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Chronic Lymphocytic Leukaemia

This PatientPlus article is written for healthcare professionals so the language may be more technical than the condition leaflets. You may find the abbreviations list helpful.

This is a malignant monoclonal expansion of B-lymphocytes with accumulation of abnormal lymphocytes in the blood, bone marrow, spleen, lymph nodes and liver. Morphologically these lymphocytes have a normal appearance but are immature and nonreactive, resulting in immunological compromise. Chronic lymphocytic leukaemia (CLL) represents about a quarter of all leukaemias seen in clinical practice and is largely a disease of older people.

Epidemiology

Chronic lymphocytic leukaemia (CLL) is most frequent in those aged over 55 and, although it does occur in younger adults, it is rare before 40 years. It affects white races more than black and is uncommon in those of Far Eastern origin. There is a male preponderance (1.7:1).

Risk factors

Some individuals with CLL may have a genetic predisposition1, although a familial history is rare.2 It is not related to exposure to radiation.3

Presentation

Symptoms

Presentation is variable with insidious onset. 90% are now asymptomatic at presentation with chronic lymphocytic leukaemia (CLL) diagnosed incidentally following routine blood tests. Symptoms may include:

Signs

Differential diagnosis

Investigations

Blood

  • FBC shows a lymphocytosis (>5 x 109 lymphocytes/L, may be ≥300 x 109 lymphocytes/L). Normocytic, normochromic anaemia is present in advanced disease with marrow infiltration or hypersplenism.
  • Peripheral blood smear confirms lymphocytosis often with smudge cells (artifacts from damage to lymphocytes during preparation of the slide).
  • Direct antiglobulin test (DAT also known as the direct Coomb's test) in all anaemic patients and prior to starting treatment (to identify autoimmune-related hemolytic anemias).
  • Bone marrow aspirate shows lymphocytic replacement of normal marrow elements. It is not necessary in all cases but may help to establish the diagnosis and assess other complications such as anaemia and thrombocytopenia, e.g. thrombocytopenia of peripheral destruction (splenic) versus 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's syndrome.
  • Immunophenotyping - peripheral blood flow cytometry is the most valuable test to confirm chronic lymphocytic leukaemia (CLL) and shows circulating clonal B-lymphocytes expressing particular antigens (CD5, CD19, CD20 and CD23).
  • Measurement of immunoglobulin levels if there are repeated infections.
  • Cytogenetics are not usually performed but trisomy 12 or 14q+ or translocation 11:14 are the most usual findings.

Imaging

Note: staging in CLL is done based on blood and clinical examination, rather than imaging.

  • Liver and spleen scan may confirm enlargement.
  • CT scan of chest, abdomen or pelvis may show obstructive uropathy or airway obstruction from lymph node compression on organs or internal structures.

Staging

The Binet system is used in Europe but in the USA the Rai-Sawitsky staging predominates.4,5 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.6 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.7

Management

With the possible exception of stem cell transplants, there is no curative treatment for chronic lymphocytic leukaemia (CLL) currently available. Despite this, most patients with CLL will have a long survival and may receive a number of different types of treatment during the course of their disease. A significant minority of patients will never require treatment at any time. Typically, patients will require initial first-line treatment (chemotherapy) at some point, which may be followed by second- or third-line treatments in the case of relapse or non-response.

The diagnosis of CLL is not a medical emergency. Most patients do not need immediate chemotherapy and are monitored over time with regular blood tests. Indications for chemotherapy are:

  • Weight loss >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 (an increase of >50% in 2 months or a doubling time of <6 months)

Molecular markers now make it possible to identify patients more likely to have rapid progression of CLL or be more resistant to standard treatment. 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.

Approximately a quarter of patients with CLL have associated autoimmune anaemia or thrombocytopenia:

  • This is accompanied by immune incompetence and specifically a progressive profound hypogammaglobulinaemia.
  • This predisposes to bacterial infections (often pneumonias).
  • Fludarabine may trigger autoimmune haemolytic anaemia.
  • Patients may benefit from monthly infusions of intravenous immunoglobulins.
  • Prednisolone may also be helpful - often with initial high doses but reduced as control is achieved.

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

Chemotherapy

Treatment for CLL is constantly evolving, based on clinical trial evidence. Current chemotherapy agents include:

  • Alkylating agents:
    • Continuous or intermittent treatment with chlorambucil or cyclophosphamide reduces total lymphocyte mass and may prevent bone marrow failure until the disease becomes refractory.
    • Their use in combination with other chemotherapy agents has dominated treatment for CLL - for example:
      • Cyclophosphamide, doxorubicin (formerly known as adriamycin), and prednisolone (CAP)
      • Cyclophosphamide, vincristine, and prednisolone (CVP)
      • Cyclophosphamide, doxorubicin (= hydroxydaunorubicin), vincristine (= Oncovin®), and prednisolone (CHOP)
    • Chlorambucil is preferred to cyclophosphamide in people with poor performance status or comorbidities, especially impaired renal function. It is usually given as an oral medication for 7 days every month for 6 to 12 months. Most patients respond to treatment but the majority will still have detectable disease meaning that recurrence over time is the norm. To date, clinical trials have not shown an increase in the efficacy of chlorambucil by adding in other drugs such as steroids or other types of chemotherapy. Side-effects from chlorambucil are usually mild compared with other agents.
  • Purine analogues:
    • 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. Prolonged overall survival with fludarabine has yet to be demonstrated.
    • The combination of fludarabine and cyclophosphamide (FC) has shown higher response rates. The use of FC with rituximab is now considered first-line treatment in patients able to tolerate this chemotherapy regime.9

Chemotherapy agents may be used with other drugs:

  • Monoclonal antibodies:8,10
    • Rituximab as a single agent has only shown partial responses and its main role is in combination 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. The National Institute for Health and Clinical Excellence (NICE) has recently approved its combined use with fludarabine and cyclophosphamide as a first-line treatment for CLL. Its use has not been approved in combination with other chemotherapy agents.9
    • Alemtuzumab is a monoclonal antibody directed at CD52 that is approved for use in CLL. It is currently licensed for use in patients who relapse after, or do not respond to, fludarabine. About half of these patients will respond.
    • 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 epratuzumab, and lumiliximab.
  • Steroids:
    These are used to:
    • Treat autoimmune complications
    • Improve bone marrow function prior to chemotherapy where there is significant bone marrow infiltration
    • Treat CLL that has not responded well to standard chemotherapies
  • 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.

Stem cell transplantation8

Allogenic stem cell transplantation is the only known curative therapy for CLL. The majority of CLL patients are elderly and the increased morbidity and mortality of such an intensive approach is rarely justified. In younger patients and particularly when standard treatment offers a poor outlook, the risks may be more balanced. The optimal timing of transplantation is unknown but delay until development of refractory disease is thought to worsen outcomes.8

Surgical

Splenomegaly and pancytopenia may require splenectomy. Up to 90% of patients show considerable improvement in Hb and platelets after splenectomy. Patients must be immunised with pneumococcal, meningococcal and Hib vaccines at least a week prior to operation.

Radiotherapy

This may be used palliatively either for splenic irradiation or external beam radiotherapy for bulky nodal masses.

Complications

  • Susceptibility to infection secondary both to the disease and its treatment. There are multiple factors involved including hypogammaglobulinaemia, neutropenia, impaired T and natural killer cell function and defective complement activity. Antibiotic prophylaxis, immunisation and VZIg are strategies used to counter this complication.
  • Autoimmune haemolytic anaemia and thrombocytopenia11 may occur at any time from presentation, but most commonly with advanced disease. There may be immune compromise with progressive profound hypogammaglobulinaemia. The autoimmune complications do not imply a poor prognosis.12
  • Hyperviscosity syndrome - extremely high WCC (>30 x 109/L) may affect 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.
  • Lymphomatous transformation - immunoblastic transformation to a terminal lymphoma (Richter's syndrome) occurs in 5-10% patients.

Prognosis

Median survival is approximately 10 years but there is considerable variation in the natural history of the disease. The majority have 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. Younger patients are more likely to die of chronic lymphocytic leukaemia (CLL)-related causes, whilst older patients more commonly die of unrelated causes, including second primary malignancies.

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 and the application of minimal residual disease approaches from other fields of leukaemia research, cure may soon be the goal, especially in younger patients.13

Document references

  1. Houlston RS, Catovsky D, Yuille MR; Genetic susceptibility to chronic lymphocytic leukemia. Leukemia. 2002 Jun;16(6):1008-14. [abstract]
  2. Slager SL, Kay NE; Familial chronic lymphocytic leukemia: what does it mean to me? Clin Lymphoma Myeloma. 2009;9 Suppl 3:S194-7. [abstract]
  3. Muirhead CR, Goodill AA, Haylock RG, et al; Occupational radiation exposure and mortality: second analysis of the National Registry for Radiation Workers. J Radiol Prot. 1999 Mar;19(1):3-26. [abstract]
  4. Linet MS, Schubauer-Berigan MK, Weisenburger DD, et al; Chronic lymphocytic leukaemia: an overview of aetiology in light of recent developments in classification and pathogenesis. Br J Haematol. 2007 Dec;139(5):672-86. [abstract]
  5. Eichhorst B, Hallek M; Revision of the guidelines for diagnosis and therapy of chronic lymphocytic leukemia (CLL). Best Pract Res Clin Haematol. 2007 Sep;20(3):469-77. [abstract]
  6. Zwiebel JA, Cheson BD; Chronic lymphocytic leukemia: staging and prognostic factors. Semin Oncol. 1998 Feb;25(1):42-59. [abstract]
  7. Montserrat E, Rozman C; Chronic lymphocytic leukaemia: prognostic factors and natural history. Baillieres Clin Haematol. 1993 Dec;6(4):849-66. [abstract]
  8. Liu D, Patel SC, Perry M, Rasool HJ; Chronic Lymphocytic Leukaemia. eMedicine, 2009.
  9. Leukaemia (chronic lymphocytic, first line) - rituximab, NICE Technology Appraisal (July 2009); Rituximab for first line treatment of chronic lymphocytic leukaemia
  10. Ferrajoli A, Faderl S, Keating MJ; Monoclonal antibodies in chronic lymphocytic leukemia. Expert Rev Anticancer Ther. 2006 Sep;6(9):1231-8. [abstract]
  11. Hamblin TJ; Autoimmune complications of chronic lymphocytic leukemia. Semin Oncol. 2006 Apr;33(2):230-9. [abstract]
  12. Kyasa MJ, Parrish RS, Schichman SA, et al; Autoimmune cytopenia does not predict poor prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol. 2003 Sep;74(1):1-8. [abstract]
  13. Yee KW, O'Brien SM; Chronic lymphocytic leukemia: diagnosis and treatment. Mayo Clin Proc. 2006 Aug;81(8):1105-29. [abstract]

Internet and further reading

Acknowledgements

EMIS is grateful to Dr Chloe Borton for writing this article and to Dr Richard Draper for earlier versions. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2010.
Document ID: 1957
Document Version: 23
Document Reference: bgp1046
Last Updated: 24 Feb 2010
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