For individuals with B-cell malignancies such as chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), targeted therapies have become an important component in the treatment of these diseases. Of note are the Bruton’s tyrosine kinase (BTK) inhibitors. These agents work by inhibiting the B-cell receptor pathway that promotes the survival and proliferation of malignant B-cells. There are also covalent and non-covalent forms of BTK inhibitors with potential use in individuals whose diseases have recurred on other targeted therapies.
The review emphasizes the need for healthcare professionals to understand disease pathogenesis, patient previous treatment and resistance mechanisms as well as therapy safety and approval.
BTK is a component of the B-cell receptor signaling pathway and is critical for B-cell proliferation, survival, migration, and interaction with the tumor microenvironment. Inhibiting BTK in B-cell malignancies leads to inhibition of tumor cell proliferation and causes apoptosis in tumor cells through blockade of signaling from the B-cell receptor.
A number of BTK inhibitors are under development and in use. They include covalent and non-covalent BTK inhibitors, designed to bind to BTK in different ways. The covalent inhibitors bind irreversibly to BTK whereas the non-covalent or “reversible” inhibitors bind in a reversible manner. Importantly, the use of covalent BTK inhibitors as single agents has been associated with disease progression in some patients, and Pirtobrutinib has been evaluated as a treatment option for such patients.
The continued evolution of the BTK inhibitors being developed for the treatment of B-cell malignancies for use following failure on covalent BTK inhibitors will ultimately define a treatment strategy for B-cell malignancies that utilizes a chemotherapy-free approach and takes into account the individual patient’s disease characteristics and prior treatment.
Zanubrutinib (Brukinsa) is a covalent BTK inhibitor that has been shown to be effective in a number of B-cell malignancies. In January 2023, Zanubrutinib was approved by the U.S. FDA for the treatment of patients with CLL/SLL. The SEQUOIA study was a randomized study that compared Zanubrutinib to bendamustine and rituximab in 479 treatment-naïve patients with CLL/SLL who lacked a 17p deletion. The PFS for Zanubrutinib was not reached and therefore cannot be reported whereas for the bendamustine and rituximab–treated patients the PFS was 33.7 months with a hazard ratio of 0.42.
A study where Zanubrutinib was evaluated in patients with CLL/SLL who were previously treated was ALPINE. It was a study that included 652 patients with relapsed or refractory CLL/SLL who were randomly assigned to receive Zanubrutinib or Ibrutinib. The overall response rate in this study was 80% for Zanubrutinib and 73% for Ibrutinib, as measured by the investigator at the time of the analysis.
The findings from the above study highlight how covalent BTK inhibitors are being utilized in the treatment of patients with CLL/SLL at different stages of their disease.
Pirtobrutinib, marketed as Jaypirca, is a non-covalent, reversible BTK inhibitor intended to maintain BTK inhibition in patients with CLL/SLL who have relapsed or are refractory on treatment with prior covalent BTK inhibitors.
On December 20, 2025, pirtobrutinib received traditional approval by the US FDA for the treatment of adults with CLL/SLL who have received prior treatment with a covalent BTK inhibitor. The approval was based on the data from BRUIN-CLL-321, a randomized study in 238 patients with previously treated CLL/SLL. The PFS, by intention-to-treat analysis, was 11.2 months for pirtobrutinib vs 8.7 months for investigator choice treatment of idelalisib/rituximab or bendamustine/rituximab.
Pirtobrutinib previously received accelerated approval for CLL/SLL after failure of two or more lines of therapy including a BTK inhibitor and a BCL-2 inhibitor. The drug received traditional approval for this indication in December 2025.
This comparison of Pirtobrutinib vs Zanubrutinib is intended to be viewed with consideration of the patient’s disease and their prior treatment history. Each of these agents has a unique method of BTK inhibition, and their FDA-approved indications are for distinct clinical situations.
Zanubrutinib has an established role in the treatment of CLL/SLL and various other B-cell malignancies. Its approvals are based on its use in different clinical settings. Specifically, Zanubrutinib is approved for CLL/SLL and WM, as well as for MCL after one prior therapy, for R/R marginal zone lymphoma following treatment with an anti-CD20–based therapy, and for treatment of R/R follicular lymphoma in combination with obinutuzumab following two or more lines of systemic therapy for FL.
Prior BTK inhibitor exposure is an important consideration in determining a treatment sequence for patients with relapsed or refractory CLL/SLL. While pirtobrutinib is being developed for use in patients with relapsed or refractory CLL/SLL previously treated with a covalent BTK inhibitor, it is not approved for use in previously untreated CLL/SLL or in the setting of a failure on non-covalent reversible BTK inhibitor (e.g. pirtobrutinib).
BTK inhibition is also relevant in the treatment of mantle cell lymphoma (MCL). Zanubrutinib was approved for adults with MCL who have received at least one prior therapy for their disease.
The non-covalent, reversible BTK inhibitor pirtobrutinib was developed for the treatment of relapsed or refractory MCL after multiple lines of systemic therapy, including prior treatment with a BTK inhibitor. In this setting, it is thought to have a different position in the treatment sequence for patients with MCL.
The number of approved targeted therapies for cancer continues to increase, making treatment sequencing an important consideration. Important information regarding use in sequence for specific patient populations must be obtained from clinical studies.
Safety is a major factor to consider when looking at BTK inhibitors. The clinician should note potential bleeding, serious infections, cases of cytopenias, cardiac arrhythmias of varying severity including atrial fibrillation, hepatotoxicity, and drug-drug interactions.
Frequent adverse reactions associated with Zanubrutinib include decreased neutrophil count, upper respiratory tract infections, decreased platelet count, hemorrhage, and musculoskeletal pain. Additionally, there have been reports of atrial fibrillation or flutter and ventricular arrhythmias.
Warning and precaution information for pirtobrutinib includes infections, hemorrhage, cytopenias, cardiac arrhythmias, secondary primary malignancies, hepatotoxicity, embryo-fetal toxicity, etc.
This is particularly important in the face of a patient’s comorbidities, other medications they are prescribed, their organ function and previous treatment with other cancer therapies.
The generation of more specific BTK inhibitors is enabling a more differentiated approach to the treatment of B-cell malignancies. Thus, BTK inhibitors need to be considered as a group of distinct agents with different modes of action, degrees of covalency and cross-resistance as well as different supportive clinical data.
The health care professional treating patients with B-cell malignancies will need to keep abreast of the FDA approval of novel targeted therapies for cancer and the data released in abstract form at national and international meetings. Future studies, particularly ones investigating treatment sequencing and the use of these agents in combination with other targeted therapies, will continue to add to the management of B-cell malignancies.
Medical Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, clinical guidelines, or a recommendation for any specific treatment.
