Paeds: Leukaemia Flashcards
Definition
Proliferation of immature WBCs (blasts).
Type
Vast majority are acute, chronic myeloid leukaemia is very rare. Classified by cell as lymphocytic (lymphoid cells) or myeloid (granulocytic or monocytic).
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.
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.
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
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)
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.
Signs and Symptoms of Acute leukaemia: General
Malaise
Anorexia
Signs and Symptoms of Acute leukaemia: Bone marrow infiltration
- Anaemia – Pallor, lethargy
- Neutropenia - Infection
- Thrombocytopenia – Bruising, petechiae, nose bleeds
Bone pain
Signs and Symptoms of Acute leukaemia: Reticulo-endothelial infiltration
- Hepatosplenomegaly
- Lymphadenopathy
Superior mediastinal obstruction (uncommon)
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.
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)
Age (high-risk)
10 years
Tumour load (measured by the white cell count, WBC)
> 50x109/L
Cytogenic/molecular genetic abnormalities in tumour cells
e.g. MLL rearrangement, t(4;11), hypodiploidy (
Speed of response to initial chemotherapy
Persistence of leukaemic blasts in the bone marrow
Minimal residual disease assessment (MRD) (submicroscopuc levels of leukaemia detected by PCR)
high
Outline of standard treatment
ALL
- Induction
- Consolidation
- Maintenance
- Intensive blocks of chemotherapy
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)
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
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
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
Acute myeloid Leukaemia: Aetiology
Accounts for 5% of all childhood malignancies and
Acute myeloid Leukaemia: Definition
AML results from malignant proliferation of myeloid cell precursors.
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
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
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.
Acute myeloid Leukaemia: Prognosis
Overall survival is >60%
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).
Acute myeloid Leukaemia: M1 and M2 AML cytogenetics
- t(8;21) translocation observed in 15% of all cases
M3 AML: cytogenetics
- t(15;17) translocation observed in 1–% of cases
M4Eo: cytogenetics
inv (16) frequently observed.
Management of AML principle:
Treatment – AML prolonged continuation therapy is not used:
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.
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.
Other genetic conditions predisposing to AML:
- Fanconi syndrome
- Bloom syndrome
- Ataxia telangiectasia
- Kostmann’s syndrome
- Diamond-Blackfan syndrome
- Klinefelters
- Turners syndrome
- Neurofibromatosis
- Incontinentia pigmenti
