Haematology - Chronic Leukaemias

Question 1

How do you distinguish acute and chronic leukaemias?

Answer 1

Chronic leukaemias are distinguished from acute leukaemias by their slower progression and presence of increased maturity of abnormal cells.

Question 2

CML: Name an important chromosomal abnormality that has been linked to CML

Answer 2

• Chronic myeloid leukaemia BCR-ABL 1 +(CML): clonal disorder of a pluripotent stem cell (accounts for 15% of leukaemias and may occur at any age)
• Diagnosis: difficult and characterised by presence of Philadelphia (22) abnormal chromosome (translocation between chromosomes 9 and 22 and transfer of oncogene ABL1 to the BCR gene on chromosome 22). This chimeric BCR-ABL1 gene codes for a protein with an excessive tyrosine kinase activity.

Question 3

CML: name some clinical features

Answer 3

• Occurs equally in males and females between 40-60 years
• Symptoms related to hypermetabolism: weight loss, lassitude, anorexia or night sweats
• Symptoms related to hyperviscosity: confusion, bleeding, SOB, pulmonary oedema
• Splenomegaly: nearly always present and frequently massive (can cause pain or indigestion)
• Features of anaemia: pallor, dyspnea and tachycardia
• Bruising, epistaxis, menorrhagia or haemorrhage (abnormal platelets)
• Gout/renal impairment: hyperuricaemia due to excessive purine breakdown
• Rare sx: visual disturbances and priapism

*Up to 50% of cases: dx made from routine FBC

Question 4

CML: what investigations should you perform?

Answer 4

• Leucocytosis: >50 x 10^9/L (can go up to >500 x 10^9)
• Blood film: complete spectrum of myeloid cells sin peripheral blood (levels of neutrophils and myelocytes exceed those of blasts and promyelocytes)
  
  • Increased circulating basophils
• Bloods:
  
  • FBC: (normochromic normocytic anaemia, variable platelet counts), flow cytometry, LDH, U+E, LFT, autoimmune screen (Felty’s), malaria screen, serum uric acid
  • PCR: presence of BCR-ABL 1 gene fusion
• BM: hypercellular with granolopoietic predominance
  
  • Cytogenetic analysis + FISH: presence of Philadelphia chromosome

Question 5

Give some treatment options for CML

Answer 5

• Cytoreduction: hydroxycarbamide (considerations include increased risk of TLS [start allopurinol], effect on fertility, flu-like sx and myelosuppression)
• Tyrosine kinase inhibitors (Imatinib): 1^st line Rx of chronic phase disease - designed as specific inhibitors of BCR-ABL1 fusion protein and blocks tyrosine kinase activity by competing with ATP binding capacity.
• Allogenic stem cell transplantation: proven to be curative for CML but is high risk t/f usually reserved for imatinib failures.

Question 6

What is CLL?

Answer 6

• Definition: group of disorders characterised by accumulation in the blood of mature lymphocytes (B or T cell) and has some overlap with NH lymphomas. I
• n many cases of NHL, lymphoma cells are found in the blood and the distinction between chronic leukaemia and lymphoma is arbitrary, depending on the relative proportion of the disease in soft tissue masses compared to blood and bone marrow.
• These diseases are incurable but tend to run chronic and fluctuating course

Question 7

How do you diagnose Chronic Lymphoid Leukaemias? How are subtypes identified?

Answer 7

• Diagnosis: characterised by chronic persistent lymphocytosis
• Subtypes: distinguished by morphology, immune-phenotype and cytogenetics

Question 8

What is Chronic Lymphocytic Leukaemia?

Answer 8

• B cell disease - most common of chronic lymphoid leukaemias
• Peak incidence is 60-80
• Tumour cells: relatively mature B cell with weak surface expression of Ig (IgM or IgD) à accumulate in blood, BM, liver, spleen and LN b/c of increased production and lifespan with impaired apoptosis

Question 9

What are some features of chronic lymphocytic leukaemia?

Answer 9

• Older subjects >50 years, male (2): female (1)
• Most cases diagnosed when routine blood test performed
• Symmetrical enlargement of cervical, axillary or inguinal LN (most frequent clinical sign)
• Features of anaemia or thrombocytopenia
• Splenomegaly and hepatomegaly (less common)
• Immunosuppression: from hypogammaglobulinaemia and cellular immune dysfunction – bacterial, viral and fungal infections seen

Question 10

Name some investigations for chronic lymphocytic leukaemia

Answer 10

Bloods:

• Normochromic normocytic anaemia in later stages (BM infiltration or hypersplenism)
• Thrombocytopenia
• Reduced concentrations of serum Ig
• Lymphocytosis:
  
  • Absolute clonal B cell lymphocyte count is >5 x 10^9/L and may be raised >300 x 10^9/L
  • Between 70 and 99% of WCC in blood film appear as small lymphocytes
  • Smudge/smear cells present
  • Immunophenotyping of lymphocytes
• BM examination:
  
  • Aspiration: lymphocytic replacement of normal marrow elements (comprise 25-95% of all cells)
  • Trephine: nodular, diffuse or interstitial involvement by lymphocytes

Question 11

What is the treatment and prognosis for chronic lymphocytic leukaemia?

Answer 11

• Cures are rare: therapy approach is conservative (symptom control instead of normal blood count)
• Beware of chemotherapy too early in disease – can shorten life
• Chemo: chemo (chlorambucil, Bendamustine) +/- Rituximab
• Other: radiotherapy (good for bulky LNs that are unresponsive to chemo), or CHOP with rituximab (used in late-stage)
• Course of disease: can transform into localised high-grade lymphoma or may never need therapy (esp if have favourable prognostic markers)

Question 12

Name some other types (apart from chronic lymphocytic leukaemia) of chronic lymphoid leukaemias:

Answer 12

• B cell diseases:
  
  • B cell prolymphocytic leukaemia
  • Hairy cell leukaemia
  • Lymphocytosis in NHL
• T cell diseases:
  
  • T cell prolymphocytic leukaemia
  • Large granular lymphocytic leukaemia
  • Adult T cell leukaemia/lymphoma