Haematology - Acute Leukaemias

Question 1

What are leukaemias?

Answer 1

• Group of disorders characterised by accumulation of malignant white cells in BM and blood. These abnormal cells cause symptoms because of bone marrow failure (anaemia, neutropenia, thrombocytopenia) and infiltration of organs (liver, spleen, LNs, meninges, brain, skin or testes)
• Genetic damage is thought to involve several key biochemical steps:
  
  • Increased rate of proliferation
  • Reduced apoptosis
  • A block in cellular differentiation
• All of these result in accumulation of blast cells (early haemopoietic cells) in BM

Question 2

What features must be present to diagnose acute leukaemia?

Answer 2

• Presence of over 20% of blast cells in blood or BM at clinical presentation
• Can be Dx with less than 20% if specific leukaemia associated cytogenetic/molecular genetic abnormalities are present.

Question 3

Acute leukaemias: How are blasts identified?

Answer 3

• Microscopic examination (morphology) on film
• Immunophenotypic: flow cytometry – proves lineage (myeloid or lymphoid)
• Cytogenetic and molecular analysis
• Will determine whether blasts are myeloid or lymphoid and localised the stage of cellular differentiation

Question 4

AML: incidence

Answer 4

Acute leukaemia of myeloid lineage

• Most common form of acute leukaemia in adults (increasingly common with increasing age – median onset is 65 years) – can progress from myeloproliferative disorder (PV or Myelofibrosis)
• Minor fraction (10-15%) of leukaemias in childhood.

Question 5

AML: clinical features

Answer 5

• Clinical features dominated by pattern of BM failure
• Neutropenia, profound thrombocytopenia (and DIC) and anaemia
• Tumour cells infiltrate tissues: gum hypertrophy and infiltration, skin involvement, CNS disease

Question 6

AML: what investigations should you do? What investigations should you do if patinet is unwell? What is your differential?

Answer 6

• Bloods:
  
  • FBC: Normochromic normocytic anaemia, thrombocytopenia (most common), WCC
  • Other: D-Dimer (raised), LFTs and clotting screen (leukaemias cause acute coagulopathies), U+Es, serum uric acid and LDH
  • Viral screen: Hep B and HIV
  • Blood film: variable numbers of blast cells (>20%) – cytogenetic and molecular analysis are critical for determining the prognosis and developing treatment plan
• BM: hypercellular and contains many leukemic blasts
  
  • Cytogenetics: karyotype and FISH
  • Flow cytometry and Immunophenotyping
  • Molecular testing
• If unwell: sepsis workup, CXR, cultures, blood product replacement, anti-emetics, antibacterial prophylaxis
• Differential: ALL, aplastic anaemia

Question 7

AML: treatment, relapse and prognosis

Answer 7

• Supportive for BM failure: central venous cannula, blood support and prevention of tumour lysis syndrome
• Specific therapy of AML: determined by age, performance status and genetic lesions of tumour
  
  • Young patients: intensive chemotherapy
  • Patients over 70 years: poor outcomes because of primary disease resistance and poor tolerability of intensive treatment protocols.
• Relapse: mot patient suffer relapse (outlook depends on age, type of AML and course of previous AML)
• Prognosis: 1/3 of group (under 60) can expect to live long term
• Allogenic stem cell transplantation: considered in poor prognosis/relapses

Question 8

ALL: what is it? At what age is it more common? Are B cell or T cell ALL more common?

Answer 8

Most common malignancy in childhood - caused by an accumulation of lymphoblasts (B or T) in the BM

• Highest incidence at 3-7 years with 75% of cases occurring before the age of 6
• Secondary wave after the age of 40
• 85% are B cell lineage
• 15% are T cell lineage (T-ALL) with male predominance
• Pathogenesis is varied and also related to BCR-ABL 1 – classification is based on underlying genetic defect. The subtype is an important guide to the optimal treatment protocol and prognosis.

Question 9

ALL: clinical features

Answer 9

• BM failure:
  
  • Anaemia: pallor, lethargy, dyspnea
  • Neutropenia: fever, malaise, features of mouth/skin/resp/perianal or other infections
  • Thrombocytopenia: spontaneous bruises, purpura, bleeding gums and menorrhagia
• Organ infiltration: tender bones, lymphadenopathy, moderate splenomegaly, hepatomegaly, meningeal syndrome (headache, nausea, vomiting, blurring of vision and diplopia)
• Fundal examination: papilledema and sometimes haemorrhage
• Less common manifestations: testicular swelling or signs of mediastinal compression in in T-ALL

Question 10

What is your differential for ALL?

Answer 10

• AML
• Aplastic anaemia (ALL can present with this)
• Marrow infiltration by other malignancies: eg Ewing’s sarcoma
• Infection (infectious mononucleosis)
• ITP

Question 11

ALL: What bloods and BM investigations should you perform?

Answer 11

• Bloods:
  
  • FBC: Normochromic normocytic anaemia, thrombocytopenia, WCCs
  • Film: variable number of blast cells
  • Serum uric acid (raised), LDH and Hypercalcaemia (rare)
  • LFT and U+Es as baseline before treatment starts
• BM examination: aspiration and trephine
  
  • Hypercellular with >20% leukemic blasts
  • Blast cells: characterised by morphology, cytochemistry and cytogenetic analysis

Question 12

ALL: What other investigations (apart from bloods and BM) should you perform?

Answer 12

• CXR: lytic lesions or mediastinal mass caused by enlargement of thymus and/or mediastinal LNs characterised by T-ALL
• PET/MRI: staging and organ involvement
• LN biopsy: asses LN involvement or investigate for lymphoma

*If LN or solid extra-nodal masses predominate with <20% blasts in marrow, the disease is called lymphoblastic lymphoma but is treated as ALL.

Question 13

ALL: treatment and prognosis

Answer 13

• General supportive for BM failure: central venous cannula, blood product replacement/support and prevention of tumour lysis syndrome (allopurinol) and neutropenic sepsis
• Treatment protocols are very complex – mostly given chemotherapy + steroids
• Other therapies: Rt, BMT, surgery
• 85% of children can expect to be cured (less than 5% of patients over 70 are cured)