Chronic Lymphocytic Leukaemia (CLL)

This is malignancy of B lymphocytes. Morphologically they appear normal but they are immature and so there is immunological compromise.

It is most frequent in those over 55 although it is seen at times below 35 years old. It affects white races more than black and is uncommon in those of Far Eastern origin. There is a male preponderance of 1.7:1.

There is evidence that a number of people with CLL may have a genetic predisposition¹ although cases running in families are very rare. It is not related to exposure to radiation.²

Symptoms

Presentation is variable. Onset is insidious, and it is not unusual for it to be discovered incidentally after a blood count is performed for another reason.

• Susceptibility to infections including pneumonia, herpes simplex, and herpes zoster
• Enlarged lymph nodes
• Abdominal discomfort from to an enlarged spleen
• Bleeding or petechiae in skin or mucous membranes from thrombocytopenia
• Tiredness and fatigue from anaemia

Signs

• Local or generalised lymphadenopathy
• Splenomegaly in 30 to 40%
• Hepatomegaly in 20%
• Petechiae
• Pallor

• Other forms of leukaemia
• Lymphoma
• Myelodysplasia and myeloproliferative diseases

Blood

• FBC shows more than 5000 lymphocytes/?L.
• Peripheral blood smear confirms lymphocytosis often with smudge cells which are artifacts from damage to lymphocytes during preparation of the slide.
• Peripheral blood flow cytometry is the most valuable test to confirm CLL. It shows circulating clonal B-lymphocytes expressing CD5, CD19, CD20(dim), CD 23, and an absence of FMC-7 staining.
• Measurement of immunoglobulin levels if there are repeated infections because monthly intravenous immunoglobulin in patients with low IgG (<500 mg/L) may help to reduce the frequency of infections.

Imaging

• Liver and spleen scan may show enlargement.
• CT of chest, abdomen or pelvis is not necessary for staging but it may show obstructive uropathy or airway obstruction from lymph node compression on organs or internal structures.

Procedures

• Bone marrow aspiration and biopsy with flow cytometry is not needed in all cases but may be necessary to establish the diagnosis and to assess other complications including anaemia and thrombocytopenia. Bone marrow examination may be necessary to distinguish between thrombocytopenia of peripheral destruction (in the spleen) and that due to marrow infiltration.
• Lymph node biopsy is required if lymph nodes enlarge rapidly to assess the possibility of transformation to a high-grade lymphoma. This transformation with fever, weight loss, and pain it is called Richter syndrome.

The Binet system is used in the Europe but in USA the Rai-Sawitsky staging predominates. The International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) has recommended integrating the two.

The Binet system is as follows:

• Stage A: Hb at least 10 g/dL, platelets at least 100 X 10⁹, and less than 3 lymph node areas involved.
• Stage B: Hb and platelet levels as in stage A and 3 or more lymph node areas involved.
• Stage C: Hb <10 g/dL, platelets <100 X 10⁹, or both.

The staging system is useful but it does have shortcomings in terms of predicting prognosis and who will benefit from certain interventions.³ Haemoglobin level, blood lymphocyte count, lymphocyte doubling time and bone marrow infiltration pattern are useful to identify subsets of patients in early stage with different progression and survival rates, with the 'smouldering' form of the disease being identified fairly accurately. Tumour mass, as reflected by splenomegaly, lymphadenopathy and bone marrow infiltration, affects prognosis.⁴

Non-Drug

Because of the risk of infection, influenza vaccination and pneumococcal vaccine should be given.

Drugs

Most patients do not need immediate chemotherapy unless they have:

• Weight loss of more than 10%
• Extreme fatigue
• Fever related to leukaemia
• Night sweats
• Progressive marrow failure
• Autoimmune anaemia or thrombocytopenia not responding to prednisolone
• Progressive splenomegaly
• Massive lymphadenopathy or progressive lymphocytosis
• Progressive lymphocytosis is defined as an increase of more than 50% in 2 months or a doubling time of less than 6 months.

Some patients develop autoimmune disease. They may benefit from prednisolone, started at a dose that may be as high as 60mg daily but reduced down as control is achieved.

Common combination regimens for chemotherapy include:

• Chlorambucil and prednisolone
• Cyclophosphamide, doxorubicin, and prednisolone (CAP)
• Cyclophosphamide, vincristine, and prednisolone (CVP)
• Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)

New drugs include fludarabine⁵ and monoclonal antibodies.⁶ NICE recommends that if there is reason to stop the first line chemotherapy as listed above, either because of adverse effects or failure to respond, that fludarabine should be the next line.⁷

Surgical

Splenomegaly and pancytopenia may require splenectomy. Up to 90% of patients show considerable improvement in Hb and platelets after splenectomy.

They should be immunised with Pneumococcus, Haemophilus and Neisseria meningitides vaccines at least a week before operation.

Around a quarter of patients with CLL have autoimmune phenomena. The commonest is haemolytic anaemia followed by thrombocytopenia.⁸ There may be immune compromise with progressive profound hypogammaglobulinaemia. A fairly common precipitant of these phenomena seems to be treatment with the purine analogues such as chlorambucil and fludarabine. Helpful treatments, if corticosteroids alone are insufficient, include cyclosporin and rituximab. The latter is one of the monoclonal antibodies.

The autoimmune complications do not not imply a poor prognosis although a major cause of death is secondary malignancy.⁹

Extremely high WCC (>300,000/?L) can produce a hyperviscosity syndrome affecting the CNS or respiratory system. Leukocytopheresis and urgent therapy with prednisolone and chemotherapy may be required. Virtually all patients requiring therapy also should be given allopurinol to prevent uric acid nephropathy.

Prognosis is highly variable. Some patients die within 2 or 3 years of diagnosis because of complications of CLL.

The majority live 5 to 10 years, with an initial course that is relatively benign but followed by a terminal progressive and resistant phase lasting a year or two. In the late phase there is considerable morbidity from both the disease and from complications of treatment.

Survival is generally dependent upon staging:

• Stage A: Survival >120 months
• Stage B: Survival around 61 months
• Stage C: Survival around 32 months

The management of CLL is aimed at palliation rather than cure but with improvements in care, including the potential for stem cell transplantation, cure may soon be the goal, especially in the younger patients.¹⁰