
- Body weight, CXR monitoring
- Monitor for thromboses (esp. Central Venous Catheter-associated)
- Anti-fungal prophylaxis during neutropenic phase
Not to do:
- No invasive / unnecessary procedures (except BM exam)
- No CVC unless absolute necessary
- Do not give G-CSF (induce uncontrolled myeloid proliferation, promote differentiation syndrome)
- Do not stop ATRA/ATO as a measure for “treating ATRA-syndrome” (control WBC and give steroids instead)
Mechanisms and SE of Arsenic trioxide, ATRA, Chemotherapy, Ascorbic acid
ATRA / Arsenic trioxide:
- Target PML-RARA —> Degradation
ATRA:
- Conversion of PML-RARA from Transcription repressor to Transcription activator
Arsenic trioxide:
- High concentration: Apoptosis of leukaemic cells by disrupting mitochondrial membrane potential
- Low concentration: Trigger differentiation
- Both concentration: PML-RARA degradation
SE of ATRA / Arsenic trioxide: 1. ***Differentiation syndrome (reversal of differentiation block) —> capillary leak —> pulmonary oedema, peripheral oedema —> ***IV Dexamethasone 2. Headache 3. N+V 4. Skin rash 5. ***Hepatitis (ATO > ATRA) 6. ***Prolonged QTc (ATO) 7. Risk of ***Herpes zoster (ATO —> T cell dysregulation)
Chemotherapy (Daunorubicin):
- Topo 2 inhibitor —> prevent relaxation of supercoiled DNA
- Produce Superoxide + H2O2 —> DNA single strand break
- SE: Cardiotoxicity
Ascorbic acid:
- Potentiate cytotoxic effect of Arsenic trioxide
Explain to patient diagnosis of acute leukaemia
Main steps in breaking bad news
Break bad news SPIKES: 1. Setting up 2. Patients’ Perception 3. Obtaining Invitation 4. Knowledge and information 5. Empathy with emotions 6. Strategy
ADA:
- Assessment
- Disclosure
- Assimilation
Importance of communication with a patient with acute leukaemia
- Reducing stress in patient
- Ensure support from family
- Promote trust
- Elimination of uncertainty
- Allow acceptance of patient
Epidemiology (pattern, risk factors and causes) of acute leukaemia
- Fast progression
- Fatal intracranial bleeding secondary to **thrombocytopenia and **DIC
- Rapidly fatal
Leukaemogenesis:
- Transcription dysregulation + Differentiation block
- Proto-oncogenes activation
- Tumour suppressor gene inactivation
- Signalling genes / Tyrosine kinases activation
Via:
- Chromosomal translocation
- Deletions
- Point mutations
- Duplications / Amplifications
- Epigenetic alterations
