Bruton tyrosine kinase inhibitors and B-cell malignancies: a guide for pharmacists

Bruton tyrosine kinase (BTK) is a protein that plays an important role in the signalling, proliferation, migration and survival of B-cells. For this reason, medicines that target BTK — known as BTK inhibitors (BTKis) — have been developed as targeted therapies to treat B-cell malignancies^​1​.

B-cell malignancies are a type of blood cancer that derive from the abnormal development of B-lymphocytes, these encompass a broad range of leukaemias and lymphomas^​1​. This article will focus on the conditions that BTKis have been approved to treat in the UK: chronic lymphocytic leukaemia (CLL), Waldenström’s macroglobulinaemia (WM), mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL)^​2–16​.

The treatment of B-cell malignancies has evolved significantly in recent years, moving from predominantly chemotherapy-based regimens towards immunotherapy and targeted therapies^​17​. The development of BTKis and other targeted therapies (e.g. venetoclax) offers an alternative to traditional chemotherapy regimens, demonstrating prolonged progression-free survival and overall survival in patients with B-cell malignancies, with the added benefit of better side-effect profiles and daily oral dosing that does not need to be done in a hospital setting^​18​.

To date, three BTKis — ibrutinib, acalabrutinib and zanubrutinib — have been approved for use in the UK^​2–16​. This article will cover:

• An overview of the mechanism of action of BTKis;
• Their indications and licensing;
• Side effects and management; 
• Interactions and other considerations to support pharmacists with their use;
• Test your knowledge questions.

Mechanism of action

BTKis work by blocking the B-cell receptor signalling cascade by binding to the BTK enzyme, preventing the proliferation and survival of B cells^​19​. See Figure 1 for additional information on signalling pathways. 

Ibrutinib, acalabrutinib and zanubrutinib all bind to the adenosine triphosphate (ATP) binding pocket of the BTK enzyme at cysteine 481 (C481)^​20​. Second-generation BTKis acalabrutinib and zanubrutinib bind with greater specificity than ibrutinib. This limits off-target effects on TEC-family kinases, which reduces side effects, such as atrial fibrillation (AF) and bleeding (see below), and improves tolerability for patients^​21​. 

All BTKis that are currently approved in the UK are covalent, which means they bind irreversibly to the BTK enzyme, causing continuous strong inhibition of BTK; however, this leaves these agents vulnerable to resistance, via the development of mutations in the C481 residue, which can then limit BTK binding^​20​.  

Resistance to BTKis can be acquired over time following exposure to these drugs, which can lead to disease progression and shortened survival^​22​. 

Non-covalent BTKis (e.g. pirtobrutinib and nemtabrutinib) have been developed to overcome this limitation^​23​. These drugs bind reversibly to BTK at sites other than C481, meaning they are not affected by mutations in this region. No non-covalent BTKis are approved for use in the UK at the time of writing; however, pirtobrutinib is currently being considered by the National Institute for Health and Care Excellence (NICE) for the treatment of CLL or small lymphocytic lymphoma, with a decision expected in early 2026^​24​.

Genetic mutations

For some B-cell malignancies, genetic mutations are used to guide treatment decisions. CLL patients who have either 17p deletion or TP53 mutations often show poor response to conventional chemotherapy regimens, while BTKis have shown efficacy in this patient group^​25​. Similarly, WM patients with mutated MYD88, particularly without CXCR4 mutations, often have better responses to ibrutinib, while patients with wild-type MYD88 have worse outcomes, regardless of CXCR4^​26​.

Ibrutinib 

Ibrutinib was the first BTKi to be approved in the United States, when it received accelerated US Food and Drug Administration (FDA) approval for the treatment of MCL in 2013^​27​, following the results of the phase II PCYC-1104-CA trial, which demonstrated a response rate of 68% and a median progression-free survival (PFS) of 13.9 months in 111 patients with relapsed or refractory MCL^​28​.

Results from the 2014 RESONATE trial showed that ibrutinib significantly improved PFS, overall survival and response rate compared with ofatumumab in previously treated CLL patients^​29​. See Figure 2 for more information and data on relevant trials and their follow-up^{​28,30–38​}.

In 2014, ibrutinib was the first BTKi to be available in the UK, when it could be accessed through a named patient scheme for the treatment of patients with relapsed/refractory CLL^​39​. It was then approved by NICE in 2017 for the same indication^​4​. In the UK, ibrutinib is approved/funded for the treatment of MCL and CLL^​2–7​. See Table 1 for more information^{​2–7,40​}.

Ibrutinib is not recommended by NICE for the treatment of WM, because it did not reach the threshold for being a cost-effective use of NHS resources^​41​. Nevertheless, it has been approved in Scotland for treatment of WM in adults who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemo-immunotherapy^​40​.

Dosing

Ibrutinib is taken orally as tablets. The recommended dose for the treatment of MCL is 560mg once daily. The recommended dose for the treatment of CLL, either as a single agent or in combination, is 420mg once daily^​42​. Tablets should be taken once a day, at around the same time each day.

For the treatment of untreated CLL in combination with venetoclax, ibrutinib should be administered as a single agent for 3 cycles (1 cycle is 28 days), followed by 12 cycles with venetoclax^​42​.

Dose modifications can be made for ibrutinib if adverse reactions occur (e.g. grade IV haematological toxicities); see summary of product characteristics (SmPCs) for more information^​42​. 

Acalabrutinib

As a second-generation BTKi, acalabrutinib was designed with greater specificity for BTK than first-generation ibrutinib, resulting in fewer off-target effects and an improved safety profile^​20,21​. In an open-label, randomised, phase III trial comparing acalabrutinib and ibrutinib in patients with CLL, acalabrutinib demonstrated sustained PFS and lower rates of most side effects, including cardiac events; however, there was a greater incidence of headaches in patients taking acalabrutinib (see Figure 3)^​43​.  

In 2021, acalabrutinib was approved by NICE as a monotherapy for untreated CLL in adults, only if:

• There is a 17p deletion or TP53 mutation, or
• There is no 17p deletion or TP53 mutation, and fludarabine plus cyclophosphamide and rituximab (FCR), or bendamustine plus rituximab (BR) is unsuitable^​14​.

In Scotland, acalabrutinib is approved for use in combination with obinutuzumab for the treatment of adult patients with previously untreated CLL^​15​.

Dosing

Acalabrutinib is taken orally as tablets. The recommended dose is 100mg twice daily. The dose interval is around 12 hours. If a dose is missed by more than 3 hours, it should be missed and the next dose should be taken at its regularly scheduled time^​44​.

Dose modifications can be made for acalabrutinib adverse reactions occur (e.g. grade III thrombocytopenia with bleeding); see SmPCs for more information^​44​.

Zanubrutinib 

Another second-generation BTKi is zanubrutinib. In 2024, results from the ALPINE trial demonstrated improved PFS of zanubrutinib over ibrutinib in patients with relapsed/refractory CLL as well as decreased incidence of adverse events, such as AF^​45​. See Figure 4 for more information on key trials and their follow-up^{​8–13,16,45–51​}.

Since it was first approved for use in the UK by NICE in 2022 for the second-line treatment of WM^​10​, zanubrutinib has been approved for the treatment of CLL, MZL and, most recently, MCL in July 2025^{​8–13,16​}. See Table 2 for more information.

Dosing

Zanubrutinib is taken orally as capsules. The recommended total daily dose of zanubrutinib is 320mg, which can be taken once daily (four 80mg capsules) or in two divided doses (as 160mg BD), ideally 12 hours apart. If a dose is missed, the next dose should be taken as normal, a double dose is not needed to make up for a forgotten dose^​52​.

Dose modifications can be made for zanubrutinib if adverse reactions occur (e.g. ≥grade 3 non-haematological toxicities); see SmPCs for more information^​52​. 

Side effects

Whilst there are many benefits to treatment regimens involving BTKis, there are notable side effects that vary in frequency and severity^​53​. The side effects that can have the most significant impact on patient safety and quality of life are the increased risk of bleeding, cardiovascular conditions and infection^​53​. See Figure 5 for an overview of the full range of potential side effects caused by BTKis^{​42,44,52,53​}. For further information, listen to this episode of The PJ Pod.

Cardiovascular toxicity

Cardiovascular toxicity is another side effect of BTKis caused by their off-target effects on other kinases (e.g. TEC, epidermal growth factor receptor [EGFR]). AF, hypertension and ventricular arrythmias are the most common cardiovascular side effects, with AF occurring in up to 16% of patients taking ibrutinib^​54​. 

Rates of cardiovascular side effects are lower in patients taking acalabrutinib and zanubrutinib. Studies have shown a lower incidence of major cardiovascular events and AF with zanubrutinib compared with acalabrutinib^​55​. 

All treatment decisions should be made based on an individual’s risk factors, treatment goals and history. BTKis are contraindicated in some patients with a history of heart failure or severe ventricular arrhythmias^{​42,44,52​}. 

All patients taking BTKis should be counselled on the following points regarding cardiovascular risk:

• General healthy living advice to reduce cardiovascular risk, this includes lifestyle modifications, such as having a healthy diet (e.g. reducing saturated fat, following the Mediterranean diet) getting adequate sleep and regular physical activity, as well as limiting alcohol consumption and salt intake;
• Report any breathlessness, dizziness, palpitations and swelling of feet or ankles to their specialist team as soon as possible;
• To call 999 if they have red-flag symptoms, such as chest pain, pressure, heaviness, tightness or squeezing across the chest or difficulty breathing^​56​.

Bleeding

Although a known class effect of BTKis, bleeding risk varies by agent. The cause of this increased bleeding risk is the antiplatelet effects of BTKis, which inhibit platelet function and aggregation through their off-target effects on kinases like TEC, which are involved in platelet signalling^​57​.

Bleeding is more common in patients taking the first-generation BTKi ibrutinib, with up to 44% of patients experiencing a bleeding event^​29​. While the majority are low grade (e.g. bruising, nosebleeds), around 4–8% of patients experience a major bleeding event (grade ≥3), which requires hospitalisation and can range from severe to fatal in nature^​29​.

While there is still a risk of bleeds in patients taking second-generation BTKis acalabrutinib and zanubrutinib, this risk is lower, with trials demonstrating a lower incidence of any bleeding event. Zanubrutinib is associated with a slightly higher risk of bleeding than acalabrutinib^​58​.

BTKis should be used with extreme caution in patients requiring anticoagulant or antithrombotic therapy owing to the risk of bleeding. Warfarin or other vitamin K antagonists are contraindicated. Use of direct oral anticoagulants (DOACs) should be considered with caution. In practice, DOAC use may be needed, considering that B-cell malignancies are more commonly found in older individuals and the risk of AF caused by BTKis. BTKi dose reductions should be considered if concomitant DOAC use is required^{​42,44,52​}.

Temporary discontinuation of BTKis may be necessary for certain surgeries and dental procedures to minimise bleeding risk. The duration of this discontinuation will be guided by the invasiveness of the procedure, the patient’s bleeding risk and history of previous bleeds and withdrawal symptoms. BTKis should be held for three days before and three days after minor procedures (e.g. colonoscopy, cataracts, dental procedures) and seven days before and seven days after major surgeries (e.g. joint replacement)^​59​. 

All patients taking BTKis should be counselled on the following points relating to bleeding risk:

• To monitor for unexplained bleeding events (e.g. bleeding gums, bruising, nosebleeds, blood in urine/stool), especially in the first three to six months of treatment when bleeding is more likely to occur. Patients should report this bleeding to their specialist team;
• To minimise bleeding risk by using soft bristle toothbrushes and electric razors;
• If pain relief is needed, non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin, should be avoided as their antiplatelet effects can increase bleeding risk. Topical preparations of ibuprofen for short courses (e.g. five to seven days) can be considered in some cases^{​60–62​}.

Infection risk

Patients taking BTKis are at increased risk of infection, owing to the disruption of B-cell signalling, which impairs the immune response^​63​.

Studies have shown similar rates of grade III or higher infections in patients taking ibrutinib, zanubrutinib and acalabrutinib^​45,53​. Infection risk is highest in the first year of treatment; one study found that rates of serious infection were 11.4% in the first year^​64​. Infection rates are highest in CLL patients with relapsed disease; a study found that 70% of relapsed CLL patients reported experiencing infection, 24% reported grade ≥3 infections^​29​. 

Patients taking BTKis are at increased risk of opportunistic fungal infections, with an estimated incidence of 2.0–7.6%^​65​. Incidence of fungal infections is lowest in patients taking zanubrutinib. The most common fungal infections in these patients are Candida and Aspergillus; invasive fungal infections with invasive aspergillosis and cryptococcosis are rare but can be severe, resulting in significant patient morbidity and sometimes death^​66​.

Antimicrobial prophylactic recommendations differ across the UK but should be considered in patients taking combination therapy; those who have a history of recurrent infections; are at increased risk of infection; or in cases of severe lymphopenia or neutropenia^​67​. In some areas of the UK, dependent on NHS trust, antimicrobial prophylaxis is given to all patients taking BTKis. Additional detail on antimicrobial prophylaxis can be seen in Table 3^{​59,68,69​}. 

All patients taking BTKis should be counselled on the following points relating to infection risk:

• To practice good hygiene (e.g. frequent hand washing, safe food handling, not touching eyes, nose, and mouth, etc.) and avoid contact with sick people to minimise risk of infection;
• To seek advice and treatment for a suspected infection from their specialist team as soon as possible. Symptoms that are suggestive of infection include temperature being ≥37.5°C or ≤36°C; feeling shivery; showing symptoms of cough, sore throat, breathlessness or diarrhoea; and frequent urination. 

See Box 1 for relevant vaccination information^{​60–62​}.

Tumour lysis syndrome

Although rare, tumour lysis syndrome (TLS) is a potentially fatal side effect that has been known to occur in patients taking acalabrutinib, ibrutinib and zanubrutinib^​76​. See: ‘Chronic lymphocytic leukaemia: diagnosis and management’ for more information.

Patients are prescribed once-daily allopurinol for the first cycle of the treatment to prevent TLS^{​59,68,69​}.

Interactions

There are a range of drug interactions that may alter the efficacy or increase the toxicity risk of BTKis that pharmacists should be aware of.

BTKis are primarily metabolised by the enzyme cytochrome P450 3A (CYP3A), which means that drugs that affect the activity of CYP3A can impact levels of BTKi in the blood (see Table 4^{​42,44,52​}).

Monitoring

It is important to take a thorough history of a patient’s cardiovascular health, including family history, before commencing treatment with a BTK. Necessary baseline investigations include blood pressure, electrocardiogram (ECG), blood tests (lipid profile and glucose/HbA1c)^{​59,68,69​}. Patients who have a high cardiovascular risk may benefit from a referral to cardiology and treatment with the second-generation BTKis (e.g. acalabrutinib, zanubrutinib) should be considered.

A full blood count (FBC) and coagulation screen are needed to assess for cytopenias and bleeding risk, they also establish a baseline for haematological toxicity monitoring)^{​59,68,69​}.

Other blood tests including urea and electrolytes (U&E) and liver function tests (LFTs) are needed at baseline to monitor for potential toxicity. Dose adjustments may be required, information based on dose adjustments can be found in individual SmPCs^{42,44,52,59,68,69}.

BTKis can reactivate latent viral infections, it is therefore important to test an individual’s hepatitis B and C infection status prior to starting therapy. A HIV test is also required as BTKis can cause immune suppression, which can exacerbate HIV symptoms and increase risk of opportunistic infections^59,68,69. 

Ongoing monitoring

Frequency of ongoing monitoring will be guided by patient risk factors (e.g. low blood counts) and history of adverse events; however, most patients will be reviewed every four weeks for the first three months following initiation of therapy and then every three months after that if stable. Patients are likely to receive both in person and telephone reviews, with blood tests being done in primary care (FBC, U&E and LFTs) to facilitate this^59,68,69.

Conclusion

The use of targeted therapies, like BTKis, mean that people with B-cell malignancies are living longer. As these patients age, they are likely to experience additional comorbidities and, as a result, take medicines to manage these conditions. Pharmacists should be aware of the potential for drug interactions and considerations for medicines use with these agents. 

While specialist cancer pharmacists will have the most contact with patients taking BTKis, pharmacists across sectors should be aware of the potential for adverse effects caused by these medicines and know what steps should be taken if recognised, including appropriate referral. 

For additional information on the use of BTKis in B-cell malignancies, see:

• ‘BTK inhibitors: what pharmacists need to know‘;
• ‘How can pharmacists best support patients with chronic lymphocytic leukaemia?‘;
• ‘Management of Waldenstrom’s macroglobulinaemia‘;
• ‘Chronic lymphocytic leukaemia: diagnosis and management‘.

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