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Flashcards in Paeds: Leukaemia Deck (36):
1

Definition

Proliferation of immature WBCs (blasts).

2

Type

Vast majority are acute, chronic myeloid leukaemia is very rare. Classified by cell as lymphocytic (lymphoid cells) or myeloid (granulocytic or monocytic).

3

Clinical features

Present due to bone marrow failure with anaemia or bruising, hepato-splenomegaly, lymphadenopathy, infection due to neutropenia or bone pain.
Bone marrow aspiration shows replacement of normal elements by blast cells.

4

ALL Aetiology

- 80% of leukaemia in children remainder is acute myeloid/acute non-lymphocytic leukaemia (AML/ANNL).
Chronic myeloid leukaemia and other myeloproliferative disorders are rare.

5

ALL Clinical presentation

- Peak presentation at 2-5 years
- Short history (days or weeks)
Clinical symptoms due to disseminated disease and systemic ill-health from infiltration of the bone marrow or other organs with leukaemic blast cells

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ALL Investigations

- FBC – low haemoglobin, thrombocytopaenia and evidence of circulating leukaemic blast cells.
- Bone marrow examination (useful for prognostic info, diagnostic)
- Chest x-ray (mediastinal mass T-cell orientation)
CSF for cytospin (CNS rapidly involved at first diagnosis)

7

ALL Classification

ALL and AML are classified by morphology. Immunological phenotyping further sub classifies ALL; the common (75%) and T-cell (15%) subtypes are the most common.

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Signs and Symptoms of Acute leukaemia: General

Malaise
Anorexia

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Signs and Symptoms of Acute leukaemia: Bone marrow infiltration

- Anaemia – Pallor, lethargy
- Neutropenia - Infection
- Thrombocytopenia – Bruising, petechiae, nose bleeds
Bone pain

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Signs and Symptoms of Acute leukaemia: Reticulo-endothelial infiltration

- Hepatosplenomegaly
- Lymphadenopathy
Superior mediastinal obstruction (uncommon)

11

Management of acute lymphoblastic leukaemia:
Remission induction –

- Anaemia may require correction with blood transfusion
- Risk of bleeding minimised by transfusion of platelets, and infection must be treated.
- Additional hydration and allopurinol (or urate oxidase when the WCC is high and the risk is greater) – given to protect renal function against the effects of rapid cell lysis.

12

Prognostic factor high-risk features

Age
Tumour load (measured by the white cell count, WBC)
Cytogenic/molecular genetic abnormalities in tumour cells
Speed of response to initial chemotherapy
Minimal residual disease assessment (MRD) (submicroscopuc levels of leukaemia detected by PCR)

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Age (high-risk)

10 years

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Tumour load (measured by the white cell count, WBC)

>50x109/L

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Cytogenic/molecular genetic abnormalities in tumour cells

e.g. MLL rearrangement, t(4;11), hypodiploidy (

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Speed of response to initial chemotherapy

Persistence of leukaemic blasts in the bone marrow

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Minimal residual disease assessment (MRD) (submicroscopuc levels of leukaemia detected by PCR)

high

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Outline of standard treatment
ALL

1. Induction
2. Consolidation
3. Maintenance
4. Intensive blocks of chemotherapy

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Induction

4 weeks
- Steroids (dexamethasone or prednisolone) throughout induction
- Weekly IV vincristine
- IM L-asparaginase (e.g. 9 doses in3 weeks or 2 doses of pegylated asparaginase)
- IV daunorubicin (2-4 doses, in intermediate and high risk cases)
Intrathecal (IT) methotrexate (day 18)

20

Consolidation

CNS directed therapy
- Low risk cases: 4-wks doses of IT methotrexate and continuous oral mercaptopurine
- Higher risk cases: add IV cyclophosphamide, cytrarabine
CNS-radiotherapy only for CNS +ve cases

21

Maintenance

Continuation treatment for at least 2 yrs (3yrs for boys)
- Daily 6-mercaptopurine (6MP), weekly oral methotrexate (doses titrated according to blood count)
- 4-weekly vincristine IV bolus and 5-day pulses of oral dexamethasone
12-weekly IT methotrexate

22

Intensive blocks of chemotherapy

One or two blocks 8 wks duration, interrupting 1st yr of maintenance. Combinations of oral steroid, vincristine, doxorubicine, cyclophosphamide, cutarabine and L-asparaginase

23

Acute myeloid Leukaemia: Aetiology

Accounts for 5% of all childhood malignancies and

24

Acute myeloid Leukaemia: Definition

AML results from malignant proliferation of myeloid cell precursors.

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Acute myeloid Leukaemia: Sub-division

M1: AML without maturation
M2: AML with maturation
M3: acute promyelocytic leukarmia (PML)
M4: acute myelomonocytic leukaemia with eosinophilia (M4Eo)
M5: acute monocytic/monoblastic leukaemia
M6: acute erythroleukaemia
M7: acute megakaryocytic leukaemia

26

Acute myeloid Leukaemia: Presentation

- symptoms and signs of bone marrow replacement
- Lymphadenopathy less prominent than in ALL
- Intrathoracic extramedullary disease less common than in ALL
- M3 may be present with coagulopathy from proteolytic enzyme activity
Solid deposits (chloroma) occasionally seen in M2, M4 or M5

27

Acute myeloid Leukaemia: Cytogenetics

Cytogenic analysis shows characteristic abnormalities:
- M1 and M2 AML
- M3 AML:
- M4Eo

These translocations are regarded as good prognostic indicators. Other complex karyotypes are associated with poor risk.

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Acute myeloid Leukaemia: Prognosis

Overall survival is >60%

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Acute myeloid Leukaemia: Relapse AML

All cases require BMT after intensive re-induction, usually in conjunction with ‘FLAG’ or ‘FLAG-Ida’ regimen (i.e. fludarabine, ara-C, and G-CSF support ± idarubicin).

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Acute myeloid Leukaemia: M1 and M2 AML cytogenetics

- t(8;21) translocation observed in 15% of all cases

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M3 AML: cytogenetics

- t(15;17) translocation observed in 1--% of cases

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M4Eo: cytogenetics

inv (16) frequently observed.

33

Management of AML principle:

Treatment – AML prolonged continuation therapy is not used:

34

AML treatment

4 courses intensive myeloablative chemotherapy
- The role of the gemtuzumab or myelotarg (a monoclonal antibody directed against CD33) given alongside chemotherapy is being explored in the context of clinical trials
- PML: all-trans retinoic acid given in induction, before chemotherapy, improves survivl.
- High risk cases, including those who fail to achieve complete remission after 2 courses, are usually offered BMT in first remission.

35

Leukaemia and down syndrome:

- Risk of development of acute leukaemia is 20-30times, commonly either a pre-B (common) ALL or AML (especially M7
- Response to chemotherapy is good and better relapse-free survival is fund in those with AML
- Patients with Down syndrome-associated leukaemia experience more complications of treatment.

36

Other genetic conditions predisposing to AML:

- Fanconi syndrome
- Bloom syndrome
- Ataxia telangiectasia
- Kostmann’s syndrome
- Diamond-Blackfan syndrome
- Klinefelters
- Turners syndrome
- Neurofibromatosis
- Incontinentia pigmenti

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