This class of drugs have had great success in recent years for many different subtypes of indolent lymphoma and CLL/SLL, both as a single (monotherapy) or in combinations with other medicines.
There are three main types of BTK inhibitors available on the market that we will discuss. There are many clinical trials currently investigating different combinations and indications around the world.
The role of Bruton’s tyrosine kinase (BTK)
Bruton’s tyrosine kinase (BTK) is a key component of the B-cell receptor (BCR) signalling pathway. BTK is an important protein that is a regulator of cell proliferation (growth) and cell survival in various B-cell lymphomas & CLL.
How do BTK inhibitors work?
Bruton’s tyrosine kinase (BTK) inhibitors work by binding to the BTK protein. BTK inhibitors block this protein’s activity by the BCR-induced BTK activation and its downstream signalling. BTK inhibitors block the activity that leads to growth of the B-cells and this causes cell death of the malignant B-cells.
The BTK inhibitors may help move abnormal cells out of their nourishing environments in the lymph nodes, bone marrow and other organs where it gets excreted. BTK is also found in normal healthy B cells so this action of blocking may cause side effects. BKI inhibitors that are currently available for the treatment of lymphoma and CLL include:
- Ibrutinib (ImbruvicaTM)
- Acalabrutinib (CalquenceTM)
- Zanubrutinib (BrukinsaTM)
The types of BTK inhibitors & information
Ibrutinib (Imbruvica®)
Ibrutinib in mantle cell lymphoma
Prof Con Tam – Peter MacCallum Cancer Centre & Royal Melbourne Hospital
Ibrutinib (Imbruvica®) is a cell signal blocker that targets a protein called Bruton’s tyrosine kinase (BTK). BTK is a part of a pathway that helps B-cells to stay alive and divide. By blocking BTK this can make B-cells die or prevent them dividing. This treatment can therefore stop the spread of cancerous B-cells.
Indications of use in lymphoma or CLL
- Chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) in patients who have received at least one prior therapy OR previously untreated patients
- CLL/SLL patients with 17p deletion
- Mantle cell lymphoma in patients who have received at least one prior therapy
- Adult patients with Waldenstroms macroglobulinemia (WM) who have received at least one prior therapy, or in first-line treatment for patients unsuitable for combination chemo-immunotherapy
Pharmaceutical benefits scheme (PBS) funding
Currently in Australia ibrutinib is publicly funded for the following indications:
- Chronic lymphocytic leukaemia (CLL) & small lymphocytic lymphoma (SLL) after at least one prior therapy in relapsed or refractory disease
- Chronic lymphocytic leukaemia (CLL) & small lymphocytic lymphoma (SLL) in front line therapy for patients with 17p (del)
- Mantle cell lymphoma (MCL) after at least one prior therapy in relapsed or refractory disease
How is it administered?
- Ibrutinib is taken orally (by mouth).
- Your recommended dose is based on the type of lymphoma you have and your general health.
- You have one tablet once a day. The tablets are available in different doses. The packs and tablets are colour-coded to make it easier to check what dose you are having.
- Swallow the tablets whole with a glass of water.
- Do not break or chew the tablets.
- Take the tablet at about the same time every day.
- Check the information you are given to find out what you should do if you miss a dose.
Common side effects
There are several common side effects that can occur. Let your doctor know if you are experiencing any side effects to monitor and manage these. They can include:
- Neutropenia (low white blood cells)
- Nausea and diarrhoea
- Musculoskeletal pain (pain in muscles and bones)
- Bruising and bleeding
- Rash
- Fever
- Bruising
- Irregular heartbeat (Atrial fibrillation)
- Muscle and bone pain
- Tiredness
Janssen product information
For more information go to the Janssen website and see the ‘Consumer Medicine Information’.
Acalabrutinib (CalquenceTM)
Acalabrutinib is a new generation Bruton’s tyrosine kinase (BTK) inhibitor. This medicine works like the other BTK inhibitors by binding to the protein called Bruton’s tyrosine kinase (BTK)). As a new generation drug, it has a more targeted effect to the BTK protein than the original BTK inhibitor ibrutinib. Acalabrutinib works by blocking the signalling through the B-cell receptor and cytokine receptor pathways.
This inhibits the proliferation (growth) of B-cells. By inhibiting the BTK, acalabrutinib may help move abnormal cells out of their nourishing environments in the lymph nodes, bone marrow and other organs where it gets excreted.
The indications for use in lymphoma/CLL
There are a few indications of use for lymphoma and CLL that include:
- Treatment of patients with mantle cell lymphoma who have received at least one prior therapy
- Treatment of patients with mantle cell lymphoma who have received at least one prior therapy
- Treatment of patients with chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL)
Pharmaceutical benefits scheme (PBS) funding
Currently Acalabrutinib is funded in Australia for the following indications:
- Single agent therapy for relapsed/ refractory mantle cell lymphoma
- CLL/ SLL patients with one prior line of treatment
How is it administered?
- This medicine is taken by mouth
- Swallow the tablets whole with a glass of water
- Do not break or chew the tablets
- Take the tablets at about the same times every day
- If a dose is missed by more than 3 hours, it should be skipped, and the next dose should be taken at its regularly scheduled time. Extra capsules should not be taken to make up for a missed dose
The recommended dose is one capsule twice a day as monotherapy (taken alone).
Common side effects
Acalabrutinib has shown to have less side effects than ibrutinib, the first BTK inhibitor on the market. This is because it is a more ‘targeted’ drug that causes less ‘off targeted’ side effects. There are several common side effects that can occur. Let your doctor know if you are experiencing any side effects to monitor and manage these.
They can include:
- Headache
- Diarrhoea
- Fatigue
- Muscle pain
- Bruising
- Neutropenia
- Anaemia
- Thrombocytopenia
AstraZeneca product information
For more information about acalabrutinib (CalquenceTM), you can visit the AstraZeneca website.
Zanubrutinib (BrukinsaTM)
Zanubrutinib is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK). Zanubrutinib is an orally active inhibitor that binds to BTK, resulting in irreversible inactivation of the protein. It is currently showing good results in several clinical trials in Australia and internationally.
BTK is a key component of the B-cell receptor signalling pathway and is an important regulator of cell proliferation and cell survival in various B cell malignancies. BTK inhibitors block BCR-induced BTK activation and its downstream signalling, leading to growth inhibition and cell death in certain malignant white blood cells called B-cells.
The indications for use in lymphoma/CLL
There are currently several clinical trials that are currently investigating:
- To treat adults with mantle cell lymphoma (MCL) for those who are front line (have never had treatment) and who have received at least one prior treatment for their cancer
- Waldenstroms macroglobulinemia (WM) for front line treatment
- Chronic lymphocytic leukaemia (CLL) & small lymphocytic lymphoma (SLL) in both front line and relapsed or refractory
- Follicular lymphoma (FL) in both front line and relapsed or refractory
- Marginal zone lymphoma (MZL) in both front line and relapsed or refractory
- Diffuse large B-cell lymphoma in both front line and relapsed or refractory
How is it administered?
- Take with or without food.
- Swallow whole with a full glass of water.
- Do not chew, break, or crush.
- Do not open the capsules.
- Keep taking zanubrutinib as you have been told by your doctor or other health care provider, even if you feel well.
Side-effects
- Decreased white blood cells (neutropenia)
- Decreased platelet count (thrombocytopenia)
- Decreased red blood cells (anaemia)
- Rash
- Diarrhoea
- Upper respiratory infection
- Bruising
- Cough
- Bleeding problems
- Infections
- Heart rhythm problems (atrial fibrillation and atrial flutter).
BeiGene product information
For more information about zanubrutinib, see the BeiGene website.
