Paeds: Leukaemia

Question 1

Definition

Answer 1

Proliferation of immature WBCs (blasts).

Question 2

Type

Answer 2

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

Question 3

Clinical features

Answer 3

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.

Question 4

ALL Aetiology

Answer 4

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

Question 5

ALL Clinical presentation

Answer 5

• 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

Question 6

ALL Investigations

Answer 6

• 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)

Question 7

ALL Classification

Answer 7

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.

Question 8

Signs and Symptoms of Acute leukaemia: General

Answer 8

Malaise

Anorexia

Question 9

Signs and Symptoms of Acute leukaemia: Bone marrow infiltration

Answer 9

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

Question 10

Signs and Symptoms of Acute leukaemia: Reticulo-endothelial infiltration

Answer 10

• Hepatosplenomegaly
• Lymphadenopathy
  Superior mediastinal obstruction (uncommon)

Question 11

Management of acute lymphoblastic leukaemia:

Remission induction –

Answer 11

• 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.

Question 12

Prognostic factor high-risk features

Answer 12

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)

Question 13

Age (high-risk)

Answer 13

10 years

Question 14

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

Answer 14

> 50x109/L

Question 15

Cytogenic/molecular genetic abnormalities in tumour cells

Answer 15

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

Question 16

Speed of response to initial chemotherapy

Answer 16

Persistence of leukaemic blasts in the bone marrow

Question 17

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

Answer 17

high

Question 18

Outline of standard treatment

ALL

Answer 18

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

Question 19

Induction

Answer 19

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)

Question 20

Consolidation

Answer 20

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

Question 21

Maintenance

Answer 21

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

Question 22

Intensive blocks of chemotherapy

Answer 22

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

Question 23

Acute myeloid Leukaemia: Aetiology

Answer 23

Accounts for 5% of all childhood malignancies and

Question 24

Acute myeloid Leukaemia: Definition

Answer 24

AML results from malignant proliferation of myeloid cell precursors.

Question 25

Acute myeloid Leukaemia: Sub-division

Answer 25

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

Question 26

Acute myeloid Leukaemia: Presentation

Answer 26

- 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

Question 27

Acute myeloid Leukaemia: Cytogenetics

Answer 27

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.

Question 28

Acute myeloid Leukaemia: Prognosis

Answer 28

Overall survival is >60%

Question 29

Acute myeloid Leukaemia: Relapse AML

Answer 29

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).

Question 30

Acute myeloid Leukaemia: M1 and M2 AML cytogenetics

Answer 30

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

Question 31

M3 AML: cytogenetics

Answer 31

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

Question 32

M4Eo: cytogenetics

Answer 32

inv (16) frequently observed.

Question 33

Management of AML principle:

Answer 33

Treatment – AML prolonged continuation therapy is not used:

Question 34

AML treatment

Answer 34

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.

Question 35

Leukaemia and down syndrome:

Answer 35

- 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.

Question 36

Other genetic conditions predisposing to AML:

Answer 36

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