PatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
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. The diagnosis of CLL is established by the following:
- The presence in the peripheral blood of ≥5,000 monoclonal B lymphocytes/mcL for the duration of at least three months. The clonality of the circulating B lymphocytes needs to be confirmed by flow cytometry.
- The leukaemia cells found in the blood smear are characteristically small, mature lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli and having partially aggregated chromatin.
- CLL is the most common leukaemia in the Western world with an incidence of 4.2/100,000/year.
- The incidence increases to >30/100,000/year at an age of >80 years. The median age at diagnosis is 72 years. About 10% of CLL patients are reported to be younger than 55 years.
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Presentation is variable with insidious onset. 90% are now asymptomatic at presentation, with CLL diagnosed incidentally following routine blood tests. Symptoms may include:
- Susceptibility to infection (pneumonia, herpes simplex, and herpes zoster).
- Symmetrically enlarged lymph nodes.
- Abdominal discomfort from an enlarged spleen.
- Bleeding or petechiae in skin or mucous membranes - from thrombocytopenia.
- Tiredness and fatigue from anaemia.
- Local or generalised lymphadenopathy.
- Splenomegaly (30-40%).
- Hepatomegaly (20%).
- Skin infiltration (rare).
- Tonsillar enlargement.
- Involvement of the lacrimal and salivary glands (Mikulicz's syndrome) is rare.
- FBC shows a minimum clonal B cell 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 (artefacts from damage to lymphocytes during preparation of the slide).
- Direct antiglobulin test (DAT) - also known as the direct Coombs' test - in all anaemic patients and prior to starting treatment (to identify autoimmune-related haemolytic 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, eg 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 is called Richter's syndrome.
- Immunophenotyping - peripheral blood flow cytometry is the most valuable test to confirm 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.
- Patients should be tested for deletion of (tumour protein) TP53 gene before treatment. This is a tumour supressor gene and deletion of it is associated with a lower response rate (to treatment), short progression-free survival and overall survival.
The status of relevant infections (hepatitis B and C, cytomegalovirus and HIV) should be evaluated prior to chemo-immunotherapy, alemtuzumab or allogeneic stem cell transplantation (alloSCT) in order to avoid virus reactivation.
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 the chest, abdomen or pelvis may show obstructive uropathy or airway obstruction from lymph node compression on organs or internal structures.
The Binet system is used in Europe but in the 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: haemoglobin (Hb) at least 10 g/dL, platelets at least 100 x 109/L, and less than three lymph node areas involved.
- Stage B: Hb and platelet levels as in stage A and three or more lymph node areas involved.
- Stage C: Hb <10 g/dL, platelets <100 x 109/L, or both.
Hb level, blood lymphocyte count, lymphocyte doubling time and bone marrow infiltration pattern are useful to identify subsets of patients in the early stage with different progression and survival rates, with the 'smouldering' form of the disease being identified fairly accurately.
With the possible exception of stem cell transplants, there is no curative treatment currently available for CLL. Although there is no cure for CLL, the disease is treatable and current standard chemotherapy regimens have been shown to prolong survival. Studies have shown that early treatment with alkylating agents does not translate into a survival advantage in patients with early-stage CLL. The standard treatment of patients with early disease is a watch and wait strategy. Blood cell counts and clinical examinations should be performed every 3-12 months.
Chemotherapy should only be given to patients with active, symptomatic disease, eg 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 (an increase of >50% in two 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 to 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. Therefore, such patients identified even at an early stage should be considered for inclusion in clinical trials.
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:
- 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 seven 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.
- Bendamustine is recommended by the National Institute for Health and Clinical Excellence (NICE) as a treatment option for the first-line treatment of CLL (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate (see 'Purine analogues', below).
- 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. Fludarabine monotherapy is not recommended for the first-line treatment of CLL.
- The combination of fludarabine and cyclophosphamide (FC) has shown higher response rates. The use of FC with rituximab (FCR) is now considered first-line treatment in patients able to tolerate this chemotherapy regime - see below. 
- Monoclonal antibodies:
- 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. Improved survival has been demonstrated following first-line chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR).NICE has approved its combined use of FCR as a first-line treatment for CLL. Its use has not been approved in combination with other chemotherapy agents.
- Rituximab in combination with fludarabine and cyclophosphamide is recommended as a treatment option for people with relapsed or refractory CLL except when the condition is refractory to fludarabine (ie not responded to fludarabine or has relapsed within six months of treatment) or has previously been treated with rituximab.
- 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 TP53 mutations in contrast to rituximab, which is not effective in TP53 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.
- Ofatumumab is not currently recommended for the treatment of CLL that is refractory to fludarabine and alemtuzumab.
- Other monoclonal antibodies undergoing study in CLL include epratuzumab, and lumiliximab.
These may be 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):
Stem cell transplantation (STC)
Allogenic stem cell transplantation (alloSTC) 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 are rarely justified. In younger patients and particularly when standard treatment offers a poor outlook (such as those with a TP53 deletion), 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.
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.
This may be used palliatively either for splenic irradiation or external beam radiotherapy for bulky nodal masses.
Treatment of relapse and refractory disease
The first-line treatment may be repeated, if the relapse or progression occurs at least 12-24 months after a monotherapy, or 24-36 months after chemo-immunotherapy. If relapse occurs within 12-24 months after monotherapy or 24-36 months after chemo-immunotherapy, or if the disease does not respond to any first-line therapy, the therapeutic regimen needs to be changed to one of the following options:
- Salvage regimen - eg, alemtuzumab, followed by allogeneic stem cell transplantation in physically fit patients.
- FCR for patients relapsed or refractory to first-line therapy with an alkylating agent.
- A regime including bendamustine or alemtuzumab in physically non-fit patients without del(17p). In subsequent relapses, high-dose ofatumumab or rituximab with high-dose steroids may be tried.
- An alemtuzumab-containing regimen in patients with del(17p).
- Susceptibility to infection secondary both to the disease and its treatment. There are multiple factors involved including hypogammaglobulinaemia, neutropenia, impaired T-cell and natural killer cell function and defective complement activity. Antibiotic prophylaxis, immunisation (influenza vaccination and pneumococcal vaccine should be given) and VZIg are strategies used to counter this complication.
- Autoimmune cytopenia, especially autoimmune haemolytic anaemia occurs in 5-10% of patients with CLL. The prognosis for these patients is not as poor as in those patients with cytopenia due to a massive bone marrow infiltration. Most patients with autoimmune cytopenia respond to corticosteroids; splenectomy is a treatment choice for those patients not responding to corticosteroid treatment.
- Hyperviscosity syndrome - extremely high WCC (>30 x 109/L) may affect the CNS or respiratory system. Leukocytapheresis 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.
- Patients with CLL have an increased risk of developing secondary malignancies, including secondary myelodysplastic syndromes or acute myelogenous leukaemia as well as solid tumours.
- The median survival from diagnosis varies between 18 months and >10 years.
- 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 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.
- Patients with a detectable del(17p) or a mutation of the p53 gene (5-10% of the patients) have the poorest prognosis, with a median overall survival of 2-3 years.
- Another poor prognostic marker has been del(11q), which is found in 20% of the patients. However, the poor outcome of patients with del(11q) is overcome by chemo-immunotherapy with FCR.
- Median survival is approximately 10 years but there is considerable variation in the natural history of the disease.
Further reading & references
- Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2015)
- Leukaemia & Lymphoma Research
- Macmillan Cancer Support
- CancerHelp UK
- Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2011)
- Houlston RS, Catovsky D, Yuille MR; Genetic susceptibility to chronic lymphocytic leukemia. Leukemia. 2002 Jun;16(6):1008-14.
- Slager SL, Kay NE; Familial chronic lymphocytic leukemia: what does it mean to me? Clin Lymphoma Myeloma. 2009;9 Suppl 3:S194-7.
- Guidelines on the diagnosis, investigation and management of Chronic Lymphocytic Leukaemia; British Committee for Standards in Haematology (July 2012)
- 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.
- 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.
- Parker TL, Strout MP; Chronic lymphocytic leukemia: prognostic factors and impact on treatment. Discov Med. 2011 Feb;11(57):115-23.
- Mir MA et al, Chronic Lymphocytic Leukaemia, Medscape, Oct 2012
- Leukaemia (lymphocytic) - bendamustine; NICE Technology Appraisal Guideline (February 2011)
- Leukaemia (lymphocytic) - fludarabine, NICE Technology Appraisal (2007)
- Leukaemia (chronic lymphocytic, first line) - rituximab; NICE Technology Appraisal (July 2009)
- Ferrajoli A, Faderl S, Keating MJ; Monoclonal antibodies in chronic lymphocytic leukemia. Expert Rev Anticancer Ther. 2006 Sep;6(9):1231-8.
- Leukaemia (chronic lymphocytic, relapsed) - rituximab; NICE Technology Appraisal Guideline (July 2010)
- Chronic lymphocytic leukaemia - ofatumumab; NICE Technology Appraisal Guideline (October 2010)
Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.
Dr Richard Draper
Dr Colin Tidy
Dr Helen Huins