Haematology - Chronic leukaemia

Chronic leukaemias are often diagnosed in a routine blood test, say Dr David Bareford and Dr Sebastian Francis.

Rubbery, painless lymphadenopathy can be a sign of a lymphoproliferative disorder, such as CLL (Photograph: SPL)
Rubbery, painless lymphadenopathy can be a sign of a lymphoproliferative disorder, such as CLL (Photograph: SPL)

There are two types of chronic leukaemia, both caused by a mutational event that leads to an unrestricted growth of mature leucocytes.

Chronic lymphocytic leukaemia (CLL) is the most common type of chronic leukaemia with six cases per 100,000 people. It most commonly occurs in people over 60 years and is very rare in people under 40 years.

Men are twice as likely to develop CLL as women and it is three times more common in first degree relatives. Five per cent of the normal population over the age of 60 will develop a similar mutational event leading to a clonal expansion of their lymphocytes (which often remain in the normal range) but only 1 per cent per year will progress to CLL.

Chronic myeloid leukaemia (CML) affects about one per 100,000 persons and is most common in older age but can occur at any age. CML is characterised by the presence of the Philadelphia chromosome, a shortened chromosome 22.

It is caused by a reciprocal exchange of genetic material resulting in the fusion of the ABL gene on chromosome 9, and the BCR gene on chromosome 22 resulting in the production of a novel tyrosine kinase (an internal cell growth factor).

Presentation
Chronic leukaemias are often diagnosed when a person has a routine blood test. The leukaemia often develops insidiously and it is the bulk of accumulating disease that eventually causes the signs and symptoms.

Signs and symptoms common in both CML and CLL include fatigue, weakness and limited capacity for exercise, weight loss, breathlessness on exertion, pallor, persistent infections, fever and night sweats.

Abdominal discomfort and a feeling of fullness when eating may be a problem with increasing splenomegaly. Hepatomegaly rarely occurs. Enlarged lymph nodes may also be present in CLL. Rubbery, painless lymphadenopathy is a sign of a lymphoproliferative disorder, such as CLL, whereas firmer tender nodes usually denote infection.

Diagnosis and referral
In CLL an FBC will confirm lymphocytosis >5x109/l. A blood film will show small lymphocytes and smear cells. The clonal nature of the disease may need confirming with special tests, such as flow cytometry.

The Binet staging system is used in CLL, and is based on the number of lymph node groups palpable and also on the FBC (see table). In CML the FBC normally shows an elevated white blood count >15x109/l. The blood film shows increased neutrophils and their precursors as well as increased basophils (pathognomonic for CML).

The result of the FBC is usually sufficient to produce a haematology outpatient referral. If the patient is not too symptomatic, referral does not have to be urgent.

The Binet staging system for CLL
Stage Lymph node
groups/spleen
FBC

Prognosis
(average
survival)

A <3 Hb at least 10g/dL
Platelets at least 100 x 109/L
>10 years
B ≥3 Hb at least 10g/dL
Platelets at least 100 x 109/L
7 years
C ≥3 Hb <10g/L
Platelets <100 x="" 109="" l="" td="">
3 years

Management
The treatment of CLL needs a combined approach between primary care and the haematology department. However, some patients may not require treatment.

Treatment is only required if there are systemic signs of disease, such as drenching night sweats, weight loss, fevers and recurrent infection. Treatment is also indicated in cases where there is progressive lymphadenopathy, splenomegaly or progression to pancytopenia.

Treatment options are changing and expanding. These vary from a combination of cyclical chemotherapy, such as rituximab, cyclophosphamide and fludarabine, to oral chlorambucil in older patients.

Patients are at risk of viral and bacterial infections and may need blood transfusions. Bone marrow transplants are reserved for a minority of younger patients. Treatment is aimed at disease control and few patients are ever cured.

In CML, the outlook has improved a great deal since the introduction of the oral tyrosine kinase inhibitor, imatinib. Once started on imatinib, treatment is assessed by regular FBC monitoring and three monthly bone marrow biopsies.

After six months of treatment, most patients have a normal FBC and normal spleen size, and after 18 months there should be no evidence of the Philadelphia chromosome.

Some patients are intolerant or resistant to imatinib. Newer tyrosine kinase inhibitors are available and show promise. Patients showing inadequate response to these can be offered a bone marrow transplant.

CML that has entered the aggressive or blast phase where the disease has undergone further mutation and de-differentiated towards acute leukaemia is more difficult to manage.

Prognosis
The median survival for CLL is about five years depending on stage. Certain cytogenetic aberrations can also influence the outcome. If the VH gene is 'mutated' then the disease develops slowly or even stabilises. Some other mutations, such as loss of chromosome 17p (containing the p53 gene), indicate a poor response to chemotherapy.

In CML, with imatinib, nearly nine out of 10 patients live for at least seven years and some may be cured. The prognosis may improve with newer tyrosine kinase inhibitors. More than half of the patients who require a bone marrow transplant will live for 15 years or more.

TEST YOUR KNOWLEDGE

1. What are the signs expected in a patient presenting with a chronic leukaemia?

2. What is the diagnostic test for CML?

3. What is the prognosis in CLL?
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  • Dr Bareford is a consultant haematologist and Dr Francis is a specialist registrar in Dudley, West Midlands

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  • Find more articles about haematology and questions on chronic leukaemia at the haematology resource centre gponline.com/haematology

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