How BTK inhibitors treat mantle cell lymphoma

B cells are an important part of the immune system. One of their jobs is to neutralize the threat from a foreign invader known as a pathogen. They do this by producing an antibody that binds with the antigen on the threatening entity. 

When an antigen binds to a receptor on a B cell, the B-cell receptor signaling pathway is activated. Bruton’s tyrosine kinase (BTK) is an enzyme that’s critical to the activation of the B-cell receptor signaling pathway.  

“Without BTK, a B cell can’t function properly,” says lymphoma specialist Michael Wang, M.D.

BTK inhibitors are a type of drug that work to treat cancers caused by defective B cells, such as chronic lymphocytic leukemia, B-cell lymphomas, and Waldenström macroglobulinemia. 

Wang has led the pivotal clinical trials that have resulted in the approval of three BTK inhibitors for mantle cell lymphoma by the Food and Drug Administration (FDA). Those BTK inhibitors are ibrutinib, acalabrutinib and, most recently, pirtobrutinib.

“BTK inhibitors have revolutionized therapy options for patients with B-cell lymphomas,” Wang says.

BTK inhibitors stop B cell growth to treat lymphoma

BTK inhibitors work by interfering with the B-cell receptor signaling pathway. When the B-cell receptor signaling pathway goes haywire, B cells can reproduce at an uncontrolled rate and lead to lymphoma. By disrupting the pathway, the abnormal B cells won’t divide. Instead, they will die. 

Currently, ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib are approved to treat patients with mantle cell lymphoma that has relapsed and/or not responded to other treatment. 

BTK inhibitors have quality-of-life benefits

BTK inhibitors are administered as an oral pill that are taken daily. “It’s much more convenient for patients,” Wang says.

In addition, patients tend to tolerate BTK inhibitors better than chemotherapy. As published by Wang in the New England Journal of Medicine, almost 70% of patients saw their mantle cell lymphoma tumors shrink by more than 50%.

Possible BTK inhibitor side effects include fatigue, rash, diarrhea, bleeding and bruising. Some patients experience neutropenia, which is caused when a patient’s white blood cell count drops. That means they’re at a higher risk of infection. Patients taking ibrutinib can experience an irregular heartbeat and hypertension. They’re more serious, but both are treatable, Wang says.

“BTK inhibitors are relatively safe drugs, and fortunately, most patients don’t have severe side effects,” Wang says.  

And because of the limited side effects, BTK inhibitors are a good option for older patients.

Reversible BTK inhibitors offer patients another option

Ibrutinib was the first BTK inhibitor, but since its approval in 2013, progress has been made to advance the field. Acalabrutinib and zanubrutinib have also become commercially available. All three drugs work in the same way to inhibit the BTK enzyme by irreversibly binding to it. “Once they’re linked, they don’t let go,” Wang says. Because they share the same binding mechanism, if one drug doesn’t work for a patient, neither will the others.  

That’s changed with the newer generation of BTK inhibitors. Pirtobrutinib is the first FDA-approved BTK inhibitor that can reverse the binding to the BTK enzyme. “This opens the door to another option, even if a patient has received another BTK inhibitor,” Wang says.

Combination therapies may offer better results with BTK inhibitors

BTK inhibitors have shown to be effective, but researchers are now exploring their use in combination with other therapies.

“The question is: Can we make these drugs work even better and for more patients by pairing them with other drugs?” Wang asks. Studies already show combining ibrutinib and the monoclonal antibody rituximab can benefit patients with newly diagnosed mantle cell lymphoma, as well as some patients whose disease has returned or not responded to treatment. 

Lastly, patients may also benefit from BKT inhibitors combined with novel cellular therapies such as CAR T cells and bispecific antibodies. Studies are underway to learn more.

“There’s more to be explored, but BTK inhibitors have already drastically changed treatment for our patients,” Wang says. “With these drugs, patients are experiencing better results with fewer side effects.”

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