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.

Risk factors

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 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 5 x10⁹ 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 (<50 g/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 Europe but in the USA the Rai-Sawitsky staging predominates.^3,4 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/L, 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/L, or both.

The staging system is useful but it does have shortcomings in terms of predicting prognosis and who will benefit from certain interventions.⁵ 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.⁶

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

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 60 mg daily but reduced down as control is achieved.

The common first line combination regimens for chemotherapy include:

• Chlorambucil and prednisolone
• Cyclophosphamide, doxorubicin (formerly known as adriamycin), and prednisolone (CAP)
• Cyclophosphamide, vincristine, and prednisolone (CVP)
• Cyclophosphamide, doxorubicin (= hydroxydaunorubicin), vincristine (= Oncovin®), and prednisolone (CHOP)

Currently 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 New NICE guidance on rituximab is expected in 2009.

Molecular markers now make it possible to identify patients more likely to have rapid progression of CLL. Current research may help define how best to treat this group of patients. Recent research indicates that patients with high risk factors are more likely to progress after chemotherapy. Other studies are in progress to determine if high-risk patients should be treated before becoming symptomatic.⁸ Therefore such patients identified even at an early stage should be considered for inclusion in clinical trials.

New drugs and treatments

Significant advances in combinations of treatment are being made and new drugs are being developed. These are making a big impact on treatment and improved response rates have been reported. However research continues and hopes for improved survival have yet to be realised. For example:

• Nucleoside analogues (including fludarabine,⁹ cladribine and pentostatin⁸):
  • Fludarabine is the most extensively studied of these nucleoside analogues.
  • Patients treated with fludarabine have much higher rates (80%) of overall responses (no higher than 47% with chlorambucil and prednisolone) and a 37% complete remission rate.
  • Studies using purine analogues, especially fludarabine, have not yet showed prolonged overall survival.
  • The combination of fludarabine and cyclophosphamide (FC) has shown higher response rates. However comparative trials of fludarabine and cyclophosphamide to fludarabine alone have not been performed.
  • Various combination regimens fail to show any survival advantage. Examples of these include:
    • Fludarabine, cyclophosphamide, and rituximab (FCR)
    • Pentostatin, cyclophosphamide, and rituximab (PCR)
    • Fludarabine, cyclophosphamide, mitoxantrone (FCM)
    • Cyclophosphamide, vincristine, and prednisone (CVP)
    • Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)
• Monoclonal antibodies:^10,8
  • Alemtuzumab is a monoclonal antibody directed at CD52 that is approved for use in CLL. It has been used as a first-line agent and for patients with fludarabine-refractory disease. Alemtuzumab has also been shown to be effective in p53 mutations in contrast to rituximab, which is not effective in p53 mutations. Although very effective in clearing disease in the bone marrow, alemtuzumab has only limited activity in clearing lymphadenopathy.
  • Alemtuzumab appears to have a role in elimination of minimal residual disease (MRD). However at present it is recommended that such treatment should only be performed in clinical trials.
  • Other monoclonal antibodies undergoing study in CLL include rituximab, epratuzumab, and lumiliximab. Rituximab as a single agent has only shown partial responses and its main role is in combination chemotherapy.
• Immunomodulatory drugs (lenalidomide):⁸
  • Lenalidomide is an immunomodulatory drug (IMiD) currently approved for use in multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q.
  • It is being tried in patients with relapsed and refractory CLL.
• New combinations of monoclonal antibodies and established chemotherapeutic agents:⁸
  • Rituximab has been used extensively in combination with chemotherapy. Fludarabine has been shown to enhance the action of rituximab. Fludarabine combined with rituximab has been shown to have higher clinical remission rates than fludarabine alone in clinical trials. Fludarabine and cyclophosphamide and rituximab (FCR) has shown clinical response rates of 76% in trials, better than either fludarabine or FC in salvage therapy for patients with CLL that have been previously treated. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR) is currently under study in clinical trials.
  • Alemtuzumab is undergoing study in combination with fludarabine, rituximab, and the FCR regimen.
• Bone marrow transplantation:⁸
  • Bone marrow transplantation has been investigated in CLL treatment.
  • Allogenic stem cell transplantation is the only known curative therapy.
  • The optimal timing of transplantation is still being investigated; however, it is known that delay of transplantation until development of refractory disease results in worse outcomes.⁸
• Patients with chronic lymphocytic leukaemia demonstrate autoimmune anaemia and or thrombocytopenia (25% of the time):
  • This is accompanied by immune incompetence and specifically a progressive profound hypogammaglobulinaemia.
  • This predisposes to bacterial infections (often pneumonias).
  • Patients are likely to benefit from monthly infusions of intravenous immunoglobulins.
  • Prednisolone may also be helpful.

Minimal residual disease (MRD)

This is disease detectable with the most sensitive testing available. Eradication of MRD has been seen to be beneficial in patients with other haematologic malignancies. It is now being considered in chronic lymphocytic leukaemia. Eradication of MRD has been shown in other haematological malignancies to result in improved overall survival.

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.¹¹ 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 ciclosporin 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.¹²

Extremely high WCC (>30 x10⁹/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 younger patients.¹³