What are BTK Inhibitors for CLL?

Chronic lymphocytic leukemia patients may hear about non-chemotherapy treatments called BTK inhibitors. Learn about what these treatments are, the different types of BTK inhibitors, typical side effects, and ways CLL specialists are working to improve the effectiveness of BTK inhibitors in the future. 

What is a BTK Inhibitor? 

The BTK (Bruton's tyrosine kinase) protein is found in B-cells. In healthy B-cells, the BTK protein plays an essential role in the normal growth and maturation of these white blood cells, making them capable of fighting against infections. 

CLL cells are dysfunctional B-cells with an over-activation of the BTK protein, which helps them grow out of control and survive. In CLL, the overactive BTK protein promotes uncontrolled cell division, leading to the accumulation of cancerous B-cells in the bone marrow, blood, and lymph nodes. 

Understanding the role of BTK in CLL is essential for developing targeted therapies that can specifically block the activation of the BTK protein and stop the expansion of CLL cells. These medicines include acalabrutinib (Calquence), zanubrutinib (Brukinsa), ibrutinib (Imbruvica), and pirtobrutinib (Jaypirca).  

Are BTK Inhibitors a Continuous-Duration CLL Therapy? 

BTK inhibitors are currently administered as a continuous-duration CLL therapy, meaning the medicine is taken indefinitely until you are unable to tolerate treatment or your CLL cells become resistant, leading to a relapse. 

An important thing to note is that BTK inhibitors do not achieve undetectable minimal residual disease (uMRD). This powerful lab test evaluates whether little to no cancer cells are left in the body following treatment. Instead, BTK inhibitors only limit cancer cells from progressing further during treatment, keeping the CLL at bay. 

Are you interested in learning more about BTK inhibitors? Click the button below to learn from CLL experts in HealthTree University videos!  

Watch the HealthTree University for CLL BTK Inhibitor Unit

What are the Differences Between First-Generation & Second-Generation BTK Inhibitors? 

The first FDA-approved BTK inhibitor was ibrutinib. Although successful for the majority of CLL patients in limiting the progression of CLL, up to 15% of patients experienced atrial fibrillation, a condition that causes an abnormal heartbeat. Atrial fibrillation may lead to stroke if not managed. 

Later, second-generation BTK inhibitors acalabrutinib and zanubrutinib were FDA-approved. These newer medicines improve treatment effectiveness over ibrutinib and have fewer heart-related side effects. 

Are you trying to decide which second-generation BTK inhibitor to choose for your CLL treatment? Click here to read more about acalabrutinib vs. zanubrutinib. 

What are the Differences Between Covalent and Non-Covalent BTK Inhibitors? 

Another distinction between BTK inhibitors is that there are covalent and non-covalent versions. 

Covalent BTK inhibitors, such as acalabrutinib, zanubrutinib, and ibrutinib, permanently bind to the BTK protein. After several years of exposure, the CLL cell often finds a way to mutate its BTK proteins, causing BTK inhibitors to stop working. When this happens, patients are considered to be covalent BTK inhibitor-resistant and, therefore, not eligible to continue treatment with these agents. 

The recently FDA-approved non-covalent BTK inhibitor pirtobrutinib (Jaypirca) binds to the BTK protein non-permanently through hydrogen and ionic bonds. This altered way of binding helps stop the activation of the BTK protein despite BTK mutations from prior use of covalent BTK inhibitors. Click here to learn more about the non-covalent BTK inhibitor pirtobrutinib. 

What are the Side Effects of BTK Inhibitors? 

Common side effects of BTK inhibitors include infections, fatigue, easy bruising or bleeding, muscle pain, and headache. Talk to your CLL specialist about ways to manage BTK inhibitor side effects. You can also click here to learn about BTK inhibitor side effects management strategies. 

What is the Future for BTK Inhibitors? 

Several ongoing clinical trials are evaluating different strategies for BTK inhibitors. Some of these include topics like: 

• Combining BTK inhibitors with venetoclax and/or obinutuzumab to create a fixed-duration therapy 
• Evaluating new non-covalent BTK inhibitors like nemtabrutinib 
• Assessing the use of the non-covalent BTK inhibitor pirtobrutinib as a first line of therapy rather than for relapsed/refractory CLL in Dr. Inhye Ahn’s study 

In conclusion, BTK inhibitors are a crucial non-chemotherapy treatment option for chronic lymphocytic leukemia (CLL). They target the overactive BTK protein in CLL cells to hinder their growth. BTK inhibitors include first-generation ibrutinib and second-generation acalabrutinib, zanubrutinib, and pirtobrutinib. They differ in their binding mechanisms and side effects, with the newer medicines offering fewer heart-related complications. Ongoing research and clinical trials aim to enhance the effectiveness of BTK inhibitors, exploring combinations with other treatments and evaluating the potential to establish more fixed-duration CLL therapies. 

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Sources:

• Imbruvica Prescribing Information 
• Brukinsa Prescribing Information 
• Calquence Prescribing Information 
• Nemtabrutinib (MK-1026)
• Treating BTK Resistant CLL with Ibrutinib and Venetoclax 
• Zanubrutinib + Sonrotoclax for CLL
• ALPINE Study Updates: Zanubrutinib vs Ibrutinib for CLL
• Clinical Trials for CLL: AVO Study
• MAJIC Study Acalabrutinib + Venetoclax
• Acalabrutinib vs Ibrutinib for CLL Treatment 
• Making the Choice in CLL: Acalabrutinib or Zanubrutinib