Chronic Lymphocytic Leukaemia

Authored by , Reviewed by Dr Hayley Willacy | Last edited | Meets Patient’s editorial guidelines

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Professional Reference articles are designed for health professionals to use. They are written by UK doctors and based on research evidence, UK and European Guidelines. You may find the Chronic Lymphocytic Leukaemia (CLL) article more useful, or one of our other health articles.

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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:[1]

  • 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.
  • Chronic lymphocytic leukaemia accounted for 1% of all new cancer cases in the UK in 2016-2018.
  • Incidence rates for chronic lymphocytic leukaemia in the UK are highest in people aged 85 to 89 (2016-2018). Each year 40% of all new chronic lymphocytic leukaemia cases in the UK are diagnosed in people aged 75 and over (2016-2018).
  • Since the early 1990s, chronic lymphocytic leukaemia incidence rates have increased by 17% in the UK.
  • Incidence rates for chronic lymphocytic leukaemia are lower in the Asian and Black ethnic groups, compared with the White ethnic group, in England (2013-2017).

Risk factors

Despite a strong familial basis to CLL, with risks in first-degree relatives of CLL cases being increased by about seven-fold, the inherited genetic basis of CLL is largely unknown.[3]


Presentation is variable with insidious onset. Most people are 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.
  • Hepatomegaly.
  • Petechiae.
  • Pallor.
  • Skin infiltration (rare).
  • Tonsillar enlargement.
  • Involvement of the lacrimal and salivary glands (Mikulicz's syndrome) is rare.

The National Institute for Health and Care Excellence (NICE) recommends:[4]

Consider a very urgent full blood count (within 48 hours) to assess for leukaemia in adults with any of the following:

  • Pallor.
  • Persistent fatigue.
  • Unexplained fever.
  • Unexplained persistent or recurrent infection.
  • Generalised lymphadenopathy.
  • Unexplained bruising.
  • Unexplained bleeding.
  • Unexplained petechiae.
  • Hepatosplenomegaly.
  • Other forms of leukaemia.
  • Lymphoma.
  • Myelodysplasia and myeloproliferative diseases.


  • 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 anaemias).
  • 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 suppressor gene and deletion of it is associated with a lower response rate (to treatment), short progression-free survival and overall survival.[5]

The status of relevant infections (hepatitis B and C, cytomegalovirus and HIV) should be evaluated prior to chemo-immunotherapy or allogeneic stem cell transplantation (alloSCT) in order to avoid virus reactivation.[1]


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.[6] 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 fewer 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.

  • Only patients with active or symptomatic disease, or with advanced Binet or Rai stages, require therapy.
  • When treatment is indicated, options include a combination of venetoclax with obinutuzumab, ibrutinib monotherapy, or chemo-immunotherapy. For physically fit patients younger than 65 (in particular when presenting with a mutated IGVH gene), chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab remains a standard therapy, since it may have curative potential.
  • At relapse, the initial treatment may be repeated, if the treatment-free interval exceeds three years. If the disease relapses earlier, therapy should be changed using an alternative regimen.
  • Patients with a del (17p) or TP53 mutation are a different, high-risk category and should be treated with targeted agents.
  • An allogeneic stem cell transplant may be considered in relapsing patients with TP53 mutations or del (17p), or patients who are refractory to inhibitor therapy.


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.
  • 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).[10]

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.[11]
  • 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.[5, 12]
  • Fludarabine is recommended as second line therapy for B-cell chronic lymphocytic leukaemia (CLL) for patients who have either failed, or are intolerant of, first-line chemotherapy, and who would otherwise have received combination chemotherapy of either cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP), cyclophosphamide, doxorubicin and prednisolone (CAP) or cyclophosphamide, vincristine and prednisolone (CVP).[13]

Monoclonal antibodies

  • Rituximab:
    • As a single agent has only shown partial responses and its main role is in combination chemotherapy.
    • 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).[1, 5]
    • The National Institute for Health and Care Excellence (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.[12]
    • In patients with relevant comorbidity, who are usually older, but without TP53 deletion/mutation, the combination of chlorambucil plus an anti-CD20 antibody (rituximab, ofatumumab or obinutuzumab) prolongs progression-free survival when compared with monotherapy and is therefore the standard approach.[1]
    • 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.[14]
    • Patients with TP53 deletion/mutation have a poor prognosis even after FCR therapy. Therefore it is recommended that patients with TP53 deletion/mutation be treated with novel inhibitors (ibrutinib; idelalisib and rituximab) in front-line and relapse settings.[1]
  • 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.[5]
    • Although very effective in clearing disease in the bone marrow, alemtuzumab has only limited activity in clearing lymphadenopathy.
  • Obinutuzumab:
    • Combined with chlorambucil this is recommended by NICE as a possible treatment for adults with untreated CLL only if neither fludarabine nor bendamustine is suitable.[15] .
  • Venetoclax:[16, 17, 18]
    • Venetoclax is a selective inhibitor of B-cell lymphoma-2 (BCL-2), an anti-apoptotic protein which is overexpressed in tumour cells. This initiates programmed cell death. It can only be used under certain criteria:
      • In the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B‑cell receptor pathway inhibitor; or
      • In the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemo-immunotherapy and a B‑cell receptor pathway inhibitor.
    • NICE has approved venetoclax for the treatment of chronic lymphocytic leukaemia (CLL). It is an option for those patients who may otherwise have supportive care (including rituximab and high-dose methylprednisolone) and it meets NICE's criteria of a treatment that could extend life at the end of life.
    • Venetoclax plus obinutuzumab is recommended as an option for untreated chronic lymphocytic leukaemia (CLL) in adults, if:
      • There is a 17p deletion or TP53 mutation; or
      • There is no 17p deletion or TP53 mutation, and fludarabine plus cyclophosphamide and rituximab (FCR) or bendamustine plus rituximab (BR) is unsuitable.
    • Venetoclax plus obinutuzumab is also recommended for use as an option for untreated CLL in adults if there is no 17p deletion or TP53 mutation, and FCR or BR is suitable, and the conditions in the managed access agreement for venetoclax plus obinutuzumab are followed.
    • Venetoclax with rituximab is recommended as an option for treating chronic lymphocytic leukaemia in adults who have had
      at least one previous therapy.

Protein kinase inhibitors

  • Acalabrutinib:[19]
    • Acalabrutinib is a Bruton tyrosine kinase inihibitor.
    • Acalabrutinib as monotherapy is recommended as an option for untreated chronic lymphocytic leukaemia (CLL) in adults, only if:
      • There is a 17p deletion or TP53 mutation; or
      • There is no 17p deletion or TP53 mutation, and fludarabine plus cyclophosphamide and rituximab (FCR) or bendamustine plus rituximab (BR) is unsuitable.
    • Acalabrutinib as monotherapy is recommended, within its marketing authorisation, as an option for previously treated CLL in adults.
  • Ibrutinib:[20]
    • Ibrutinib alone is recommended as an option for treating chronic lymphocytic leukaemia in adults:
      • Who have had at least one prior therapy; or
      • Who have a 17p deletion or TP53 mutation, and in whom chemo-immunotherapy is unsuitable.
  • Idelalisib:
    • Idelalisib is an inhibitor of the delta isoform (p110δ) of the enzyme phosphoinositide 3-kinase.
    • Idelalisib, in combination with rituximab, is recommended:[21]
      • For untreated chronic lymphocytic leukaemia in adults with a 17p deletion or P53 mutation; or
      • For chronic lymphocytic leukaemia in adults when the disease has been treated but has relapsed within 24 months.


Steroids 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.

Stem cell transplantation (STC)

Allogeneic 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[1]

  • As for the first-line therapy, treatment at relapse should only be started in symptomatic patients. Many patients with relapsed but asymptomatic CLL can be followed with no therapy for a long period of time.
  • First-line treatment may be repeated if the relapse or progression occurs at least 24-36 months after chemo-immunotherapy and if TP53 deletion/mutation was excluded.
  • If relapse occurs within 24-36 months after chemo-immunotherapy, or if the disease does not respond to any first-line therapy, the therapeutic regimen should be changed.
  • Autologous stem-cell transplantation is not useful in CLL. An allogeneic stem cell transplantation may be considered.
  • 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 varicella-zoster immune globulin (VZIg) are strategies used to counter this complication. Although influenza, pneumococcal and Haemophilus influenzae vaccinations are recommended, responses are often suboptimal due to immunosuppression[23] .
  • 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. For patients not responding to corticosteroids, rituximab may be a reasonable treatment option before considering splenectomy.[1]
  • 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 should also 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.[1]
  • Five-year relative survival for chronic lymphocytic leukaemia (CLL) in men in England (67%) is similar to the average for Europe (68%). Wales (65%) and Scotland (72%) are also similar to the European average but Northern Ireland (51%) is below the European average.
  • Across the European countries for which data are available, five-year relative survival in men ranges from 42% (Bulgaria) to 80% (Switzerland).
  • Five-year relative survival for CLL in women in England (73%) is similar to the average for Europe (74%). Wales (71%) and Northern Ireland (75%) are also similar to the European average but Scotland (81%) is above the European average.
  • Across the European countries for which data are available, five-year relative survival in women ranges from 50% (Bulgaria) to 82% (France).
  • The Rai and Binet clinical staging systems create prognostic information by using results of physical examination and blood counts.
  • Various biological and genetic markers also have prognostic value. Deletions of the short arm of chromosome 17 (del [17p]) and/or mutations of the TP53 gene, predict resistance to chemo-immunotherapy and a shorter time to progression, with most targeted therapies.
  • A comprehensive, international prognostic score (CLL-IPI) integrates genetic, biological and clinical variables to identify distinct risk groups of CLL patients.

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Further reading and references

  1. Eichhorst B, Robak T, Montserrat E, et al; Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021 Jan32(1):23-33. doi: 10.1016/j.annonc.2020.09.019. Epub 2020 Oct 19.

  2. Chronic lymphocytic leukaemia (CLL) statistics; Cancer Research UK.

  3. Speedy HE, Sava G, Houlston RS; Inherited susceptibility to CLL. Adv Exp Med Biol. 2013792:293-308. doi: 10.1007/978-1-4614-8051-8_13.

  4. Suspected cancer: recognition and referral; NICE guideline (2015 - last updated December 2021)

  5. Schuh AH, Parry-Jones N, Appleby N, et al; Guideline for the treatment of chronic lymphocytic leukaemia: A British Society for Haematology Guideline. Br J Haematol. 2018 Jul 15. doi: 10.1111/bjh.15460.

  6. Molica S, Shanafelt TD, Giannarelli D, et al; The chronic lymphocytic leukemia international prognostic index predicts time to first treatment in early CLL: Independent validation in a prospective cohort of early stage patients. Am J Hematol. 2016 Nov91(11):1090-1095. doi: 10.1002/ajh.24493. Epub 2016 Aug 8.

  7. Sharma S, Rai KR; Chronic lymphocytic leukemia (CLL) treatment: So many choices, such great options. Cancer. 2019 May 1125(9):1432-1440. doi: 10.1002/cncr.31931. Epub 2019 Feb 26.

  8. Tomlinson R; Chronic lymphocytic leukaemia: An updated approach to diagnosis and management in general practice. Aust Fam Physician. 201746(7):493-496.

  9. Hallek M; Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment. Am J Hematol. 2019 Nov94(11):1266-1287. doi: 10.1002/ajh.25595. Epub 2019 Oct 4.

  10. Bendamustine for the first-line treatment of chronic lymphocytic leukaemia; NICE Technology appraisal guidance, February 2011

  11. Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia; NICE Technology appraisal guidance, February 2007

  12. Rituximab for the first-line treatment of chronic lymphocytic leukaemia; NICE Technology appraisal guidance, July 2009

  13. Guidance on the use of fludarabine for B-cell chronic lymphocytic leukaemia; NICE Technology appraisal guidance, September 2001

  14. Rituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia; NICE Technology appraisal guidance, July 2010

  15. Obinutuzumab in combination with chlorambucil for untreated chronic lymphocytic leukaemia; NICE Technology appraisal guidance, June 2015

  16. Venetoclax for treating chronic lymphocytic leukaemia; NICE Technology appraisal guidance, June 2022

  17. Venetoclax with obinutuzumab for untreated chronic lymphocytic leukaemia; NICE Technology appraisal guidance, December 2020

  18. Venetoclax with rituximab for previously treated chronic lymphocytic leukaemia; NICE Technology appraisal guidance, February 2019

  19. Acalabrutinib for treating chronic lymphocytic leukaemia; NICE Technology appraisal guidance, April 2021

  20. Ibrutinib for previously treated chronic lymphocytic leukaemia and untreated chronic lymphocytic leukaemia with 17p deletion or TP53 mutation; NICE Technology appraisal guidance, January 2017

  21. Idelalisib for treating chronic lymphocytic leukaemia; NICE Technology appraisal guidance, October 2015

  22. Stilgenbauer S, Furman RR, Zent CS; Management of chronic lymphocytic leukemia. Am Soc Clin Oncol Educ Book. 2015:164-75. doi: 10.14694/EdBook_AM.2015.35.164.

  23. Grigoropoulos NF, Petter R, Van 't Veer MB, et al; Leukaemia update. Part 2: managing patients with leukaemia in the community. BMJ. 2013 Apr 9346:f1932. doi: 10.1136/bmj.f1932.