Front-line treatment

While CLL is not yet curable, it is very treatable and can be controlled for most CLL patients. Many patients will have a normal life-span with a good quality of life after diagnosis. The aim of treatment is mostly to reduce patient symptoms and improve blood counts.

Until recently the treatment of CLL was chemoimmunotherapy (combination of chemotherapy and a monoclonal antibody). Anti-CD20 monoclonal antibodies such as rituximab and obinutuzumab that target specific proteins on the CLL cell surface were often used.

New, oral, targeted treatments known as small molecule inhibitors target specific proteins that are keeping the CLL cells alive. They include

  • B-cell receptor (BCR) inhibitors:
  • CLL cells have proteins on the outside of the cell called BCRs as do the normal B-cells. When a protein binds to a BCR, it sends a signal to the cell to divide. Because CLL cells are very sensitive to the BCR signals, they just keep dividing and produce too many CLL cells.
  • BCR inhibitors that have been developed include:
  • Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib or acalabrutinib
  • Phosphatidylinositol 3-kinase (PI3K) inhibitors such as idelalisib

B-cell lymphoma-2 (BCL-2) inhibitors:

The BCL-2 protein family regulates apoptosis. Apoptosis is the natural self-destruct process that the body uses to eliminate damaged or worn out cells.

Some proteins from the BCL-2 protein family encourage apoptosis such as the BAX proteins, and others prevent apoptosis such as the BCL-2 proteins.

CLL leukaemia cells have a distinctive defect in apoptosis (Billard 2014). Because they cannot regulate their numbers due to the defective apoptosis, the CLL cells accumulate. This led to the development of BCL-2 inhibitors.

Venetoclax is one of the first BCL-2 inhibitors and is known to be effective often when other treatments fail. It is possibly even more effective when used in combination with chemotherapy, immunotherapy and other small molecule inhibitors.

  • Different front-line treatments can be used:
  • Continuous treatment with BTKs such as ibrutinib or acalabrutinib until progression of the CLL
  • Combination of venetoclax and obinutuzumab
  • Fixed-duration therapy with chemotherapy and a CD20 monoclonal antibody

For patients with a 17p deletion or TP53 mutation

BCR inhibitors and BCL-2 inhibitors are appropriate initial treatment options because chemoimmunotherapy is not effective for these patients. Options include:

  • Ibrutinib or acalabrutinib
  • Fixed-duration therapy with venetoclax and obinutuzumab
  • Venetoclax continuous monotherapy
  • Idelalisib in combination with rituximab
  • For patients >65 years of age or with significant comorbidity
  • The following options are most appropriate:
  • Venetoclax and obinutuzumab
  • Ibrutinib plus obinutuzumab
  • Chlorambucil plus obinutuzumab
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