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VesaLindström

Chronic Lymphocytic Leukaemia (CLL)

Essentials

  • Chronic lymphocytic leukaemia is a slowly progressing (chronic) malignant blood disease where morphologically normal looking B lymphocytes accumulate in the bone marrow, blood and lymphoid tissue (lymph nodes, spleen), leading to leucocytosis, lymphocytosis and, in the majority of cases, to enlarged lymph nodes and/or splenomegaly.
  • The clonal lymphocyte population gradually displaces the normal healthy haematopoiesis in the bone marrow. The subsequent bone marrow failure will lead to anaemia, neutropenia and/or thrombocytopenia.
  • The diseased cells exhibit characteristic chromosomal changes, which have formed as a result of acquired mutations. The disease is not hereditary, but about 5-10% of the patients have a familial predisposition to CLL.
  • In chronic monoclonal B-cell lymphocytosis (MBL), blood lymphocytes frequently carry surface antigens typical to CLL, i.e. they have the immunophenotype of CLL, but the number of lymphocytes is only slightly increased (less than 5 × 109 /l) and other cell counts are normal. MBL is not considered a malignant condition, but the patient should, however, be monitored (for example, annually) because in some cases MBL may progress to CLL.

Epidemiology

  • In the industrialised countries, CLL is the most common leukaemia type. Its annual incidence is 4 cases per 100 000 inhabitants.
  • CLL is more common in the elderly population; ⅔ of patients are over 60 years of age. The disease is very rare in patients under 30 years of age, and it does not occur in children.
  • CLL is twice as common in men as in women.

Signs and symptoms

  • CLL is typically diagnosed in the early stages of the disease as an incidental finding, for example during a routine health check, when the blood test results reveal leucocytosis and the differential count shows lymphocytosis whilst the rest of the blood counts remain normal.
  • In the more advanced stages of the disease anaemia, neutropenia and/or thrombocytopenia are also present.
  • The disease may be associated with autoimmune cytopenias, including autoimmune haemolytic anaemia (AIHA) and autoimmune thrombocytopenia (ITP). In such cases, the lymphocytic infiltration in the bone marrow may be limited allowing for normal, or even enhanced, haematopoiesis.
  • Typical findings include splenomegaly and enlarged lymph nodes in the neck, axilla, groin or abdomen.
  • CLL is often associated with a complex immunodeficiency state. Infections may develop frequently, opportunistic infections are common (table T1) and severe infections are in fact the most common cause of death.

Micro-organisms causing the most common atypical infections in patients with CLL

Type of micro-organismMicrobes
BacteriaPneumococci, pseudomonas, staphylococci, streptococci, haemophilus
VirusesHerpes viruses: HHV-1, HHV-6, varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV)
Adenovirus, parvovirus
Hepatitis B virus (particularly in association with monoclonal antibodies)
FungiPneumocystis jiroveci (sulfamethoxazole/trimethoprim prophylaxis)
Candida, aspergillus, cryptococcus
ProtozoaToxoplasma gondii (sulfamethoxazole/trimethoprim prophylaxis)

Investigation of atypical infections in patients with CLL

  • Serology may be unreliable due to the impaired immune response.
  • Bacterial, viral and fungal cultures should be taken from discharge or tissue samples.
  • Atypical pneumonia: bronchoscopy and bronchoalveolar lavage (provides good quality samples)
  • Non-specific fever that does not respond to standard antimicrobial treatment: CMV- nucleic acid assay, mycobacterial blood cultures; fungi: Aspergillus antigen; samples to confirm bacterial colonisation, empirical treatment
  • Infections of the central nervous system
    • Cerebrospinal fluid (before lumbar puncture, platelet count should be > 40 × 109 /l; good quality samples, MRI of the brain
    • Bacteria: see above
    • Viruses: Herpes viruses (see above), adenovirus, polyomavirus
    • Fungi: aspergillus, candida (also resistant species, for example, C. krusei), cryptococcus, mucor fungus.

Diagnosis

  • Diagnostic criteria
    1. Lymphocyte count > 5 × 109 /l
    2. Peripheral blood smears are characterised by large populations of small, morphologically mature lymphocytes.
    3. The immunophenotype of CLL, determined from blood or bone marrow with the aid of flow cytometry, is: CD5+, CD19+, CD20+ weak, CD23+, surface immunoglobulin (sIg) weak, CD79b weak, FMC7-.
    4. A bone marrow examination is not necessary at the time of diagnosis, but should be carried out before any treatment is started.
  • Diagnosis is confirmed by analysing surface antigens on blood or bone marrow lymphocytes with flow cytometry (immunophenotyping). The investigation is used to verify the clonal nature of the B lymphocytes and to differentiate CLL from other lymphoproliferative disorders.

Investigations

Primary investigations

  • Full blood count
  • Peripheral blood smear
  • Immunophenotyping of blood lymphocytes by flow cytometry; a blood (or bone marrow) sample should be sent to a specialist centre for analysis.
  • Clinical investigation
    • Clinical lymph node status (palpation)
    • Size of the liver and spleen

Further investigations

  • Additional investigations at diagnosis
    • Lactate dehydrogenase (LDH), bilirubin, direct Coombs' test, reticulocyte count, creatinine (if haemolysis is suspected)
    • Chest x-ray and abdominal ultrasound examination
  • Specialist investigations (only before starting therapy by haematologist):
    • Chromosome analysis of blood or bone marrow cells with the interphase-FISH technique
      • Deletion of chromosomes 17p and 11q are suggestive of poor prognosis.
    • Mutational status of TP53 derived from blood.
      • If a mutation is detected, the disease usually progresses faster.
    • By discretion
      • Mutational status of the immunoglobulin gene derived from blood or bone marrow CLL cells with PCR technique
      • An unmutated gene is suggestive of poor prognosis and a mutated gene of good prognosis.
    • Chromosome analysis of bone marrow cells with the G banding technique
      • Deletion of chromosomes 17p and 11q and a complex karyotype are suggestive of poor prognosis.

Disease progression

  • No benefits have been gained from treating the disease at the early stages.
  • Treatment is started when
    • the disease involvement becomes extensive:
      • anaemia (Hb < 100 g/l), thrombocytopenia (< 100 × 109 /l) or neutropenia (< 1 × 109 /l) caused by extensive bone marrow infiltration.
      • lymphocytosis > 200-250 × 109 /l (a relative indication; does not cause symptoms in CLL)
      • glucocorticoid-resistant AIHA or ITP
      • enlargement of the lymph nodes > 4-5 cm or splenomegaly > 15-20 cm
    • or the disease progresses:
      • the lymphocyte doubling time less than 6-12 months (a relative indication; the lymphocyte count often increases temporarily in response to infections or glucocorticoid treatment and sometimes spontaneously)
      • the enlarged lymph nodes continue to grow
    • and/or there are general symptoms associated with the disease:
      • unintentional weight loss of at least 10% during the last 6 months
      • significant tiredness
      • fever at least 38.0°C for at least 2 weeks without a confirmed infection
      • nocturnal sweating for at least 1 month.

Treatment Purine Antagonists Compared to Alkylating Agents for Chronic Lymphocytic Leukaemia, Bendamustine for Patients with Indolent B Cell Lymphoid Malignancies Including Chronic Lymphocytic Leukaemia

  • The first-line chemotherapy regime for patients in good overall condition and tested negative for 17p deletion/TP53 mutation is fludarabine and cyclophosphamide combined with the monoclonal anti-CD20 antibody rituximab (FCR). A combination of bendamustine and rituximab is used in over 65-year-old patients in good condition.
  • Chlorambucil combined with a monoclonal anti-CD20 antibody (rituximab or obinutuzumab) is used in patients who have comorbidities or whose general condition does not allow the first-line therapy used for patients in good general condition.
  • In patients with 17p deletion/TP53 mutation, the first-line therapy is carried out with B-cell receptor inhibitors (ibrutinib, idelalisib) or the BCL-2 inhibitor venetoclax, if treatment with a B-cell receptor inhibitor is not applicable.
  • Immunological cytopenias (AIHA, ITP) are treated with glucocorticoids.
  • Allogeneic stem cell transplantation is the only curative treatment form in CLL, but it may only be considered for younger with very high-risk CLL due to the risks associated with the procedure.
  • Disease recurring soon after previous therapy is treated with B-cell receptor inhibitors (ibrutinib, idelalisib).
  • Disease recurring after treatment with a B-cell receptor inhibitor is treated with venetoclax or a combination of venetoclax and rituximab.
  • Supportive treatment is important: careful management and prophylaxis of infections, red cell transfusions (or in some cases epoetin or darbepoetin) in symptomatic anaemia, platelet transfusions in thrombocytopenia-induced bleeding and prophylactically in chemotherapy-induced thrombocytopenia (but not in thrombocytopenia associated with chronic disease).
  • A bone marrow examination may be used to investigate the reason behind unexplained reduced blood cell counts.
    • Causes of reduced blood cell counts in CLL include:
      • disease progression and increased bone marrow infiltration
      • autoimmune cytopenias: AIHA, red cell aplasia, ITP
      • splenomegaly (hypersplenism).
    • Reduction in blood cell values during treatment:
      • development of resistance to the treatment
      • toxicity of the treatment.
  • The tasks at the different levels of care are presented in table T2.

Arrangement of CLL care (indicative, based on the division of responsibilities within the Finnish health care system)

Care levelTasks
University hospital (teaching hospital)Responsibility for education and clinical trials
Critical assessment and instructions relating to new methods and treatments
Diagnostic and prognostic specialist studies
Central hospital (Regional hospital)Patient-specific diagnosis
Patient information
Patient-specific treatment plan, monitoring guidelines
Local hospitalCheck-ups every 3-6 months during the treatment free period (cell counts and palpation of lymph nodes)
Responsibility for carrying out the treatment as per guidelines issued by the Central Hospital staff (treatment is chosen individually for each patient)
  • Cell counts: always before the next treatment cycle (treatment must not start until neutrophils > 1 × 109 /l or platelets > 70 × 109 /l or at least at baseline value) and every 1-2 months during ongoing treatment.
  • Responsibility for stopping the treatment if an infection is suspected.
Health centreIn stable or slowly progressing disease with good prognosis, check-ups every 6-12 months during the treatment free period (cell counts and palpation of lymph nodes)
Check-ups every 12-18 months in monoclonal lymphocytosis (MBL)

Follow-up in primary health care

  • If a patient with CLL remains stable, the follow-up in primary health care may continue for a considerably long time. The check-ups should initially be carried out every 4-6 months, and should no progression be detected the check-up interval may be extended to 6-12 months.
  • During each appointment the blood picture should be checked and the lymph nodes palpated at the neck, axilla and groins. The spleen should also be palpated.
  • A haematologist should be consulted about starting treatment when the haemoglobin or platelet count shows a downward shift or the neutrophils are repeatedly below 1 × 109 /l, leucocytes increase to 100-150 × 109 /l or the lymph nodes show marked enlargement.
  • Infections must be carefully managed. Infections caused by encapsulated bacteria are the most common form of bacterial infections, and pneumococcal infections are the most common cause of death in CLL.
  • If the disease is of long duration, opportunistic infections are also possible (fungi, mycobacteria, Pneumocystis jiroveci, see table T1). Therefore, if the patient remains febrile despite broad-spectrum antimicrobials, a hospital admission for further investigations is usually warranted.
  • Response to vaccination is usually poor, but response has been achieved with the conjugated pneumococcal vaccine (Prevenar® ) and vaccination is recommended. Live vaccines must not be administered.

    References

    • Hallek M. Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment. Am J Hematol 2017;92(9):946-965. [PubMed]
    • Byrd JC, Furman RR, Coutre SE et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369(1):32-42. [PubMed]
    • Furman RR, Sharman JP, Coutre SE et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014;370(11):997-1007. [PubMed]
    • Roberts AW, Davids MS, Pagel JM ym. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 2016;374(4):311-22. [PubMed]
    • Seymour JF, Kipps TJ, Eichhorst B ym. Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med 2018;378(12):1107-1120. [PubMed]