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Flashcards in Haematology Acute leukaemias Deck (48):
1

Leukaemia Biology and General Features →

Clonal Proliferation of malignant blood cells derived from primitive haemopoitic stem cells in bone marrow. Uncontrolled expansion of hypofunctional cells in blood, bone marrow and other organs leads to suppression of normal haemopoiesis.

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Main clinical problems include

• Anaemia
• Bleeding and susc/L with blast cells visible on the peipheral eptibility to infection
• Lymphadenopathy
• Hepatosplenomegaly
• Skin and CNS infiltration

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Acute Leukaemia types

Acute myeloid leukaemia (AML)
Acute lymphoblastic leukaemia (ALL)

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Acute Leukaemia definition

• Proliferation of primitive immature blast cells
• Rapid onset and progression if untreated

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Chronic Leukaemia types

• Chronic myeloid leukaemia
• Chronic lymphocytic leukaemia

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Chronic Leukaemia definition

• Proliferation of more mature precursor cells
• Slower progression and less aggressive course

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Aetiopathogenesis of Leukemia → Endogenous factors


Chromosome fragility syndromes
Downs syndrome
Hereditary immune deficiency
Familial

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Aetiopathogenesis of Leukemia → Exogenous factors

Radiation
Chemotherapy
Benzene
Viral infection
Acquired immune deficiency

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Aetiopathogenesis of Leukemia →

Haemopoeitic stem cell
Clonal initiation
Clonal expansion
Suppression of normal haemopoiesis
Clonal regression (expanding sub-clones)
Clinical leukaemia

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(AML) Target population

Commoner in adults (old age is very common)

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(AML) Incidence

1:10,000 annually

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(AML) Frequency/Age distribution

Increases with age (median >70 yr)

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(AML) Presentation

May be de novo or secondary to other haematological disorders e.g. myelodysplasia, myeloproliferative disorders

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(AML) Prognosis (brief)

Curable with potentially a near to normal life as before

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(AML) Morphology

Lots of blasts in marrow
Primitive nuclei with a high Nuclei:Cytoplasm ratio

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Acute Promyelocytic Leukaemia with t (15;17) → Urgency

Urgent – this is a true haematological emergency
If you survive the first 48 hours – there I a good prognosis

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Acute Promyelocytic Leukaemia with t (15;17) → Pathophysiology

Granules released causing coagulopathy and potentially CNS ischemia = death

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Acute Promyelocytic Leukaemia with t (15;17) → Major investigations

FBC
Bone marrow
Flow cytometry
Cytogenetics

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Acute Promyelocytic Leukaemia with t (15;17) → FBC shows

Low hB and platelet count
WBC usually 20-100 x 109/L
Blast cells visible on the peripheral blood film

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Acute Promyelocytic Leukaemia with t (15;17) → Bone marrow shows

Blasts >20% of nucleated cells

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Acute Promyelocytic Leukaemia with t (15;17) → Flow cytometry

CD+13, CD33+: Helpful to confirm AML

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Acute Promyelocytic Leukaemia with t (15;17) → Cytogenetics

Important prognostic indicator e.g. t(15;17), t(8;21), inv16 good.
Monosomy 7, abnormalities chromosome 5, complex cytogenetics (>5 abnormalities) poor prognosis.

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Acute Promyelocytic Leukaemia with t (15;17) → T (15,17) marker of

Good prognosis

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Acute Promyelocytic Leukaemia with t (15;17) →T (8,21) marker of

Poor prognosis (M2 type)

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Acute Promyelocytic Leukaemia with t (15;17) → Monosomy 7, 5 marker of

Poor prognosis

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Acute Promyelocytic Leukaemia with t (15;17) → Treatment

Combination chemotherapy
• Important drugs include cytosine arabionoside and daumrubicin
• Retinoic acid/ arsenic trioxide used in acute promyelocytic leukaemia – high dose ara-C important in optimising outcome.

Supportive care
• Transfusions of red cells and platelets
• Antiseptic mouthwashes, clean diet
• Oral prophylactic ant-fungal agents and antibiotics (ciprofloxacin)
• Prompt iv antibiotic therapy for infections (broadspec)

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Acute Promyelocytic Leukaemia with t (15;17) → Chemotherapy plan

3-4 cycles of therapy given 4-6 weekly
Treatment induces profound marrow suppression, prolonged pancytopenia

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Acute Promyelocytic Leukaemia with t (15;17) → Emergency ATRA

Alltrans retinoic acid – matures cells and prevents granulocyte release

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Acute Promyelocytic Leukaemia with t (15;17) → Complications of treatment

• Nfection: mainly bacterial and fungal
• Bleeding (if in CNS can be fatal)
• Debility, profound weight loss
• Social: inpatient for most of 6 months, loss of employment, stress on family (in hospital 70-90% of he time)

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AML Prognosis

Better if <10% of over 60 yrs and poor risk cytogenetics

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AML Favourable cytogenetics

FLT3 negative and NMP1 positive

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AML Poor risk cytogenetics

FLT3 positive

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AML Allogenic bone marrow transplantation

If <50 yrs with HLA – matched donor, 50-70% cure rate. But risk of early transplanted-related mortality and graft versus host disease.
Often used as salvage therapy in 2nd remission.

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ALL Definition

Primitive lymphoblasts infiltrate bone marrow and circulate in blood, infiltrate liver and spleen.

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ALLEpi

Commonest leukaemia in children: peak age 2-10 years. Another peak at >60

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ALL Clinical features

Similar to AM but more frequently:
1. Lymphadenopathy
2. Hepatosplenomegaly and CNS involvement (meninges)

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ALL Symptoms

Classic: bone pain
Sweats
LOW

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ALL Investigations

• Lumbar puncture. As for AML. Important to determine if there is evidence of CNS disease (usually when peripheral blasts cleared)
• Flow cytometry – may show blasts of B cell 9CD10+, CD 19+) or T cell lineage (20%)
• Cytogenetics

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ALL Cytogenetics

• Philadelphia chromosome t(9;22) seen in 20-25% of adults – poor prognostic marker but specific therapy with tyrosine kinase inhibitors
• Other poor prognostic lesions t(4;11). T(8;14) and complex cytogenetics

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ALL Morphology

• Common ALL: blast cells positive for CD10 on flow cytometry

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ALL Treatment of ALL

• Chemotherapy with complex combinations of cytotoxic drugs e.g. steroids, vincristine, daunorubicin, asparginase.
• Different drugs for second phase of induction

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ALL Induction protocol

2 months. Remission induction

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ALLConsolidation

4 month intensive chemotherapy and CNS prophylaxis (intra-thecal (4-6 injects) and methotrexate

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ALL Maintenance

2 years therapy; mainly oral cytotoxic drugs

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ALL ALL Prognosis

>80% cure in childhood ALL
Best prognosis if 1-10 years, female with low presenting WBC and no CNS disease (<35 mean a better prognosis

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ALL Allogenic bone marrow transplant in 1st C.R considered

In adults and children with poor prognostic indicators (eg. Ph+ ALL) → 40% cure rate. Role in other patients controversial.

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Minimum residual disease:

1. Leukaemia clone can be identified by DNA fingerprinting and accurately measured using Q PCR. Sensitive (2 in 10,000 cells or better)
2. Response to therapy after 2 months may override other pre-treatment prognostic factors
3. MRD used to decide treatment in children and adults.

Remission testing via:

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Remission testing via:

1. Morphological remission (cant see it on blood films)
2. Cytomorphology
3. FISH detection (1 in 100 cells are abnormal)
4. Immunophenotyope (1 in 10,000)
5. PCR detection

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