Chronic Lymphocytic Leukaemia (CLL)

Essentials

• Chronic lymphocytic leukaemia (CLL) 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).
• The clinical picture includes lymphocyte-predominant leucocytosis and, in the majority of cases, 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 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 monoclonal B-cell lymphocytosis (MBL), an abnormal population of B lymphocytes is detected in the blood, expressing surface antigens typical 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.

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 leucocyte differential count shows lymphocytosis whilst the rest of the blood counts remain normal.
• In the more advanced stages of the disease anaemia 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. Patients are more susceptible to bacterial and viral infections. Opportunistic infections are also possible (table T1). CLL treatments which suppress immunologic defence increase susceptibility to infections. Severe infections are, along with the underlying disease, the most common cause of death in patients with CLL.

Diagnosis

• Diagnostic criteria
  • Lymphocyte count ≥ 5 × 10⁹ /l
  • Peripheral blood smear is characterized by large populations of small, morphologically mature lymphocytes.
  • 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-.
• A bone marrow examination is not necessary as there are typically a lot of disease cells in the blood. It can, however, help in the differential diagnosis of, for example, ITP associated with CLL.

Investigations

Disease progression

• CLL is of chronic character, that is, virtually always recurring.
• Treatment of early-stage disease has not been shown to have a life-prolonging effect.
• Treatment is started when
  • the disease involvement becomes extensive:
    • anaemia (Hb < 100 g/l) or thrombocytopenia (< 100 × 10⁹ /l) caused by extensive bone marrow infiltration
    • glucocorticoid-resistant AIHA or ITP
    • enlargement of the lymph nodes > 10 cm or splenomegaly > 15-20 cm
    • symptomatic lymph nodes (e.g. large lymph node mass in the neck)
  • 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

• Currently implemented mostly through highly selective drugs.
• Highly selective drugs used in the treatment of CLL include BTK inhibitors (ibrutinib, akalabrutinib and tsanubrutinib) and the BCL2 inhibitor venetoclax. The PI3K inhibitor idelalisib is also an alternative. All aforementioned medicines are tablet medicines. The use of idelalisib is nowadays low due to an unfavourable adverse effect profile.
  • In a disease with a TP53 mutation or 17p deletion, the best results are obtained with continuous BTK inhibitor therapy. BTK inhibitors expose patients to atrial fibrillation, increase the risk of bleeding and often raise blood pressure. The risk of atrial fibrillation associated withakalabrutinib andzanubrutinib is lower than with ibrutinib.
  • In first-line treatment, venetoclax has been combined with obinutuzumab. Treatment lasts 12 months and leads to long and deep responses in most patient groups.
• Chemoimmunotherapy (a combination of CD-20 antibodiesrituximab or obinutuzumab and cytostatic therapy) is mainly used to treat only IGHV-mutated patients. The most intensive chemoimmunotherapy (rituximab andfludarabine as well as cyclophosphamide; R-FC) leads to good treatment outcomes in under 65-year-old patients who are in good general condition and at favourable risk. On the other hand, intensive chemoimmunotherapy is associated with prolonged cytopenias, infections and risk of secondary malignancies.
• When treating a recurring disease one should take into account the response to previous treatments and, if necessary, switch to a drug with a different mechanism of action. Treatment of a recurring disease is always carried out with highly selective drugs. In practice, the options are continuous BTK inhibitor therapy or a temporary 24-month combination therapy of rituximab and venetoclax.
• Chlorambucil-based treatments are well tolerated but largely palliative in nature.
• Immunological cytopenias (AIHA, ITP) are treated primarily with a glucocorticoid.
• 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.
• Supportive treatment is important: careful management and prophylaxis of infections (seasonal vaccines, pneumococcal vaccine and herpes prophylaxis), red cell transfusions (or in some cases erythropoietin preparations) 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 can 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 treatmen:
    • Development of resistance to the treatment
    • Toxicity of the treatment
• Organization of care
  • A haematologist is responsible for choosing the treatment and following up the patient during treatment.
  • Treatment can lead to long remissions, and the patient can be followed up in primary health care between treatments. A haematologist gives instructions on how to carry out this follow-up.
  • If there are changes in the patient's condition during the follow-up in primary health care, a haematologist should be consulted as necessary.

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. See also local guidance.
• 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, 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.