# Treatment approaches for chronic lymphocytic leukaemia
The treatment of chronic lymphocytic leukaemia (CLL) has changed significantly over recent years. Whereas chemotherapy was once the first choice, doctors nowadays more often use targeted treatments that attack specific characteristics of diseased cells. The choice of treatment depends on the stage of the disease, whether patients have received prior treatment, certain genetic properties of the leukaemia cells, and the patient's overall health.
Watch and wait
In some patients, CLL grows very slowly and causes little trouble for a long time. In these cases, careful observation (also called 'wait and see') may be the initial approach. This means that no chemotherapy or targeted treatments are given, but blood values are checked regularly.
ProveniIncluded in official guidelines, or approved by EMA or FDA
Waiting is based on years of research showing that early treatment for patients with a slow form does not necessarily lead to a longer life. Doctors start treatment once the disease grows faster, symptoms develop, or certain blood values worsen. This shortens the duration of treatment and possible side effects. There are no direct side effects from waiting itself, but regular checks are needed to intervene in time.
Bruton tyrosine kinase inhibitors (BTK inhibitors)
These treatments block a protein (BTK) that plays a role in the growth and survival of CLL cells. They are usually given as tablets.
Ibrutinib
ProveniIncluded in official guidelines, or approved by EMA or FDA
Ibrutinib was the first BTK-inhibiting treatment and is included in official treatment guidelines. It targets a signalling pathway in the diseased cells that is necessary for their growth. Studies show that patients taking ibrutinib remain free of disease recurrence for longer than with conventional chemotherapy.
Known side effects include diarrhoea, fatigue, infections (because the medication also affects immune cells), heart rhythm abnormalities and bleeding. Elevated blood pressure can also occur. In recent studies (2026), attention is given to serious infections under ibrutinib, including fungal infections, and to changes in heart rhythm that require regular monitoring.
Acalabrutinib
ProveniIncluded in official guidelines, or approved by EMA or FDA
This is a newer BTK-inhibiting treatment that works more selectively than ibrutinib — it targets BTK more directly and leaves other proteins in the body more unaffected. Studies show comparable effectiveness with possibly fewer side effects.
Side effects are overall similar to ibrutinib (infections, diarrhoea, fatigue), but some patients experience fewer problems with diarrhoea. Heart rhythm problems can also occur, although in some studies less frequently than with ibrutinib.
Nemtabrutinib
ResearchediPositive results in clinical studies, not yet standard treatment
This is an even newer BTK-inhibiting treatment currently being tested in large clinical trials (including BELLWAVE-011 and BELLWAVE-010, ongoing in 2026). Early results suggest comparable effectiveness with possibly a more favourable side effect profile. Because research is still ongoing, it is not yet standard treatment everywhere.
Preliminary data point to infections and fatigue as possible side effects, but the complete picture is still being determined.
BCL-2 inhibitors
Venetoclax
ProveniIncluded in official guidelines, or approved by EMA or FDA
This treatment works at a different point than BTK inhibitors: it blocks BCL-2, a protein that leukaemia cells need for their survival. Venetoclax is usually given as a tablet, often in combination with other treatments.
Side effects include low white blood cells (which can cause infections), low platelets (blood clots less well), nausea, diarrhoea and fatigue. In recent publications (2026), attention is given to rare autoimmune skin reactions (bullous dermatitis) under venetoclax. Kidney problems can also occur.
Monoclonal antibodies
Rituximab
ProveniIncluded in official guidelines, or approved by EMA or FDA
This antibody targets a protein (CD20) on the surface of leukemia cells and marks them for the immune system. Rituximab is given by infusion and has been used for twenty years, often in combination with chemotherapy.
Side effects can occur during the infusion itself (fever, chills, headache) or afterwards (infections, fatigue, low blood cells).
Obinutuzumab
ProveniIncluded in official guidelines, or approved by EMA or FDA
This is an improved antibody against the same target (CD20), with a stronger effect on leukemia cells. It is given by infusion and is mentioned in treatment guidelines, especially in combination with venetoclax.
Side effects are similar to rituximab, but obinutuzumab can have a stronger effect, which can be associated with infections and low blood cells.
CD20-directed T-cell antagonistic antibody (AZD5492)
ExperimentaliOngoing in study setting, outcome still unknown
This is an experimental agent currently being investigated in clinical trials (ongoing trial AZD5492, 2026). It combines two mechanisms of action: it targets CD20 on leukemia cells and simultaneously attracts T-cells (immune cells) to attack those cells. Because it is still under investigation, its efficacy and full side effect profile are not yet clear.
Classical chemotherapy
Bendamustine with or without rituximab
ProveniIncluded in official guidelines, or approved by EMA or FDA
This is a chemotherapeutic agent that causes DNA damage in leukemia cells. It is mainly used in patients who cannot use BTK inhibitors or for whom they no longer work.
Side effects of chemotherapy include low blood cells (anaemia, infections, bleeding), nausea, vomiting, hair loss, fatigue and increased risk of secondary cancers in the long term.
Combination regimens
In many patients, more than one agent is given at the same time. For example, BTK inhibitors can be combined with antibodies, or venetoclax with obinutuzumab. These combinations are based on clinical trials that demonstrate that efficacy is greater than each agent alone.
ProveniIncluded in official guidelines, or approved by EMA or FDA
Many combinations (such as venetoclax + obinutuzumab, or BTK inhibitors + rituximab) are included in official guidelines. The advantage of combinations is often that they work longer and relapse is delayed. The disadvantage is that side effects may increase or potentiate each other — infection risk and low blood cells are important points of concern.
Treatment of recurrence or resistance
When CLL grows again after earlier treatment, or does not respond well to an agent (refractory), the options depend on what has been used before.
ProveniIncluded in official guidelines, or approved by EMA or FDA
Guidelines from 2026 (EHA guidelines) indicate that patients with recurrent or resistant CLL usually switch to a different agent — for example from a BTK inhibitor to venetoclax, or vice versa. Combinations can also be reformulated differently.
ResearchediPositive results in clinical studies, not yet standard treatment
For difficult-to-treat forms, new combinations and doses are being tested in trials (including the BELLWAVE trials with nemtabrutinib + venetoclax).
Treatment of complications
Autoimmune anaemia or thrombocytopenia
Some CLL patients develop autoimmune problems: their body attacks their own red blood cells or platelets. This may warrant additional medications.
ProveniIncluded in official guidelines, or approved by EMA or FDA
For autoimmune haemolytic anaemia (AIHA) or thrombocytopenia, corticosteroids can be given, or antibodies such as sutimlimab (against complement, a component of the immune system). These agents suppress the autoimmune reaction.
Infections
Because many CLL treatments weaken immunity, infections are a major risk. This sometimes requires antibacterial, antiviral or antifungal treatments.
ProveniIncluded in official guidelines, or approved by EMA or FDA
Prophylactic ('preventive') antibiotics or antivirals can be given to prevent infections, especially in patients with very low blood cell counts or with certain risk factors. This is mentioned in guidelines.
Experimental approaches
T-cell therapy directed at neoantigen
ExperimentaliOngoing in study setting, outcome still unknown
This is a very advanced approach in which T-cells (immune cells) from the patient are genetically modified in the laboratory to recognise tumour-characteristic mutations ('neoantigen'). This is now undergoing clinical trials (including 'Autologous T Cells Transduced With TCRs for Neoantigen', 2026).
This is still highly experimental and only available in a research setting. Because it is made to order, side effects and effectiveness can vary greatly.
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_This information never replaces a doctor's judgment. Always discuss your situation with your own healthcare provider._