Chronic lymphocytic leukaemia

Published on 03/04/2015 by admin

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Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is a disease characterised by a clonal proliferation of antigen-stimulated mature B-lymphocytes. It is the most frequent form of leukaemia in the Western world and is a disease of the elderly; almost all patients are over 50 years old at diagnosis. Recent research has highlighted the biological diversity of CLL. The disease can be most broadly divided into two types dependent on whether the leukaemic cells have a mutation of the immunoglobulin heavy chain variable region (IgV_H) gene. Patients with cells lacking this mutation tend to have more aggressive disease with shortened survival.

Clinical features

Many patients survive long periods with minimal symptoms, while others have a rapid demise with bone marrow failure, bulky lymphadenopathy and hepatosplenomegaly. Fortunately, the former group is in the majority. Indeed, the diagnosis is increasingly made by chance on a routine blood count. Elderly patients with early CLL are very likely to die from other causes.

Where problems do arise, patients commonly complain of symptoms of anaemia, lymphadenopathy, unusually persistent or severe infections and weight loss. The most frequent findings on examination are lymphadenopathy and splenomegaly. In more advanced cases other tissues such as skin, the gastrointestinal tract, the central nervous system, lungs, kidneys and bone may be infiltrated by leukaemic cells. Occasionally there is transformation into a poorly differentiated large cell lymphoma which carries a poor prognosis (Richter syndrome). The immunodeficiency in CLL is caused mainly by hypogammaglobulinaemia, which predisposes to infections (Fig 23.1) and also accounts for an increased incidence of other malignancies.

Fig 23.1 CLL is a cause of acquired immunosuppression.
(a) Oral candidiasis; (b) severe chickenpox.

Diagnosis

The diagnosis is suggested by a high lymphocyte count confirmed by the blood film appearance. Lymphocyte counts in CLL exceed 5 × 10⁹/L and may reach levels of 500 × 10⁹/L or more. The cells resemble normal mature lymphocytes but are often slightly larger with a tendency to burst during preparation of blood films, resulting in ‘smear cells’ (Fig 23.2). Unexplained persisting lymphocytosis in an elderly person should always suggest CLL. The diagnosis is made by proving that the lymphocytosis is a proliferation of clonal B-cells; this is most simply demonstrated by using in situ or flow cytometry techniques (see p. 21) to show that the cells have characteristic B-lymphocyte antigens and that a single immunoglobulin light chain (kappa or lambda) exists on the cell surface (i.e. it is a monoclonal population). The bone marrow aspirate shows increased numbers of small lymphocytes and a trephine biopsy is worthwhile as the pattern of lymphocyte infiltration gives prognostic information. The blood film appearance may suggest autoimmune haemolysis or autoimmune thrombocytopenia, both of which can complicate CLL.

Fig 23.2 Blood film in CLL.
The malignant cells resemble mature lymphocytes but are prone to burst during film preparation leading to the formation of smear cells.

The term monoclonal B-cell lymphocytosis is used where there are fewer than 5 × 10⁹/L monoclonal B-lymphocytes in the blood in the absence of other disease features such as lymphadenopathy. In the majority of cases the immunophenotye is identical to CLL and some of these patients will progress to CLL over time.

Staging

Staging is important in CLL as it helps in making a rational decision as to whether to commence treatment, and it also gives useful prognostic information. The easiest method is the Binet adaptation of the previous Rai system (Table 23.1); this is simple to apply and correlates closely with survival.

Table 23.1

Binet staging system for CLL

Stage A	No anaemia or thrombocytopenia
	Fewer than three lymphoid areas¹ enlarged
Stage B	No anaemia or thrombocytopenia
	Three or more lymphoid areas enlarged
Stage C	Anaemia (Hb less than 100 g/L) and/or platelets less than 100 × 10⁹/L

¹ Lymphoid areas are cervical, axillary and inguinal lymphadenopathy (uni- or bilateral), spleen and liver.

Other variables are increasingly important in predicting prognosis. As gene sequencing is expensive and time-consuming, expression of the signalling molecule ZAP-70 can be used as a surrogate marker for unmutated IgV_H genes and a poor prognosis (Table 23.2).

Table 23.2

Other prognostic factors in CLL ¹

¹ Factors not included in Binet staging system.

² Complete remission.

³ p53 mutation/deletion.

Management

When to start treatment

There has to be a reason to start treatment in CLL – many patients with early stage disease are completely well and need reassurance as to its relatively benign nature. Early treatment may slow progress but does not improve survival and can lead to significant side-effects including other neoplasms, and the emergence of resistant disease.

Choice of treatment

Treatment should be commenced when the patient develops significant symptoms, when the disease is progressing rapidly or when it is already at an advanced clinical stage. For many years, oral chlorambucil (usually given intermittently) has been the traditional first-line agent for treatment. Chlorambucil is still useful in older patients and where there is significant comorbidity but it has now been mostly replaced in first-line treatment by the more effective purine analogue fludarabine. The combination of fludarabine with other agents has brought benefits with higher levels of complete remission (Fig 23.3) translating into a survival advantage; the current favoured regimen is a combination of fludarabine, cyclophosphamide and the monoclonal antibody rituximab (anti-CD20). The alkylating agent bendamustine is a promising new approach to first-line treatment. Steroids (e.g. prednisolone) are best reserved for patients with pancytopenia or autoimmune complications such as haemolysis or immune thrombocytopenia. Treatment decisions are increasingly influenced by risk factors (see Table 23.2) in addition to stage – for instance, patients with 17p deletions are known to respond poorly to fludarabine and may be considered for more novel therapies such as alemtuzumab (anti-CD52) and ibrutinib.

Fig 23.3 Efficacy of fludarabine in CLL.
Fludarabine, usually in combination with other agents, is now the favoured first-line treatment. Its general superiority over chlorambucil is demonstrated in this patient – the chest infection is a reminder that fludarabine is, however, more immunosuppressive than chlorambucil.

Radiotherapy can be used as palliation, particularly where enlarged lymph nodes or spleen cause compressive problems. Splenectomy can be beneficial for painful splenomegaly or autoimmune cytopenia. In hypogammaglobulinaemia and recurrent infection, regular intravenous immunoglobulin has been shown to be well tolerated and quality of life is often improved.

None of the above drug regimens or other treatment modalities will cure CLL; the emphasis is on control of symptoms and prolongation of life. In the rare younger patient with CLL a more aggressive approach to treatment may be justified to try and eradicate disease. Allogeneic stem cell transplantation should be considered in younger fit patients with refractory CLL or with very poor prognostic features (e.g. 17p deletion).

Fig 23.4 The combination of different agents as first-line treatment for CLL leads to improved response rates.
(Reproduced from Hallek M 2009 State-of-the-art treatment of chronic lymphocytic leukaemia. American Society of Haematology Educational Book). CR, complete remission; OR, overall response; Chl, chlorambucil; F, fludarabine; C, cyclophosphamide; R, rituximab.

Chronic lymphocytic leukaemia

CLL is the commonest form of leukaemia in the Western world. It is a disease of the elderly.

There is a clonal proliferation of B-lymphocytes.

Symptoms/signs include anaemia, recurrent infections, weight loss, lymphadenopathy and hepatosplenomegaly.

The clinical course is often indolent but it can be more aggressive in advanced stages.

Chemotherapy is often not immediately needed in early CLL.

The combination of fludarabine, cyclophosphamide and rituximab (FCR) is the initial treatment of choice in most cases.

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