Treatment of chronic lymphocytic leukaemia

Seek expert advice.

The early stages (Binet stage A and B without active disease; Rai 0, I and II without symptoms) require no treatment (1).

Given that most patients with CLL are asymptomatic, treatment is not recommended for everyone

• the recommendation for treatment depends on severe disease symptoms or rapidly progressing disease
  • symptoms such as severe fatigue interfering with daily activities, B-symptoms, recurrent infections, or increased tumor burden are an indication for early treatment
    • rapidly progressing disease such as an absolute lymphocyte count doubling time of fewer than 12 months is also an indication for early treatment
      
      
  • early-stage (low risk) CLL (lymphocytosis alone; Rai stage 0, Binet stage A) has an estimated median life expectancy of approximately 13 years and normally are not treated (4)
    
    
  • intermediate-stage CLL (lymphocytosis with lymphadenopathy, hepatosplenomegaly, or both; Rai stage I or II, Binet stage B) has an estimated median life expectancy of 8 years and can be treated if they have signs of disease activity (5)
    
    
  • advancedstage (high-risk) CLL (lymphocytosis with lymphadenopathy, hepatosplenomegaly, or both, as well as marrow infiltration–related anemia, thrombocytopenia, or both; Rai stage III or IV, Binet stage C) should always be treated
    • formerly had an estimated median life expectancy of only 2 years, according to data derived from the period when alkylating agents constituted the primary treatment of CLL
    • survival has improved substantially with the more recent, widespread use of the novel agents. For example, 83% of patients with CLL remain alive 5 years after starting frontline ibrutinib therapy, and 55% of patients with relapsed or refractory CLL remain alive 7 years after starting ibrutinib salvage therapy

Indications for therapy of patients with CLL include late-stage disease, evidence for rapid disease progression or disease-related symptoms (5)

• the Bruton tyrosine kinase (BTK) and hosphoinositide 3-kinase (PI3K) inhibitors and venetoclax have replaced chemotherapy-based treatments for most patients who have this leukaemia
  
  
• the BTK inhibitors (i.e., ibrutinib and acalabrutinib) induce durable remissions in the majority of patients
  
  
• the B-cell lymphoma 2 (BCL2) antagonist venetoclax is typically given for a limited time, together with anti-CD20 antibodies, to induce deep remissions, but resistant clones can emerge and clinical relapses occur, especially in high-risk patients

• use of chemoimmunotherapy is steadily declining, given the better side-effect profiles and improved survival with the novel agents
  • an exception is the small group of younger, fit patients with low risk CLL, who often stay in remission for more than 10 years after treatment with the FCR (fludarabine, cyclophosphamide, and rituximab) regimen
• corticosteroids - lymphocytic and not myelosuppressive. Indicated when there is severe bone marrow failure and/or for autoimmune phenomena. Continuing use is contraindicated because of risk of infection.
• radiotherapy - to treat localised lymphadenopathy if it is obstructive or unsightly, or painful splenomegaly
• supportive care - regular transfusions
• allogeneic stem cell transplantation
  • the only curative therapy
  • used in high risk [del(17p), del(11q)] and/or refractory disease (1)
• splenectomy - if cannot control autoimmune phenomena

Reference:

• (1) Eichhorst B et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v162-4
• (2) Dighiero G, Hamblin TJ. Chronic lymphocytic leukaemia. Lancet. 2008;371(9617):1017-29.
• (3) Taneja A et al. Cancer, Chronic Lymphocytic Leukemia (CLL),StatPearls [Internet] (December 26th 2019).
• (4) Kipps TJ et al. Chronic lymphocytic leukaemia. Nat Rev Dis Primers. 2017 Jan 19; 3: 16096.
• (5) Burger JA. Treatment of Chronic Lymphocytic Leukemia. N Engl J Med 2020;383:460-73.